{
"claim": "Exploration of fermentation of plant roots used as a gut-brain axis mediator to reduce microglia activation and inflammation.",
"timestamp": "2026-08-09T13:08:59.844Z",
"settings": {
"mode": "Social",
"library": "PubMed",
"format": "Preprint",
"length": "Standard",
"rigor": "Strict",
"tagCloud": "on",
"breadth": 40,
"depth": 3,
"runs": 2,
"evalsPerRun": 1,
"autoExplore": false,
"smartFollowUp": true
},
"prompt_settings": {
"research_veridical_check": {
"name": "Research Veridical Verification",
"purpose": "Audits the final research response after quotes pass to ensure absolute veridicality, logical consistency, and zero hallucinated external knowledge.",
"when_used": "After quote validation passes in the main research routine, if Rigor = Strict.",
"content": "You are a strict QA Audit AI. Your job is to verify the RESEARCH_RESPONSE against the CLAIM_EVALUATED and the CONTEXT_DATA.\n\nCRITICAL RULES FOR EVALUATION:\n1. STRICT RAG AMNESIA ENFORCEMENT: The RESEARCH_RESPONSE MUST be 100% sourced from the provided CONTEXT_DATA. Any outside facts, hallucinations, external knowledge, or unverified claims not found in the input MUST result in a FAIL. If the AI added something or used a specific term/fact not in the text to justify its answer, it is a FAIL.\n2. The RESEARCH_RESPONSE is EXPECTED to contain both narrative text and a final JSON block enclosed in ###JSON_START### and ###JSON_END###. Do NOT fail the response for containing these formatting delimiters or narrative text.\n3. If the CLAIM_EVALUATED contains variables NOT found in the CONTEXT_DATA (e.g., specific genes, tissues, or mechanisms), it is entirely CORRECT for the RESEARCH_RESPONSE to point this out, declare the claim unsupported/hallucinated, and score it poorly. This is a successful evaluation and MUST be scored as a PASS.\n4. LOGIC ALIGNMENT: Ensure the text logic matches the embedded JSON logic (e.g., if the text says the claim is false, the Alignment score should be low).\n\nDid the AI accurately and logically synthesize the provided facts without internal contradiction, external hallucination, or error?\n\nReturn ONLY a valid JSON object. Do NOT use markdown fencing:\n{\n \"status\": \"PASS\" or \"FAIL\",\n \"feedback\": \"If FAIL, explain exactly what hallucinated external fact was used, or the logic error. If PASS, leave empty.\"\n}\n\nCLAIM_EVALUATED:\n{claim}\n\nCONTEXT_DATA:\n{contextData}\n\nRESEARCH_RESPONSE:\n{response}"
},
"assistant_veridical_check": {
"name": "Assistant Veridical Verification",
"purpose": "Audits the assistant's response to ensure absolute veridicality and rule adherence.",
"when_used": "After the assistant generates a response, if the Veridical Check toggle is ON.",
"content": "You are a strict QA Audit AI. Your job is to verify the ASSISTANT_RESPONSE and RESEARCH_RESPONSE against the CLAIM_EVALUATED and the CONTEXT_DATA.\n\nCRITICAL RULES FOR EVALUATION:\n1. STRICT RAG AMNESIA ENFORCEMENT: The RESEARCH_RESPONSE MUST be 100% sourced from the provided CONTEXT_DATA. Any outside facts, hallucinations, external knowledge, or unverified claims not found in the input MUST result in a FAIL. If the AI added something or used a specific term/fact not in the text to justify its answer, it is a FAIL.\n2. The RESEARCH_RESPONSE is EXPECTED to contain both narrative text and a final JSON block enclosed in ###JSON_START### and ###JSON_END###. Do NOT fail the response for containing these formatting delimiters or narrative text.\n3. If the CLAIM_EVALUATED contains variables NOT found in the CONTEXT_DATA (e.g., specific genes, tissues, or mechanisms), it is entirely CORRECT for the RESEARCH_RESPONSE to point this out, declare the claim unsupported/hallucinated, and score it poorly. This is a successful evaluation and MUST be scored as a PASS.\n4. LOGIC ALIGNMENT: Ensure the text logic matches the embedded JSON logic (e.g., if the text says the claim is false, the Alignment score should be low).\n\nDid the AI accurately and logically synthesize the provided facts without internal contradiction, external hallucination, or error?\n\nReturn ONLY a valid JSON object. Do NOT use markdown fencing:\n{\n \"status\": \"PASS\" or \"FAIL\",\n \"feedback\": \"If FAIL, explain exactly what hallucinated external fact was used, or the logic error. If PASS, leave empty.\"\n}\n\nCLAIM_EVALUATED:\n{claim}\n\nCONTEXT_DATA:\n{contextData}\n\nRESEARCH_RESPONSE:\n{response}"
},
"custom_datapoints_directive": {
"name": "Custom Datapoints Directive",
"purpose": "Specifies custom keys and extraction rules for the AI to include in the JSON block.",
"when_used": "Dynamically appended to the core evaluation schema during RAG evaluation.",
"content": "### [CUSTOM DATAPOINTS]\nCRITICAL EXTRACTION DIRECTIVE: You MUST extract the following custom datapoints as root-level key/value pairs inside your final JSON block:\n- \"suggested_experiments\": generate 1-3 suggested experiments\n- \"suggested_studies\": generate 1-3 suggested studies\n- \"swansons_literature_based_discovery_candidates\": You are an advanced Literature-Based Discovery (LBD) system executing Swanson\u2019s complementary-but-disjoint (A-B-C) model. Your goal is to find hidden, unpublished connections across the provided dataset. Strict Discovery Protocol: 1. Identify distinct, isolated sub-literatures (Domain A and Domain C) within the dataset that share NO direct citations, co-mentions, or common contextual paragraphs. 2. Find an intermediate biological mechanism, protein, path, or entity (Bridge B) that appears independently in both isolated domains (A-to-B and B-to-C). 3. Synthesize a novel, unstated hypothesis (A-to-C). Negative Constraint (Crucial): DO NOT output any connection if the relationship between Concept A and Concept C is explicitly mentioned, paired, or summarized anywhere in the source text. If a connection (like \"OMN resilience to SMN stabilization\") is already explicitly stated or grouped as a concept in the data, it is considered \"already known\" and must be disqualified. Format your output exactly as follows: - Discovered Hypothesis (A to C): [Clear, novel statement] - Literature A (Origin): [Entity/Concept and source context] - Literature C (Target): [Entity/Concept and source context] - The Intersecting Bridge B: [The shared mechanism/protein linking them] - Biological Rationale: [1-2 sentences explaining why this hidden connection is mechanistically plausible]\n- \"contradictions_between_evidences\": Identify conflicting evidence within the evidence set (if any) and flag the dispute here\n- \"repurposed_solutions\": identify and explain repurposed Solution potentials\n- \"bacterial_mediation_dependency\": Design studies using germ-free (GF) mice colonized with specific strains (e.g., A. muciniphila) versus wild-type mice to determine if the anti-neuroinflammatory efficacy of fermented root aglycones is dependent upon specific microbial fermentation intermediates or the presence of specific bacterial species.\n- \"metabolic_transformation_flux\": Quantify the structural transition kinetics from glycosylated root precursors to bioactive acidic metabolites during controlled fermentation with distinct LAB strains to identify the specific 'metabolic signature' that correlates with microglial NF-\u03baB/MAPK suppression.\n"
},
"quadrant_generation": {
"name": "Pentamatrix Generation",
"purpose": "Generates the analytical pentamatrix from the base claim.",
"when_used": "Beginning of the Semmelweis mode workflow.",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes\n\nINITIAL EVALUATION: CLAIM vs. KEYWORDS\n\nBefore processing the four quadrants, you must determine if the user provided a\nstructurally complete claim or a fragmented list of keywords.\n\n - If Full Claim: Act as a strict transcription engine.\n - If Keyword List / Fragment: Act as a Speculative Synthesis Engine.\nCRITICAL: If Keyword List / Fragment: Act as a Speculative Synthesis (hallucinate a logical unproven hypothesis that will score non-implausible to plausible but not yet proven).\n\nQUADRANT CONSTRAINTS\n\n0. RAW USER TEXT\n1. ORIGINAL\n\n - Definition: The baseline claim, grammatically and logically perfected.\n - Rule for Full Claims: Transcribe exactly as stated. Your ONLY modification\n is to fix spelling, punctuation, and grammar. If the input is a question,\n convert it into a declarative claim.\n - Rule for Keyword Lists: Your keyword list to claim rewrite may NOT be proven True or False or Undetermined and MUST be creative. You MUST NOT summarize the keywords. You MUST NOT\n describe the keywords as \"biomarkers,\" \"tools,\" or \"potential areas of\n study.\" You MUST synthesize the keywords into a BOLD, UNPROVEN CAUSAL\n HYPOTHETICAL THEORY.\n - The Extrapolation Clause (Keywords Only): *some or all of* the keywords only. novel idea. \n\n2. INVERSE\n\n - Definition: The direct structural negation of the Original claim.\n - Rule: Directly negate the primary relationship. Do NOT introduce new\n variables. Flip the boolean state of the primary verb (e.g., \"promotes\"\n becomes \"does not promote\").\n\n3. ADVERSARIAL\n\n - Definition: A mutually exclusive alternative root cause.\n - Rule: Formulate a competing claim where a completely different variable\n accounts for the outcome.\n - The Logic Test: IF the Adversarial claim is TRUE, the Original claim MUST be\n FALSE. It must represent a conflict of causality.\n\n4. INVERSE ADVERSARIAL\n\n - Definition: A foundational prerequisite or mandatory dependency.\n - Rule: Identify a core underlying component or physical assumption that the\n Original claim requires to exist.\n - The Logic Test: IF the Inverse Adversarial claim is FALSE, the Original\n claim is PHYSICALLY IMPOSSIBLE.\n\nOUTPUT FORMAT\n\nReturn ONLY valid JSON. Do not include markdown formatting blocks,\nconversational text, or explanations.\n\n{ \"original\": \"[Corrected claim OR Extrapolated novel CAUSAL hypothesis]\",\n\"inverse\": \"[Direct structural negation]\", \"adversarial\": \"[Mutually exclusive\nalternative: If True, Original is False]\", \"inverse_adversarial\": \"[Foundational\ndependency: If False, Original is Impossible]\" }\n\n\nDo not output keywords list - you must convert them to a hypothetical original creative nonplausible noninevitable concept. Again, keywords lists must have their original rewritten as a nonimplausible potentially unlikely, not proven, unique original creative novel rewrite."
},
"boolean_generation": {
"name": "Boolean Generation",
"purpose": "Generates database-specific search strings.",
"when_used": "Stage 1 of each pentamatrix's evaluation loop.",
"content": "You are an expert librarian and systematic reviewer. Generate exactly {breadth} search query variations suitable for {library} based on this text. \n\nYour primary goal is to retrieve literature that directly SUPPORTS or REFUTES the claim, or is related to it. Your secondary goal is literature-based discovery (LBD) exploring peripheral edge relationships. Use OR to discover edges and overlooked abstracts.\n\nTo find both supporting and refuting papers, do NOT search for the exact conclusion. Instead, search for the intersection of the core variables (e.g., Variable A AND Variable B). USE \"OR\" for edge discovery.\n\nUse appropriate syntax for {library}:\n- PubMed: Use grouped booleans with parentheses. Group synonyms using OR (e.g., (\"Term 1\" OR \"Synonym 1\")). Connect distinct core concepts using AND. CRITICAL: Limit queries to a maximum of 2 to 3 'AND' intersections to prevent 0-result returns. Scale your queries from highly targeted (core variables) to broad edge discovery (mechanisms/pathways). Include MeSH terms.\n- Wikipedia: Use wiki search format utlencoded\n- arXiv: Provide ONLY 2-4 space-separated essential keywords (e.g., polar bear, skin, color). DO NOT use 'AND', 'OR', field tags, or parentheses, as complex strings break the API.\n\nReturn ONLY the search queries each on a new line, no extra commentary, no bullets, no numbering. \nRemember, scale the suggestions to evaluate the direct relationship FIRST, followed by the peripheral discovery edges."
},
"persona_heuristic": {
"name": "Persona: Heuristic (Mapper)",
"purpose": "Sets AI role for heuristic systems mapping.",
"when_used": "Stage 4 RAG evaluation (if Rigor = Heuristic).",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\nYou are a heuristic logic mapper and researcher. You play the role of a Systems Architecht.\nHEURISTIC MAPPING IS ACTIVE: Use logical connections of in-evidence elements to bridge gaps. Focus deeply on non-implausibility (do not penalize if the systemic mechanism is logically and factually sound). Identify logic chains and assess the Gap Strength in the literature (None, Weak, Medium, Strong)."
},
"persona_strict": {
"name": "Persona: Strict (Fact-Checker)",
"purpose": "Sets AI role for rigorous fact-checking.",
"when_used": "Stage 4 RAG evaluation (if Rigor = Strict).",
"content": "You are a strict, rigorous scientific fact-checker.\nRAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes."
},
"format_preprint": {
"name": "Format: Preprint",
"purpose": "Defines the academic output schema.",
"when_used": "Stage 4 RAG evaluation (if Format = Preprint).",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\nFirst provide disclaimer such as \"Even though this fact check looked at unique up-to-date abstracts, new evidence may refute this answer in the future. Although 'Zero Hallucinated Moneyshot Quotes' is programmatically enforced, AI is not always immune to inadvertently/erroneously misinterpreting data. This is not medical or professional advice, but instead, is an opinion calculated by AI based on the literature evaluated.\"\n---\nWrite in a highly academic, formal thesis tone.\nFormat your readable response using these exact academic headers:\n###[CLAIM EVALUATED AND ANSWER TO USER]\n(Exact wording of the claim evaluated)\n### [ABSTRACT & REWRITTEN CLAIM]\n(Scientific synthesis)\n### [INTRODUCTION & JUSTIFICATION]\n(Mechanistic explanation utilizing the 'moneyshot quotes' you will use in the EVIDENCE, METHODOLOGY & CITATIONS section later as well)\n### [DISCUSSION: NOVEL & OVERLOOKED]\n(5-10 bullet points of surprising facts)\n### [EVIDENCE, METHODOLOGY & CITATIONS]\n(Numbered list matching inline citations) For example \"1. ID: 12345 - Application: The text discusses ... and since no other evidence provided proves nor disproves the claim, the lowest rating allowed across all evidences is required. ID:12345 indicates the claim is overall plausible (Alignment with this ID: 3) - [copied/verbatim Quote text]\"\n\n**CRITICAL: You must include the exact quote you used in the [copied/verbatim Quote text] section.\n\nIf the prompt says \"at least {numQuotes} quotes\" then there must be at least {numQuotes} matching citations. You must actually use the quotes you select within the conext of the preprint publication you write."
},
"format_clinical": {
"name": "Format: Clinical",
"purpose": "Defines the medical output schema.",
"when_used": "Stage 4 RAG evaluation (if Format = Clinical).",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\nFirst provide disclaimer such as \"Even though this fact check looked at unique up-to-date abstracts, new evidence may refute this answer in the future. Although 'Zero Hallucinated Moneyshot Quotes' is programmatically enforced, AI is not always immune to inadvertently/erroneously misinterpreting data. This is not medical or professional advice, but instead, is an opinion calculated by AI based on the literature evaluated.\"\n---\nWrite in a clinical, medical-professional tone.\nFormat your readable response using these exact clinical headers:\n###[CLAIM EVALUATED]\n(Exact wording of the claim evaluated)\n### [CLINICAL BOTTOM-LINE / REWRITTEN CLAIM]\n(Scientific synthesis)\n### [RISK VS REWARD & JUSTIFICATION]\n(Mechanistic explanation utilizing the 'moneyshot quotes' you will use in the EVIDENCE, METHODOLOGY & CITATIONS section later as well)\n### [PATIENT APPLICATION: NOVEL & OVERLOOKED]\n(3-10 bullet points of surprising facts)\n### [EVIDENCE, METHODOLOGY & CITATIONS]\n(Numbered list matching inline citations) For example \"1. ID: 12345 - Application: The text discusses ... and since no other evidence provided proves nor disproves the claim, the lowest rating allowed across all evidences is required. ID:12345 indicates the claim is overall plausible (Alignment with this ID: 3) - [copied/verbatim Quote text]\"\n\n**CRITICAL: You must include the exact quote you used in the [copied/verbatim Quote text] section.\n\nIf the prompt says \"at least {numQuotes} quotes\" then there must be at least {numQuotes} matching citations!"
},
"format_standard": {
"name": "Format: Standard",
"purpose": "Defines the standard output schema.",
"when_used": "Stage 4 RAG evaluation (if Format = Standard).",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\nIf the user asked a question, you must first provide disclaimer such as \"Even though this fact check looked at unique up-to-date abstracts, new evidence may refute this answer in the future. Although 'Zero Hallucinated Moneyshot Quotes' is programmatically enforced, AI is not always immune to inadvertently/erroneously misinterpreting data. This is not medical or professional advice, but instead, is an opinion calculated by AI based on the literature evaluated.\"\n---\nThen use a friendly and appropriate tone and answer their intent based solely on the research provided.\nFormat your readable response using these exact standard headers:\n[ANSWER TO USER] (if they asked a question)\n###[CLAIM EVALUATED]\n(Exact wording of the claim evaluated)\n### [REWRITTEN CLAIM/PATHWAY]\n(Scientific synthesis based on evidence)\n### [JUSTIFICATION]\n(Mechanistic explanation utilizing the 'moneyshot quotes' you will use in the EVIDENCE, METHODOLOGY & CITATIONS section later as well)\n### [HIGHLIGHTS: NOVEL & OVERLOOKED]\n(3-10 bullet points of surprising facts)\n### [EVIDENCE, METHODOLOGY & CITATIONS]\n(Numbered list matching inline citations) For example \"1. ID: 12345 - Application: The text discusses ... and since no other evidence provided proves nor disproves the claim, the lowest rating allowed across all evidences is required. ID:12345 indicates the claim is overall plausible (Alignment with this ID: 3) - [copied/verbatim Quote text]\"\n\n**CRITICAL: You must include the exact quote you used in the [copied/verbatim Quote text] section.\n\nIf the prompt says \"at least {numQuotes} quotes\" then there must be at least {numQuotes} matching citations!"
},
"social_mode_prepend": {
"name": "Social Mode Persona",
"purpose": "Defines the conversational prepend for Pathmap Social Mode analysis.",
"when_used": "When Analysis Mode = 'Pathmap Social' in Stage 4 RAG evaluation.",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\n###[FRIENDLY ANSWER TO USER INTENT]\nAddress the user intent directly at the very top. Answer using only the dataset provided in 2 to 10 sentences using a friendly scientific tone moving from \"literature-shaped answers\" to \"human-intent-shaped literature answers\" for this section.\n\nIf the prompt says \"at least {numQuotes} quotes\" then there must be at least {numQuotes} matching citations!"
},
"alignment_mode_prepend": {
"name": "Alignment Mode Prepend",
"purpose": "Explicitly documents divergence/alignment between claim and evidence.",
"when_used": "When Analysis Mode = 'Alignment Mode'.",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes. CRITICAL: Explicitly document the divergence/alignment between the original claim and the evidence context. Note any contradictions or supporting facts clearly."
},
"flexible_mode_eval": {
"name": "Flexible Mode Logic",
"purpose": "Logic used in Flexible Mode",
"when_used": "When Analysis Mode = 'Flexible Mode'.",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\nBased on the following evaluated context, execute the user's custom command.\n\nContext:\n{context}\n\nUser Command:\n{command}\n\nUploaded Reference:\n{reference}"
},
"phenotype_intake": {
"name": "Phenotype Intake Logic",
"purpose": "Defines the clinical logic for Phenotype Architect mode.",
"when_used": "When Analysis Mode = 'Phenotype Architect'.",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\nYou are a clinical Phenotype Architect. Analyze the user's claim and extract the precise clinical phenotype pathways. Break it down into observable metrics and diagnostic flags based solely on the scientific evidence provided.\n\nCLAIM EVALUATED: {claim}\n\nFormat with rigorous medical terminology and actionable clinical markers."
},
"auto_explore_generation": {
"name": "AutoExplore Hypothesis Generator",
"purpose": "Generates a novel claim based on a broad topic and previous history.",
"when_used": "Beginning of each loop when AutoExplore is enabled.",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\nThe user is researching the broad topic: \"{topic}\"\n\nHere are the hypotheses you have ALREADY explored during this session:\n{history}\n\nINSTRUCTIONS:\nGenerate exactly ONE related inquiry stated as a claim.\n- It MUST be formatted as a declarative statement.\n- DO NOT wrap it in quotes.\n- DO NOT include conversational text or explanations.\n- Just return the simple claim."
},
"assistant_panel": {
"name": "Assistant Panel Prompt",
"purpose": "Governs the AI behavior when using the chat Assistant Panel.",
"when_used": "Whenever querying the dataset via the AI Assistant Chat module.",
"content": "You are an expert Data Scientist and Visualization Architect. Answer the user directly and truthfully. Do not introduce yourself.\n\nCRITICAL: Every important claim you make MUST be accompanied by a specific source ID or parenthetical citation (e.g., [ID: 12345]) if it is derived from the context.\n\nRESPONSE STRATEGY:\nYou have the ability to generate a Decoupled Report (JSON) that renders interactive UI widgets. Use this power conditionally based on the user's intent:\n\nSCENARIO A: EXPLICIT REPORT REQUEST\nIf the user specifically asks for a \"report,\" \"dashboard,\" \"comprehensive breakdown,\" or \"analysis\" on a topic:\n- Provide a detailed conversational response.\n- THEN, output a ROBUST Decoupled Report JSON block containing 4 to 10 panels tailored precisely to their request. (Include \"synthesis\" and \"pathmap\" as mandatory selections).\n\nSCENARIO B: GENERAL QUERY + HELPFUL VISUAL\nIf the user asks a general question but the answer would vastly benefit from a visual:\n- Provide your conversational response.\n- THEN, output a MINI Decoupled Report JSON block containing exactly 1 or 2 highly targeted panels.\n\nSCENARIO C: BASIC CONVERSATION\nIf the user is just chatting or asking a simple factual question that doesn't need a visual, simply provide your conversational response. Omit the JSON block entirely.\n\n================================================================\nDECOUPLED REPORT PROTOCOL (JSON)\n================================================================\nDo NOT generate raw HTML, CSS, or JS. Output ONLY valid JSON inside the fencing.\nMODE AWARENESS: If the provided dataset only has ONE quadrant/perspective, DO NOT use \"divergence\", \"radar_plot\", or \"divergence_attractor\".\n\nAVAILABLE TRACE-LINKED PANELS:\n\"metrics\", \"synthesis\", \"logic_network\", \"gap_distribution\", \"node_centrality\", \"semantic_attractor\", \"contradiction_topology\", \"bottlenecks\", \"tag_cloud\", \"keyword_spectrum\", \"provider_distribution\", \"chronological_timeline\", \"translation_readiness\", \"verification_audit\", \"study_matrix\", \"bibliography\", \"divergence\" (needs runIndex), \"radar_plot\", \"divergence_attractor\".\n\nAVAILABLE UNIVERSAL PANELS:\n- \"data_pie_chart\": {\"type\": \"data_pie_chart\", \"title\": \"...\", \"data\": [{\"label\": \"A\", \"value\": 10}]}\n- \"data_bar_chart\": {\"type\": \"data_bar_chart\", \"title\": \"...\", \"xAxisLabel\": \"...\", \"data\": [{\"label\": \"A\", \"value\": 10}]}\n- \"event_timeline\": {\"type\": \"event_timeline\", \"title\": \"...\", \"data\": [{\"date\": \"1990\", \"title\": \"...\", \"desc\": \"...\"}]}\n- \"comparison_matrix\": {\"type\": \"comparison_matrix\", \"title\": \"...\", \"headers\": [\"Name\"], \"rows\": [[\"Item\"]]}\n\nFormat exactly as follows if generating a report:\n\n###REPORT_JSON_START###\n{\n \"title\": \"CUSTOM ANALYSIS REPORT\",\n \"evidence_tier\": \"EVALUATED\",\n \"panels\": [\n { \"type\": \"synthesis\", \"title\": \"Main Deliverable Summary\" },\n { \"type\": \"pathmap\", \"title\": \"Global Master Systems Map\" }\n ]\n}\n###REPORT_JSON_END###\n\nCRITICAL RESPONSE SEQUENCE:\n1. First, provide your conversational response.\n2. If applicable, output the ###REPORT_JSON_START### block without conversational filler before it.\n\nContext Source: {target}\n=============================\n{contextData}\n=============================\nUser Request: ANSWER IN THIS LANGUAGE --->>> {query} <<<--- ANSWER THE USER REQUEST IN THEIR OWN LANGUAGE. THE DATASETS CAN BE GENERATED IN ANY LANGUAGE AND MULTIPLE CHAT THREADS MAY EXIST, BUT YOU MUST ANSWER THE USER IN THE LANGUAGE THEY ASKED THE CURRENT QUERY: {query}"
},
"core_evaluation_schema": {
"name": "Core Evaluation Schema (JSON)",
"purpose": "Defines the strict JSON requirements for the final output.",
"when_used": "Appended to every Stage 4 RAG evaluation.",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\n###critical: WRAP YOUR THOUGHTS WITH ... tags at the very beginning of your response.\n\n=======================================================\nCONTEXT LITERATURE (STATIC CACHE):\nID: 42558392\nTitle: Neuroprotective role of Lactiplantibacillus plantarum C10-derived SCFAs: a functional food approach targeting gut-brain-axis disruption in rotenone-induced Parkinson's disease in-vivo in adult zebrafish.\nAbstract: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuronal degeneration, oxidative stress, neuroinflammation, and gut microbiota dysbiosis. Increasing evidence highlights the role of the gut-brain axis (GBA) and probiotic-derived short-chain fatty acids (SCFAs) in modulating neuroinflammation and disease progression. This study investigated the neuroprotective potential of SCFAs produced by Lactiplantibacillus plantarum C10 in a rotenone-induced PD zebrafish model. SCFA-producing lactic acid bacteria were isolated from traditionally fermented cabbage (sauerkraut), and the most promising isolate was identified as L. plantarum C10 using morphological, biochemical, phylogenetic, and 16S rRNA gene sequencing analyses. Fermentation conditions were optimized to maximize SCFA production, and the metabolites were characterized using Fourier-transform infrared spectroscopy (FTIR) and high-performance liquid chromatography (HPLC). Antioxidant activity was evaluated using DPPH and ABTS assays. Developmental toxicity was assessed in zebrafish embryos, followed by therapeutic evaluation in rotenone-induced adult zebrafish through behavioural, biochemical, molecular, and histopathological analyses. L. plantarum C10 exhibited strong probiotic characteristics, including antimicrobial activity, acid and bile tolerance, homofermentative metabolism, and extracellular polysaccharide production. Optimized fermentation significantly enhanced SCFA-associated metabolite production, while FTIR and HPLC confirmed the presence of fermentation-derived organic acid metabolites. The metabolites demonstrated potent antioxidant activity and showed minimal developmental toxicity up to 30 mg/mL in zebrafish embryos. In the rotenone-induced PD model, C10-derived SCFAs restored antioxidant enzyme activities, reduced oxidative stress, improved locomotor and cognitive performance, modulated genes associated with neuronal function, inflammation, the NRF2 signalling pathway, intestinal barrier integrity, and gut microbiota, and preserved normal brain and intestinal histoarchitecture. These findings demonstrate that L. plantarum C10-derived SCFA metabolites exert antioxidant, anti-inflammatory, and neuroprotective effects through modulation of the gut-brain axis. This study highlights the potential of probiotic-derived SCFAs as functional food-based therapeutic candidates for managing Parkinson's disease and associated gut dysbiosis.\n\nID: 42354205\nTitle: Fermented Dendrobium officinale Ameliorates Sleep Deprivation-Induced Depressive-like Behaviors by Attenuating Neuroinflammation and Restoring 5-HT Synthesis via the Gut-Brain Axis.\nAbstract: Chronic sleep deprivation (SD) disrupts gut-brain axis (GBA) homeostasis and is closely associated with gut microbiota dysbiosis, neuroinflammation, and depression-like behaviors. This study investigated whether fermentation enhances the antidepressant-like effects of Dendrobium officinale by comparing fermented Dendrobium officinale (FDO) with unfermented Dendrobium officinale (DO) in a chronic SD mouse model. FDO significantly ameliorated anxiety and depressive-like behaviors in SD mice. It reshaped gut microbial structures, enriched beneficial bacteria taxa such as Dubosiella, [Eubacterium]_coprostanoligenes_group, and Allobaculum, and increased SCFA levels. FDO also enhanced colonic ZO-1 and Occludin expression and reduced serum levels of LPS and the pro-inflammatory cytokines. At the central nervous system level, FDO inhibited the activation of hippocampal microglia and astrocytes; alleviated neuroinflammation; restored hippocampal TPH2, 5-hydroxytryptamine (5-HT), and 5-HIAA levels; and modulated the 5-HT1A/5-HT2A receptor balance. In addition, FDO upregulated BDNF, PSD-95, and SYN expression and reduced corticosterone (CORT) levels. Compared with DO, FDO showed more pronounced regulatory effects. Correlation analysis suggested that 5-HT may link gut microbial metabolites, inflammation, and synaptic plasticity. In summary, these findings support FDO as a potential GBA-targeted functional food for SD-related depressive-like behaviors.\n\nID: 42197281\nTitle: Nutrients and Functional Components of Medicine and Food Homology Substances on Antidepressant Effects: A Mechanism-Oriented Review.\nAbstract: Depression is one of the most common mental disorders in modern society, and it has become a serious threat to human health. The limitations of existing antidepressant drugs have prompted people to turn to the multi-target, low-toxic side effects of natural products. This article reviews the conventional nutrients (omega-3 fatty acids, folic acid, and mineral elements) and functional active ingredients (flavonoids, polysaccharides, saponins, and terpenoids) in medicinal and food homologous substances (MFHs). They show antidepressant potential by regulating neurotransmitters, improving hypothalamic-pituitary-adrenal (HPA) axis function, promoting neuroplasticity, inhibiting neuroinflammation, regulating ferroptosis, and interfering with the gut-brain axis. In addition, this paper discusses the application prospects of modern technologies such as microbial fermentation and nano-delivery in improving the bioavailability of MFHs and product development. In summary, MFHs have potential application value in dietary intervention and adjuvant therapies for depression; in the future, randomized controlled clinical trials should be strengthened, and multi-omics technology should be combined to promote the development of precision products so as to provide a new perspective for the development of new antidepressant drugs.\n\nID: 42171826\nTitle: Emerging roles of combined curcumin and berberine in disease modulation: a comprehensive review of mechanisms and therapeutic relevance.\nAbstract: Curcumin, a polyphenolic compound derived from Curcuma longa, and berberine, an isoquinoline alkaloid extracted from plants such as Coptis chinensis, exhibit multifaceted pharmacological properties, including potent antioxidant, anti-inflammatory, antimicrobial, and anticancer effects. This narrative review evaluates their therapeutic potential across a diverse range of conditions, including nonalcoholic fatty liver disease (NAFLD), various malignancies, wound and plant infections, Alzheimer's disease, cardiovascular disorders, irritable bowel syndrome, cyclophosphamide-induced toxicity, interstitial cystitis, and systemic lupus erythematosus. Mechanistically, curcumin and berberine modulate gut microbiota, suppress lipogenic and inflammatory pathways (e.g., SREBP-1c and NF-\u03baB), and activate PI3K/Akt and PPAR\u03b3 signaling, thereby reducing hepatic steatosis and inflammation. Furthermore, they induce apoptosis, inhibit the PI3K/Akt/mTOR pathway, and modulate the tumor microenvironment, with their enhanced combined effects being significantly amplified by nanodelivery systems, such as liposomes. Their antimicrobial efficacy targets methicillin-resistant Staphylococcus aureus (MRSA) and plant pathogens by disrupting biofilms and generating reactive oxygen species via nanofibers and self-assembled submicron particles. Moreover, they reduce amyloid-beta aggregation, promote autophagy, and mitigate neuroinflammation. Additionally, their immunomodulatory properties effectively suppress autoimmune responses. Ultimately, this review synthesizes the current evidence regarding the therapeutic versatility of curcumin and berberine across multiple pathologies.\n\nID: 41909488\nTitle: Function of the large intestine and its interaction with the brain after ischemic stroke: a comprehensive literature review.\nAbstract: The large intestine, part of the distal gastrointestinal tract, is vital for water and electrolyte absorption and microbial fermentation. It is also a significant immune organ endowed with an extensive and intricate neural network. Intestinal epithelial cells are essential for endocrine regulation and maintaining the integrity of the intestinal barrier. Stroke, a leading cause of adult mortality and disability, occurs when there is a lack of oxygen to the brain and involves complex cerebrovascular dynamics that significantly impact systemic functions. In this framework, the gut-brain axis-the bidirectional circuitry connecting the gut and the central nervous system (CNS)-emerges as a critical interface. This review examines the immunological, neurological, endocrine, and barrier functions of the large intestine and explores its interplay with stroke pathophysiology. By detailing the interrelation between stroke and large intestinal functions, this paper aims to provide a foundational reference for advancing research into their intertwined mechanisms and identifying potential therapeutic targets.\n\nID: 41846005\nTitle: Targeting orofacial pain: From pathophysiological mechanisms to Traditional Chinese Medicine approaches.\nAbstract: Orofacial pain is a heterogeneous group of painful conditions affecting the facial and oral regions that can substantially impair quality of life. In some patients, stimulus-evoked pain manifestations such as allodynia further aggravate the disease burden. Current drugs, including carbamazepine and pregabalin, offer only partial relief and are limited by adverse effects, underscoring the need for alternative therapeutic strategies. Traditional Chinese Medicine (TCM), characterized by holistic and multi-targeted actions, shows therapeutic promise. This review summarizes recent advances in peripheral and central mechanisms of orofacial pain, emphasizing ion channel dysregulation, central sensitization, neuroinflammation, and gut-brain axis modulation. We further evaluate TCM-derived phytochemicals, including resveratrol, curcumin, and \u03b1-bisabolol. These compounds act by modulating neuroimmune pathways, suppressing glial activation, restoring synaptic plasticity, and rebalancing gut microbiota. Finally, we highlight challenges-such as standardization, biomarker-guided diagnostics, and the lack of large-scale clinical trials-and propose future directions. By linking traditional insights with contemporary neuroscience, this review aims to provide a mechanistic framework for effective, personalized, and sustainable therapies.\n\nID: 41831719\nTitle: Influence of ginger root extract supplementation on the microbiota-gut-brain axis in individuals with sciatica: Study protocol for a double-blind, placebo-controlled randomized trial.\nAbstract: Neuropathic pain (NP) is caused by damage to the peripheral or central nervous system and is associated with adverse complex sensory and affective symptoms. There are few current treatment options for NP, and opioid analgesics have severe side effects which can lead to opioid abuse. Therefore, the development of innovative, effective, and safe alternatives is urgently needed. This study will assess the effects of ginger root extract's anti-inflammatory and anti-oxidant properties on individuals with sciatica via the microbiome-gut-brain axis. Eighty participants (18-85 years) with chronic sciatica, classified as lean (n = 40, BMI <25 kg/m2) or obese (n = 40, BMI \u226530 kg/m2), will be stratified by age, sex, and BMI to receive 2000 mg/day of ginger extract or placebo for eight weeks. Primary outcomes are pain-associated outcomes and brain neuroplasticity by assessing functional (resting state-fMRI) and structural (Diffusion Tensor Imaging) connectivity. Secondary outcomes include gut function (gut microbiota composition using 16S rRNA sequencing analysis, intestinal permeability assessing concentrations of plasma lipopolysaccharide binding protein and fecal zonulin, and fecal metabolites using LC-MS/MS analysis) and neuroinflammation: nCounter\u00ae Neuroinflammation Panel analysis. We will evaluate outcomes at baseline and end of study. We will employ intention-to-treat principle and per-protocol for data analysis. Hierarchical linear modeling is utilized to estimate ginger supplementation's effects while properly accounting for data dependency and identified covariates. This study was approved by the Bioethics Committee of the Texas Tech University Health Sciences Center, Lubbock, TX. Participants will sign an informed consent form before enrolling in the study. Our team will actively disseminate the results from this trial through academic conference presentations and peer-reviewed journals. We are now actively recruiting subjects for this study. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT06817018.\n\nID: 41798063\nTitle: Microbial SCFAs as epigenetic mediators: fine-tuning the gut-brain axis in neurodegenerative disorders.\nAbstract: The gut-brain axis is a bidirectional communication system linking the gastrointestinal tract and the central nervous system (CNS). Short-chain fatty acids (SCFAs) are microbial metabolites produced through the anaerobic fermentation of dietary fiber. Growing evidence positions SCFAs as critical signaling molecules within this axis, capable of modulating key neurobiological processes relevant to neurodegenerative diseases (NDs), such as Alzheimer's disease (AD) and Parkinson's disease (PD). SCFAs exert neuroprotective effects by mitigating neuroinflammation, promoting neurogenesis, enhancing synaptic plasticity, and preserving blood-brain barrier integrity. These actions are largely mediated through epigenetic mechanisms. Butyrate functions as a histone deacetylase inhibitor to alter gene expression related to neuronal survival, inflammation, and metabolism. SCFAs also influence DNA methylation dynamics via modulation of DNA methyltransferases and ten-eleven translocation (TET) enzymes. Emerging findings suggest their involvement in novel histone modifications, such as lactylation. This review synthesizes current understanding of SCFA production, metabolic fate, and their multifaceted epigenetic actions in the brain, while evaluating their translational and therapeutic potential. Gut-derived SCFAs represent promising modulators of the brain's epigenetic landscape. Elucidating their mechanisms offers a foundation for developing novel interventions, including dietary, probiotic, and epigenetics-based strategies, for the prevention and treatment of NDs.\n\nID: 41716273\nTitle: Interactions of bile acids and gut microbiota modulate neurological health: a comprehensive review on mechanisms and therapeutic potential of dietary phytochemicals.\nAbstract: Bile acids (BAs), classically regarded as detergents for dietary lipid absorption, have emerged as pivotal signaling molecules with systemic endocrine functions. The discovery of the Farnesoid X Receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5) as BAs-activated receptors unveiled their profound influences on glucose, lipid, and energy metabolism. BAs are first synthesized in hepatocytes and further metabolized by gut microbes, can either circulate in enterohepatic system or be found in circulations to exert various effects. More recently, the gut-brain axis has been identified as a critical pathway through which BAs exert significant effects on central nervous system (CNS) function and health. Based on research progresses mentioned above, this review systematically delineates the synthesis, metabolism, and classification of BAs, with a focus on the intricate crosstalk between the hepatic-gut BA axis and the brain. In addition, we explore the compelling evidences linking BAs dysregulation to a spectrum of neurological disorders, including neurodegenerative diseases (Alzheimer's and Parkinson's disease), depression, and hepatic encephalopathy. Besides, the potential mechanisms, such as alleviating neuroinflammation, maintaining the integrity of blood-brain barrier, increasing the neuronal survival, and modulating neurotransmitter systems are further elucidated. Finally, strategies of dietary intervention through phytochemicals to modulate the BAs pool for improved neurological outcomes are summarized and discussed. By integrating pre-clinical and clinical findings, this review aims to establish a foundation for understanding BAs as novel therapeutic targets in neurology and nutritional neuroscience.\n\nID: 41678917\nTitle: Plant-derived bioactive compounds modulate the gut microbiota in Alzheimer's disease: Metabolite signaling, neuroimmune circuits, and systems-level regulation.\nAbstract: Alzheimer's disease (AD) is increasingly recognized as a multisystem disorder shaped not only by central neurodegeneration but also by peripheral metabolic and immune dysregulation. Growing evidence highlights the gut microbiota and its metabolites as key modulators of amyloid accumulation, tau phosphorylation, neuroinflammation, and microglial dysfunction. This review aims to synthesize current advances on how plant-derived bioactive compounds modulate AD pathophysiology through microbiota-dependent metabolic and neuroimmune mechanisms, and to establish a systems-level framework linking botanical interventions to gut microbiota remodeling and metabolite signaling. A comprehensive literature survey was conducted using PubMed, Web of Science, ScienceDirect, and Google Scholar, covering publications from 2010 to 2026. Studies investigating gut microbiota, microbial metabolites, and plant-derived bioactive compounds in AD-related metabolic, immune, and neurodegenerative pathways were systematically reviewed and integrated. Plant-derived bioactive compounds, including phytochemicals, polysaccharides, and multi-herb formulations, interact extensively with the gut microbiota, undergoing microbial biotransformation to yield more active metabolites while simultaneously reshaping microbial community structure and metabolite profiles. These bidirectional interactions position the microbiota as a central mediator of plant-derived therapeutic activity. We summarize current evidence on how plant-derived compounds influence AD pathophysiology through microbiota-dependent metabolic and neuroimmune pathways. Major microbial metabolites, including short-chain fatty acids (SCFAs), trimethylamine N-oxide (TMAO), bile acids (BAs), and indole derivatives, are discussed, together with their regulatory roles in signaling networks such as nuclear factor \u03baB (NF-\u03baB), phosphatidylinositol 3-kinase/Akt (PI3K/Akt), cAMP response element-binding protein/brain-derived neurotrophic factor (CREB/BDNF), and triggering receptor expressed on myeloid cells 2 (TREM2)-associated microglial states. We further summarize evidence for synergistic strategies combining plant bioactives with probiotics and highlight advances in microbial biotransformation, precision metabolite modulation, and engineered microbial systems. Finally, future directions integrating multi-omics, personalized microbiota-guided interventions, and synthetic biology are outlined to support the development of targeted, mechanism-based therapies. By framing AD through a gut microbiota-centered perspective, this review provides a unified mechanistic foundation for the development of next-generation interventions based on plant-derived compounds and microbiota regulation.\n\nID: 41653907\nTitle: Preventive effects of GABA-producing postbiotics derived from Levilactobacillus brevis against chronic sleep deprivation-induced gut-brain axis dysfunction, neuroinflammation, and behavioral impairments in mice.\nAbstract: Chronic sleep deprivation (CSD) is increasingly recognized as a contributor to gut dysbiosis, systemic inflammation, and neurobehavioral impairments via the gut-brain axis. \u03b3-Aminobutyric acid (GABA)-producing postbiotics, derived from microbial fermentation, offer potential in mitigating such dysfunctions. This study investigates the effects of GABA-producing postbiotics produced by Levilactobacillus brevis on CSD-induced gut and brain disturbances in mice. Male C57BL/6 mice were subjected to 30 days of sleep fragmentation and treated with low (250\u202fmg/kg) or high (500\u202fmg/kg) doses of postbiotics. Behavioral tests revealed that GABA-producing postbiotics significantly alleviated anxiety- and depression-like behaviors. Postbiotic treatment restored intestinal tight junction protein expression (ZO-1, Claudin-1), increased glutathione peroxidase activity, and reduced serum lipopolysaccharide and TNF-\u03b1 levels, indicating improved intestinal barrier function and attenuated systemic inflammation. Postbiotic treatment promote the growth of beneficial genera such as Ruminococcus and Akkermansia, while also elevating fecal propanoic acid concentrations. In the brain, postbiotics upregulated blood-brain barrier (BBB) associated genes and reduced neuroinflammatory gene expression. Correlation analysis highlighted microbial signatures linked to short-chain fatty acids, intestinal tight junction proteins, serum LPS and TNF-\u03b1 levels, as well as hypothalamic inflammatory, BBB gene expressions and anxiety. These findings suggest that GABA-producing postbiotics ameliorate CSD-induced gut-brain axis disruption by modulating the microbiota, restoring barrier functions, and suppressing systemic and neuroinflammation. This study supports the potential application of GABA-producing postbiotics as a dietary strategy to mitigate sleep loss-related physiological and behavioral impairments.\n\nID: 41594549\nTitle: Advances in Bioactive Compounds from Plants and Their Applications in Alzheimer's Disease.\nAbstract: Alzheimer's disease (AD), the leading cause of dementia worldwide, is characterized by progressive neuronal loss, amyloid-\u03b2 (A\u03b2) aggregation, tau hyperphosphorylation, oxidative stress, neuroinflammation, cholinergic dysfunction, and gut-brain axis dysregulation. Despite advances in anti-amyloid therapeutics, current interventions provide only modest symptomatic relief and face limitations in accessibility, cost, and long-term efficacy. Plant-derived bioactive compounds, rooted in traditional medicine systems such as Ayurveda and Traditional Chinese Medicine, have gained increasing attention as multi-target therapeutic agents due to their pleiotropic actions, relative safety, and ability to cross the blood-brain barrier. This review synthesizes mechanistic and translational evidence on major phytochemicals, including withanolides (Withania somnifera), curcumin (Curcuma longa), ginkgolides and bilobalide (Ginkgo biloba), bacosides (Bacopa monnieri), ginsenosides (Panax ginseng), crocin/safranal (Crocus sativus), epigallocatechin-3-gallate (Camellia sinensis), rosmarinic acid (Salvia officinalis, Melissa officinalis), and asiaticosides (Centella asiatica). These compounds exert neuroprotective effects by inhibiting A\u03b2 aggregation, reducing tau phosphorylation, scavenging reactive oxygen species, attenuating NF-\u03baB-mediated inflammation, modulating cholinergic signaling, enhancing synaptic plasticity via brain-derived neurotrophic factor/cAMP response element-binding protein (BDNF/CREB) activation, and regulating gut microbiota. Multi-target approach analyses underscore their synergistic potential in targeting interconnected AD pathways. However, translation remains hindered by poor oral bioavailability, rapid metabolism, and variability in clinical outcomes. Advances in delivery platforms, including liposomes, bilosomes, solid lipid nanoparticles, and nanostructured lipid carriers, are improving stability, blood-brain penetration, and therapeutic efficacy in preclinical models. Collectively, plant-derived phytochemicals serve as promising, affordable, and multi-modal candidates for reshaping AD management, bridging traditional knowledge with modern therapeutic innovation.\n\nID: 41474946\nTitle: Decoding the Protective Mechanisms of Rosa roxburghii Fermented Juice against CUMS-Induced Depression-like Behaviors: Insights from Gut Microbiota and Neuroinflammation.\nAbstract: Depression, recognized for its complex pathophysiology, remains a prevalent psychiatric disorder. The gut-brain axis is increasingly implicated in the pathophysiology of depressive symptoms, highlighting it as a promising intervention target. This study evaluated the protective effects of Rosa roxburghii fermented juice (RRFJ) in a chronic unpredictable mild stress (CUMS) mouse model. Results showed that RRFJ pretreatment significantly mitigated CUMS-induced depressive-like behaviors and hippocampal damage in C57BL/6J mice. Mechanistic investigations revealed that RRFJ induced remodeling of the gut microbiota characterized by an increased Firmicutes-to-Bacteroidetes ratio. This enhanced intestinal barrier integrity by reducing gut-derived lipopolysaccharide and upregulating tight junction proteins, ultimately resulting in decreased neuroinflammation in the hippocampus. Furthermore, RRFJ pretreatment modulated host metabolic profiles in plasma and brain tissue. In conclusion, RRFJ mitigates depressive-like behaviors, highlighting its preventive potential via mechanisms, including gut microbiota modulation, neuroinflammation suppression, and metabolic shifts in both plasma and brain.\n\nID: 41348525\nTitle: Orally Administered Bacillus licheniformis F0726 Attenuates MPTP/P-Induced Neurodegeneration by Modulating Gut Microbiota and Suppressing Inflammatory Responses.\nAbstract: Extensive studies have shown that Parkinson's disease (PD) is associated with disruption in the gut microbiota. Bacillus licheniformis has attracted the attention of researchers due to its function in regulating the composition of intestinal microbiota. This study investigated the neuroprotective effects of orally administered B. licheniformis F0726 in an MPTP/P-induced mice model of PD. The results showed that B. licheniformis F0726 significantly alleviated MPTP/P-induced motor dysfunction and depletion of dopamine-containing neurons. Notably, B. licheniformis F0726 alleviated neuroinflammation by inhibiting glial cell activation and reducing serum pro-inflammatory cytokine levels. Furthermore, 16S rRNA sequencing revealed that intervention with B. licheniformis F0726 alleviated the gut dysbiosis. Crucially, B. licheniformis F0726 significantly increased the level of short-chain fatty acids, which are key signaling molecules of the gut-brain axis. In conclusion, B. licheniformis F0726 may alleviate neurodegenerative lesions in PD mice by modulating the gut microbiota and suppressing inflammatory responses.\n\nID: 41247064\nTitle: Emerging insights into dairy products and Alzheimer's disease: exploring the potential neuroprotective effects.\nAbstract: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, synaptic dysfunction, and chronic neuroinflammation. While genetic and environmental factors are well-established contributors, emerging evidence suggests that diet, particularly dairy intake, may modulate AD risk. This review critically evaluates epidemiological and clinical findings on the neuroprotective potential of dairy products. Bioactive components, including milk-derived peptides, milk fat globule membrane (MFGM), and fermentation-derived metabolites, exhibit antioxidant and neurotrophic properties that support mitochondrial function and synaptic plasticity. Fermented dairy products may further influence cognition through modulation of the gut-brain axis and production of neuroactive microbial metabolites. Observational studies often indicate a positive association between dairy consumption and cognitive health, yet findings remain inconsistent, with neutral or contradictory outcomes reported. Clinical investigations are limited by small cohorts, heterogeneous methodologies, and population variability. Literature for this review was systematically retrieved from PubMed and Google Scholar. To clarify the role of dairy in AD prevention, future research should integrate precision nutrition approaches that account for genetic susceptibility, microbiota composition, and metabolic profiles. Overall, dairy represents an accessible source of bioactive compounds with potential to promote cognitive resilience, though robust longitudinal and interventional studies are required to establish causality and inform dietary guidelines.\n\nID: 41222739\nTitle: Microbiota-Derived SCFAs in Multiple Sclerosis: From Immune Priming to Neurodegeneration.\nAbstract: Multiple sclerosis (MS) is a chronic, immune-mediated neuroinflammatory and neurodegenerative disorder characterized by demyelination, axonal injury, and widespread disruption of central nervous system (CNS) integrity. Clinically heterogeneous and often presenting in young adults-especially women-MS manifests with motor deficits, cognitive impairment, depression, fatigue, sexual and sensory dysfunctions, and autonomic disturbances. Despite advances in immunotherapies, including disease-modifying agents and monoclonal antibodies, current treatments inadequately address progressive neurodegeneration or restore neuronal integrity. Traditional risk factors such as Epstein-Barr virus infection, vitamin D deficiency, smoking, and childhood obesity only partially explain disease onset, reflecting the multifactorial and elusive nature of MS pathogenesis. Recent research has turned attention toward the gut-brain axis, particularly the role of intestinal dysbiosis and microbial metabolites in modulating systemic and CNS inflammation. Among these, short-chain fatty acids (SCFAs)-produced through microbial fermentation of dietary fibres-have emerged as pivotal regulators of immune homeostasis, neuroinflammation, and glial function. Furthermore, MS patients consistently exhibit a depletion of SCFA-producing bacteria, implicating these metabolites development and progression of MS. In the prodromal phase, SCFAs influence gut immune priming and tolerance; in relapsing-remitting MS, they modulate T cell differentiation, cytokine profiles, and remyelination processes; and in progressive MS, they support mitochondrial function, reduce oxidative stress, and influence neuroglial dynamics. While SCFAs show promise as diagnostic biomarkers and adjunctive therapeutic targets, their context-dependent, bidirectional effects necessitate a precision-medicine approach. This review synthesizes current insights into the stage-specific roles of SCFAs across the MS disease continuum. The present work not only elucidates the mechanistic underpinnings of SCFA action in MS but also outlines future directions for microbiota-centred interventions tailored to disease stage and individual microbiome profiles.\n\nID: 41123675\nTitle: Short-Chain Fatty Acids as a Therapeutic Strategy in Parkinson's Disease: Implications for Neurodegeneration.\nAbstract: Neurodegeneration involves the progressive deterioration of neuronal structure and function, leading to deficits in cognition, motor skills, and other neurological processes. Parkinson's disease (PD) is notably prevalent among neurodegenerative disorders, characterized by dopaminergic neurodegeneration, protein misfolding, and an inflammatory brain environment. Despite advancements in understanding its pathophysiology, PD and other neurodegenerative conditions still lack effective disease-modifying therapies. This shortfall highlights the need for novel, multifactorial approaches to treatment. Recent research has spotlighted the gut-brain axis as a significant player in neurological health, particularly through the activity of gut-derived short-chain fatty acids (SCFAs). These microbial metabolites, primarily acetate, propionate, and butyrate, are produced via the fermentation of dietary fibers and are vital for maintaining intestinal and neural homeostasis. SCFAs exert anti-inflammatory effects, preserve blood-brain barrier integrity, and modulate neurotransmitter systems. Among them, butyrate shows notable neuroprotective capabilities, including histone deacetylase inhibition and mitochondrial enhancement. Disruption in SCFA production has been associated with PD progression, further underscoring their relevance. This review explores the mechanistic roles of SCFAs in modulating neurodegeneration, with an emphasis on PD. SCFA-based strategies offer a promising adjunctive route to restoring microbial balance, mitigating neuroinflammation, and safeguarding neurological function in neurodegenerative disorders.\n\nID: 41103968\nTitle: Extracellular vesicles from water kefir can interact with human neurons in vitro: a potential explanation for the role of probiotics consumption in mental health.\nAbstract: Major depressive disorder is one of the most burdensome mental health disorders. Probiotics have been shown to ameliorate depressive symptoms, though the mechanism remains unclear. This study was conducted to investigate whether extracellular vesicles (EVs) extracted from the probiotic beverage water kefir could influence gene and protein expression in human-derived neuroblastoma cells in vitro. EVs were extracted from lab-cultured water kefir and a control solution without water kefir grains by ultracentrifugation. Water kefir vesicles were imaged via electron microscopy. Neuroblastoma, microglia, and neuroblastoma-microglia co-cultures were exposed to water kefir EVs or negative control medium. Uptake of water kefir EVs was identified by microscopy. All conditions were quantified for brain derived neurotrophic factor, fractalkine, and synaptophysin RNA and protein. Data were analyzed using factorial ANOVAs with significance set at 0.05. Water kefir vesicles were taken up by neuroblastoma cells, and incubation in neuroblastoma-microglia co-culture resulted in significantly higher levels of fractalkine protein compared to media-only control (p = 0.029). To our knowledge, this is the first study to identify potential interactions between EVs derived from the probiotic beverage water kefir and human neuronal cells. Further research is needed to fully elucidate the role played by probiotic-derived EVs in human health.\n\nID: 41009475\nTitle: Neuroactive Phytochemicals as Multi-Target Modulators of Mental Health and Cognitive Function: An Integrative Review.\nAbstract: The growing prevalence of mental health issues and cognitive impairment poses a significant challenge to global public health. Conditions such as depression, anxiety, neurodegenerative diseases, and stress-related cognitive dysfunction are becoming more common, while conventional pharmacotherapies are often limited by suboptimal efficacy, adverse side effects, and concerns about long-term use. Against this backdrop, neurophytochemistry-the study of plant-derived bioactive compounds-has emerged as a promising area of research. This review explores the potential of selected phytochemicals to support mental well-being and cognitive function via various molecular mechanisms. Compounds such as apigenin, hesperidin, and epigallocatechin gallate have been shown to have a significant impact on key regulatory pathways. These include enhancing neurogenesis via brain-derived neurotrophic factor, modulating neurotransmitter systems (such as GABA and serotonin), and attenuating oxidative stress and neuroinflammation. The therapeutic relevance of these compounds is discussed in the context of depression, anxiety, Alzheimer's disease, Parkinson's disease, and stress-related cognitive dysfunction, often referred to as 'brain fog'. This review synthesizes evidence published between 2010 and 2025 from several scientific databases, including PubMed, Scopus, Web of Science, and Embase. Preliminary evidence from in vitro studies and animal models indicates that neurophytochemicals could enhance synaptic plasticity, protect neurons from oxidative damage, and modulate inflammatory pathways, particularly those involving NF-\u03baB and the Nrf2/ARE antioxidant response. In addition, early human clinical trials have shown that phytochemical supplementation can lead to improvements in mood regulation, stress response, and cognitive performance. Furthermore, emerging evidence suggests that the gut-brain axis plays a key role in mediating the effects of phytochemicals. Several compounds have been found to modulate the composition of gut microbiota in ways that could enhance the function of the central nervous system. While the initial results are encouraging, more high-quality clinical trials and mechanistic studies are required to validate these findings, optimize dosage regimens, and guarantee the safety and efficacy of long-term use. Thus, neurophytochemicals represent a promising integrative approach to alleviating the increasing burden of mental and cognitive disorders through naturally derived therapeutic strategies.\n\nID: 40895097\nTitle: Gut-brain axis modulation in remote rehabilitation of Parkinson's disease: reconstructing the fecal metabolome and nigral network connectivity.\nAbstract: The pathogenesis of Parkinson's disease (PD) is gradually evolving from a central neurodegeneration-centered concept to a multi-pathway pathological model at the gut-brain system level. Studies have shown that PD patients commonly exhibit dysbiosis, reduced short-chain fatty acids (SCFAs; microbial fermentation products of dietary fiber that play key roles in host metabolism and immune regulation), abnormal tryptophan metabolism, and impaired gut barrier function. These alterations may contribute to dopaminergic neuronal damage through mechanisms including neuroinflammation, oxidative stress, and \u03b1-synuclein (\u03b1-syn) aggregation. The vagus nerve plays a critical role in bidirectional gut-brain signaling, and its dysfunction may represent a key route for pathological protein transmission from the periphery to the brain. In response, remote rehabilitation and gut-targeted interventions-including probiotics, prebiotics, dietary modulation, fecal microbiota transplantation (FMT), and transcutaneous vagus nerve stimulation (tVNS)-have shown potential in improving neurological function and inflammation in both animal and clinical studies. Multimodal data analyses have revealed significant associations between SCFA levels in fecal metabolomics and brain imaging features. Despite ongoing challenges in mechanistic extrapolation, biomarker sensitivity, and translational implementation, the integration of metagenomics, metabolomics, neuroimaging, and digital therapeutics-collectively referred to as multi-omics and digital profiling techniques-represents an emerging research direction with the potential to inform future clinical paradigms for precision remote management of PD.\n\nID: 40878211\nTitle: Pediococcus acidilactici KCTC 15831BP-fermented industrial hempseed (Cannabis sativa L.) supplementation corrects metabolite and gut microbiota dysbiosis, potentially mitigating Alzheimer's disease-like symptoms induced by obesity in high-fat diet-fed mice.\nAbstract: A long-term high-fat diet (HFD) intake causes obesity, disrupting the gut microbiota and body metabolite balance, and increasing the risk of Alzheimer's disease (AD). Fermented hempseed may restore microbiota balance, improve metabolism, and reduce neuroinflammation, potentially protecting against cognitive decline. This study investigates the protective effects and mechanisms of action of Pediococcus acidilactici KCTC 15831BP-fermented hempseed (FHS) against AD-like symptoms induced by obesity in high-fat diet-fed mice. Nine-week-old male C57BL/6 mice were fed an HFD and supplemented with either orlistat, raw hempseed, FHS, or live Pediococcus acidilactici KCTC 15831BP (PA) for 15 weeks. At the end of the experiment, the impacts of supplementation on obesity- and AD-related markers, brain and blood metabolites, and fecal microbiota were assessed. HFD-fed mice exhibited obesity markers, such as increased body weight, altered serum lipids, insulin resistance, high leptin but low adiponectin levels, fatty liver, and enlarged adipose tissue. They also showed AD-related disorders, including cognitive decline, oxidative stress, neuroinflammation, and beta-amyloid accumulation. HFD feeding also led to gut microbiota dysbiosis and unfavorable changes in serum and brain metabolites. FHS intervention reversed most adverse effects, restoring gut microbiome balance, improving the Firmicutes/Bacteroidetes ratio, and normalizing disrupted serum and brain metabolites, including increasing protective compounds like L-tryptophan and trans-cinnamic acid. The beneficial changes in the gut microbiota and metabolite profiles caused by FHS positively correlated with improvements in obesity and AD markers. These findings highlight the interconnection between the diet, gut, and brain, emphasizing the role of the diet-microbiota-gut-brain axis in mitigating neurodegenerative diseases.\n\nID: 40860878\nTitle: Cistanche tubulosa glycosides ameliorate cognitive decline in APP/PS1 mice via modulation of gut microbiota and fatty acid metabolism: insights from multi-omics and experimental validation.\nAbstract: The dried succulent stem of C. tubulosa (Schenk) Wight has long been used as herbal medicine in China and other regions of Asia for its tonifying properties. This study aimed to elucidate the pharmacological mechanisms of the total glycosides from Cistanche tubulosa (GCT) in ameliorating cognitive decline, with a focus on gut microbiota remodeling and metabolic regulation. Six-month-old APP/PS1 double-transgenic mice received oral GCT at three doses or donepezil for 60 days. Cognitive function was assessed by the Morris water maze. A\u03b2 burden and inflammatory factors were evaluated by immunohistochemistry and ELISA. Gut microbiota was analyzed using 16S rRNA sequencing. Metabolomic profiles of mice serum and brain were profiled by a targeted metabolomics approach that enabled simultaneous quantitation of 306 metabolites. The effect of GCT on pure-cultured bacterial strain was assessed via growth curve analysis in vitro. GCT treatment significantly improved spatial memory and reduced the protein levels of A\u03b2 and proinflammatory factors in APP/PS1 mice. Multi-omics analyses revealed that GCT rapidly enriched beneficial taxa like Akkermansia and suppresses Firmicutes since the seventh day of intervention, leading to increased neuroprotective short-chain fatty acids (e.g., \u03b2-hydroxybutyrate) and decreased pro-inflammatory long-chain fatty acids in both serum and brain. Crucially, in-vitro experiments demonstrated that GCT directly promoted the proliferation of Akkermansia muciniphila, a key probiotic implicated in AD amelioration. This work uncovers a novel \"gut microbiota-fatty acid metabolism-neuroinflammation\" axis as the primary mechanism underlying GCT's anti-AD effects. These findings highlight GCT's therapeutic potential and offer new mechanistic insights into how low-bioavailability phytochemicals exert systemic benefits via the gut-brain axis.\n\nID: 40802223\nTitle: Postbiotics as a Therapeutic Tool in Depression: Exploring into Molecular Pathways and Neuroprotective Effects.\nAbstract: Depression, a debilitating mood disorder characterized by persistent sadness and anhedonia, affects millions worldwide, yet available therapies remain suboptimal and often cause undesirable side effects. Emerging evidence highlights the crucial role of gut microbiota in regulating mental health through the gut-brain axis, paving the way for novel therapeutic strategies. As per preclinical and clinical studies, there is a causal relationship between gut dysbiosis and depression via modulation of brain activity through the gut-brain axis (GBA), and the key to targeting microbes is key to treating depression. Postbiotics-bioactive compounds derived after fermentation have been shown to provide several health benefits, particularly in terms of neuroinflammation, neurotransmitter imbalance, mitochondrial dysfunction, and restoration of neuroplasticity associated with depression.\u00a0This review explores the neuroprotective mechanisms by which postbiotics alleviate depression, including the modulation of neurotransmitter synthesis, suppression of neuroinflammation, mitigation of oxidative stress and mitochondrial dysfunction, and restoration of neuroplasticity. Furthermore, postbiotics hold potential as adjuvant therapy alongside conventional antidepressants, enhancing treatment efficacy and minimizing side effects. Despite promising initial findings, challenges such as standardized formulation, clinical dose optimization, and regulatory framework development must be addressed. Large-scale clinical trials are imperative to validate their therapeutic potential and facilitate integration into mainstream depression management. As research advances, postbiotics may redefine mental health treatment, emerging as a revolutionary microbiome-based approach for long-term patient care.\n\nID: 40649341\nTitle: Phytotherapy and the Role of Bioactive Compounds in Modulating Mechanisms of Overweight and Obesity Comorbid with Depressive Symptoms-A Scoping Review of Mechanisms of Action.\nAbstract: Obesity and depression frequently coexist, sharing overlapping molecular pathways such as inflammation, oxidative stress, gut microbiota dysbiosis, and neuroendocrine dysfunction. Recent research highlights the therapeutic potential of plant-derived bioactive compounds in targeting these shared mechanisms. This scoping review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and included 261 peer-reviewed studies identified through PubMed, Scopus, and the Web of Science up to December 2024. Studies were screened based on predefined inclusion and exclusion criteria. This review synthesizes data from peer-reviewed studies, including both preclinical and clinical investigations, focusing on polyphenols, flavonoids, alkaloids, and other phytochemicals with anti-inflammatory, antioxidant, neuroprotective, and metabolic effects. Compounds such as quercetin, epigallocatechin gallate (EGCG), resveratrol, curcumin, anthocyanins, and luteolin demonstrate promise in modulating adenosine monophosphate-activated protein kinase (AMPK), brain-derived neurotrophic factor (BDNF), nuclear factor kappa B (NF-\u03baB), and gut-brain axis pathways. Our scoping review, conducted in accordance with PRISMA guidelines, identifies promising combinations and mechanisms for integrative phytotherapy. These findings underscore the potential of botanical strategies in developing future interventions for metabolic and mood comorbidities.\n\nID: 40431358\nTitle: Beneficial Effects of Traditional Fermented Soybean Sauce (Kanjang) on Memory Function, Body Water, and Glucose Metabolism: Roles of Gut Microbiota and Neuroinflammation.\nAbstract: Background: Traditional fermented soybean foods, acting as potential synbiotics, may help mitigate cognitive impairment associated with amnesia. This study investigated the neuroprotective effects of four kanjang (Korean fermented soy sauce) varieties and their underlying mechanisms. Methods: Male Sprague Dawley rats (n = 70) were divided into seven groups: normal control, scopolamine control, positive control (1 mg/kg bw/day of donepezil), and four scopolamine-treated groups receiving different kanjang varieties (0.5% in high-fat diet). Based on their Bacillus content, the kanjang samples were categorized as traditionally made kanjang (TMK) with high Bacillus (SS-HB), TMK with medium Bacillus (SS-MB), TMK with low Bacillus (SS-LB), and factory-made kanjang (SS-FM). Results: Scopolamine administration disrupted energy, glucose, and water metabolism and impaired memory function (p < 0.05). All kanjang treatments improved insulin sensitivity, reduced inflammation, enhanced glucose tolerance, and decreased visceral fat. SS-MB, SS-HB, and SS-FM increased skeletal muscle mass. They maintained body water homeostasis by suppressing the renin-angiotensin-aldosterone system. Kanjang treatments improved memory function, with SS-FM showing the least significant effects. The treatments reduced neuronal cell death in the hippocampal CA1 region, decreased acetylcholinesterase activity, and increased brain-derived neurotrophic factor mRNA expression. Gut microbiota analysis revealed that kanjang treatments increased Lactobacillaceae and decreased Lachnospiraceae, with SS-HB and SS-LB specifically elevating Ligilactobacillus. Metagenomic analysis demonstrated enhanced glycolysis/gluconeogenesis pathways and enhanced butanoate metabolism while reducing lipopolysaccharide biosynthesis and pro-inflammatory signaling. SS-MB and SS-LB increased intestinal goblet cell counts and the serum butyrate concentration. Conclusions: These findings suggest that kanjang consumption, particularly SS-HB and SS-LB varieties, can ameliorate memory impairment in this murine model through multiple mechanisms: metabolic improvements, enhanced neurotrophic signaling, gut microbiota modulation, and reduced neuroinflammation via gut-brain axis activation. Human clinical trials are warranted to determine if these promising neuroprotective effects translate to clinical applications.\n\nID: 40362814\nTitle: Modulating Gut Microbiota with Dietary Components: A Novel Strategy for Cancer-Depression Comorbidity Management.\nAbstract: Gut microbiota play a critical role in mediating the bidirectional association between cancer and depression. Emerging evidence indicates that adjusting the dietary component intake can significantly alter gut microbiota composition, thereby influencing the host's metabolism and immune function. Changes in gut microbiota and their metabolites may represent key factors in preventing cancer-depression comorbidity. English publications were searched in databases including the Web of Science, Scopus, and PubMed using a series of keywords: \"cancer\", \"depression\", \"gut microbiota\", \"dietary components\", and related terms, individually or in combination. The search focused on preclinical and clinical studies describing the regulatory effects of dietary component interventions. This narrative review summarizes the associations among gut microbiota, cancer, and depression, and synthesizes current evidence on the modulatory effects and mechanisms of specific dietary component interventions, including dietary patterns, probiotics, prebiotics, and diet-derived phytochemicals, on gut microbiota. On the one hand, these interventions inhibit abnormal proliferation signals in the tumor microenvironment and enhance anticancer immune responses; on the other hand, they modulate neurotransmitter homeostasis, suppress neuroinflammation, and improve mood behaviors through the gut-brain axis interactions mediated by microbial metabolites. The complex associations among cancer, depression, and gut microbiota require further clarification. Modulating gut microbiota composition through dietary components represents a novel therapeutic strategy for improving cancer-depression comorbidity. Regulated gut microbiota enhance immune homeostasis and intestinal barrier function, while their metabolites bidirectionally modulate one another via systemic circulation and the gut-brain axis, thereby improving both the tumor microenvironment and depressive-like behaviors in cancer patients while reducing the adverse effects of cancer.\n\nID: 40284169\nTitle: Beyond the Gut: Unveiling Butyrate's Global Health Impact Through Gut Health and Dysbiosis-Related Conditions: A Narrative Review.\nAbstract: Short-chain fatty acids (SCFAs), mainly produced by gut microbiota through the fermentation process of dietary fibers and proteins, are crucial to human health, with butyrate, a famous four-carbon SCFA, standing out for its inevitably regulatory impact on both gut and immune functions. Within this narrative review, the vital physiological functions of SCFAs were examined, with emphasis on butyrate's role as an energy source for colonocytes and its ability to enhance the gut barrier while exhibiting anti-inflammatory effects. Knowledge of butyrate synthesis, primarily generated by Firmicutes bacteria, can be influenced by diets with specifically high contents of resistant starches and fiber. Butyrate can inhibit histone deacetylase, modulate gene expression, influence immune functionality, and regulate tight junction integrity, supporting the idea of its role in gut barrier preservation. Butyrate possesses systemic anti-inflammatory properties, particularly, its capacity to reduce pro-inflammatory cytokines and maintain immune homeostasis, highlighting its therapeutic potential in managing dysbiosis and inflammatory diseases. Although butyrate absorption into circulation is typically minimal, its broader health implications are substantial, especially regarding obesity and type 2 diabetes through its influence on metabolic regulation and inflammation. Furthermore, this narrative review thoroughly examines butyrate's growing recognition as a modulator of neurological health via its interaction with the gut-brain axis. Additionally, butyrate's neuroprotective effects are mediated through activation of specific G-protein-coupled receptors, such as FFAR3 and GPR109a, and inhibition of histone deacetylases (HDACs). Research indicates that butyrate can alleviate neurological disorders, including Alzheimer's, Parkinson's, autism spectrum disorder, and Huntington's disease, by reducing neuroinflammation, enhancing neurotransmitter modulation, and improving histone acetylation. This focus will help unlock its full therapeutic potential for metabolic and neurological health, rather than exclusively on its well-known benefits for gut health, as these are often interconnected.\n\nID: 42510662\nTitle: Gut Microbiota and Metabolic Syndrome: A Narrative Review.\nAbstract: Obesity is a major global health problem and is closely associated with a broad range of metabolic disorders, including metabolic syndrome (MetS), dyslipidemia, hypertension, atherosclerosis, type 2 diabetes mellitus, and cardiovascular disease. The gut microbiota plays a central role in maintaining intestinal epithelial integrity, regulating glucose and lipid metabolism, and modulating immune function. Through the gut-brain axis, it also contributes to appetite regulation and energy homeostasis by influencing the release of anorexigenic hormones. Dysbiosis, including alterations in the relative abundance of major bacterial phyla such as Firmicutes and Bacteroidetes, has been associated with increased intestinal permeability, metabolic endotoxemia, and chronic low-grade inflammation, all of which may contribute to the development of obesity and insulin resistance. Diets rich in plant-derived fiber can beneficially shape gut microbiota composition. Bacterial fermentation of dietary fiber produces short-chain fatty acids (SCFAs), including butyrate, acetate, and propionate, which contribute to intestinal barrier integrity, inflammatory regulation, immune regulation, and metabolic homeostasis. Overall, the interaction between gut microbiota, diet, and host metabolic pathways represents a promising field for therapeutic and nutritional interventions aimed at preventing and managing MetS and metabolic diseases.\n\nID: 42424676\nTitle: Dark tea-derived exosome-like nanovesicles suppress hepatocellular carcinoma via inhibiting Akt pathway and modulating immune profiles.\nAbstract: Accumulating evidence indicates the microbial fermentation enhanced the health benefits and potential anti-tumor effect of dark tea. However, low bioavailability and unclarified therapeutic mechanisms impeded its deeply application. Plant-derived exosome-like nanoparticles offered a promising option for improving bioavailability and targeted delivery capability. To obtain dark tea-derived exosome-like nanovesicles (DTELNs) and clarify their material basis, investigate the therapeutic effects on hepatocyte carcinoma (HCC) and potential mechanisms. DTELNs were isolated by tangential flow filtration, TEM, NTA, nucleic acid & protein analysis system and LC-MS/MS were used to characterize their morphological characteristics and chemical composition. Orthotopic HCC model mice were established and employed for DTELNs' oral administration. Living imaging, H&E staining and biochemical assays were used to evaluate therapeutic effects. Untargeted metabolomic, 16S rRNA sequencing and cytometry by time-of-flight (CyTOF) were used to investigate the alteration of endogenous substances and immune features. Potential targets were explored by network pharmacology, protein-protein interaction, and verified by western blot. Finally, HCC patient-derived organoids were generated to evaluate the clinical applicability of DTELNs. DTELNs exhibited typical exosomal features, major components including flavonoids, phenolic acids, lipids, amino acids and their derivatives, and miRNAs. DTELNs markedly suppressed tumor proliferation, modulated gut microbial diversity, normalized liver-gut axis physiological homeostasis and enhanced immune responses. DTELNs distinctly downregulated the expressions of p-Akt, NF-\u03baB, Bcl-2, cyclin D1, upregulated the expressions of p-p53, PTEN, Bax, cleaved-caspase 3 and p21. DTELNs also exhibited potent inhibitory effect on HCC organoids. DTELNs demonstrated potent therapeutic efficacy against HCC. The mechanisms mainly involved directly modulating Akt-related signalling pathways, rebalancing gut microbiota and related metabolites, and further boosting anti-tumor immune responses.\n\nID: 42404789\nTitle: Gut microbiota-mediated cardiovascular effects of Gastrodia elata polysaccharides: resolving the bioavailability-efficacy paradox.\nAbstract: Growing evidence suggests that many plant-derived polysaccharides exert systemic effects through gut microbiota-mediated mechanisms rather than direct absorption. Gastrodia elata polysaccharides (GEPs) represent a promising but mechanistically complex class of bioactive compounds with potential cardiovascular relevance. This review aims to examine the role of gut microbiota in mediating the biological effects of GEPs, with particular focus on resolving the bioavailability-efficacy paradox through host-microbe interactions. A narrative synthesis of recent literature was conducted, integrating data on microbiota-polysaccharide interactions, microbial fermentation processes, metabolite production, and downstream host signaling pathways. Due to limited systemic bioavailability, GEPs undergo extensive fermentation by gut microbiota, generating bioactive metabolites such as short-chain fatty acids and secondary bile acids. These metabolites modulate key host pathways including inflammation, oxidative stress, endothelial function, and lipid metabolism. Emerging evidence highlights the central role of the gut-heart axis in mediating these effects. The biological activity of GEPs is best understood within a microbiota-centered framework. This perspective provides new insights into polysaccharide pharmacology and supports the development of microbiome-targeted therapeutic strategies.\n\nID: 42275884\nTitle: The neutral and acidic polysaccharides from Ginseng are metabolized by specific gut microbial taxa and confer immunomodulatory effects.\nAbstract: Ginseng (Panax ginseng C. A. Mey.) exerts immunomodulatory effects partly mediated by its polysaccharides and interactions with gut microbiota. However, due to the structural complexity of ginseng polysaccharides, knowledge of their oral fate and direct microbiota interactions remains limited. This study aims to elucidate the oral fate of neutral and acidic polysaccharides in ginseng, analyze core gut microbiota genera and their immunomodulatory effects mechanisms. Structural analysis was conducted on neutral and acidic polysaccharides from ginseng. Thereafter, in vitro digestion and fermentation were performed, with metagenomic and metatranscriptomic profiling. The results were validated in conventional and pseudo\u2011germ-free immunosuppressed mouse models, and the immunomodulatory mechanisms of the core gut microbiota were investigated. The in vivo and in vitro findings indicated that neutral and acidic polysaccharides exhibit different digestive properties and gut microbiota degradation patterns, differ in short-chain fatty acid production tendencies, bind to GPR-41/43 receptors, upregulate MAPK-p38 phosphorylation, and promote proliferation of intestinal immune cells. This work systematically elucidated the digestive characteristics of ginseng polysaccharides and laid the groundwork for future studies on the specificity and structure-function relationships of plant-derived polysaccharides.\n\nID: 42249843\nTitle: Atractylodes lancea Polysaccharides Protect against Staphylococcus aureus-Induced Lung Injury by Remodeling Gut Microbiota and Restoring Tryptophan Metabolism.\nAbstract: Gut microbiota and their metabolites may shape pulmonary immune responses and infection progression. Plant-derived polysaccharides, such as Atractylodes lancea polysaccharides, have shown prebiotic activity, yet their protective mechanisms in pneumonia remain unclear. Here, A. lancea polysaccharides (ALPs), a water-soluble acidic fraction mainly composed of arabinose, galacturonic acid, glucose, and galactose with a predominant molecular weight of 3.52 kDa, were evaluated in a murine model of Staphylococcus aureus-induced lung injury. Oral pretreatment with ALP (100 or 400 mg/kg) alleviated lung injury, improved intestinal barrier integrity, reshaped the gut microbiota by enriching Limosilactobacillus, restored tryptophan-related metabolites, increased AhR expression in the lung and colon, and reduced inflammatory responses. Broad-spectrum antibiotic treatment markedly blunted the effects. Collectively, ALP protected against S. aureus-induced lung injury in association with gut microbiota remodeling, improved barrier integrity, and restored tryptophan metabolism along the gut-lung axis.\n\nID: 42173606\nTitle: Structural characterization of acetylated mannan from Typha angustifolia pollen and the impact of acetylation on its growth-promoting effect toward Lactobacillus johnsonii.\nAbstract: Acetylated mannan (PTPS-W-2) was isolated from Typha angustifolia Pollen through hot-water extraction followed by ion-exchange and size-exclusion chromatography. Structural characterization indicated that PTPS-W-2 is a homogeneous polysaccharide with an average molecular weight of approximately 42\u00a0kDa, composed exclusively of mannose residues. The backbone consists predominantly of \u21924-\u03b2-Manp-(1\u21924)-\u03b2-Manp-(1\u2192 linkages, with partial O-acetyl substitution at the C-2 and C-3 positions. Notably, this represents the first report of isolating a plant-derived acetylated mannan with a high degree of purity and structural homogeneity. In vivo administration for two weeks demonstrated that PTPS-W-2 selectively modulated the gut microbiota community by significantly enriching Lactobacillus johnsonii and enhancing intestinal phenyllactic acid production, which was further confirmed using an in vitro monoculture fermentation model. Notably, deacetylated PTPS-W-2 exhibited a markedly weaker growth-promoting effect on L. johnsonii. Comparative physicochemical analyses further showed that deacetylation markedly reduced the aqueous solubility of the mannan. These findings suggest that acetylation-associated structural and physicochemical features, particularly those related to hydration and substrate accessibility, may contribute to the microbial responsiveness of PTPS-W-2. Overall, this study highlights the potential importance of acetylation-associated structural features in shaping the physicochemical properties and microbiota-modulating behavior of plant-derived mannans, providing new insights into their structure-property-function relationships.\n\nID: 42163964\nTitle: Branched-chain amino acids from plants and the metabolic syndrome: pathways and pharmacological applications.\nAbstract: Metabolic syndrome (MetS) affects approximately 1.54\u202fbillion adults worldwide and is characterized by central obesity, insulin resistance, hypertension, and dyslipidemia. Chronic low-grade inflammation is central to the development of MetS. A global shift toward a plant-based diet has prompted a reevaluation of the differing impacts of protein sources on metabolic health. The purpose of this review is to provide a systematic overview of how BCAAs from plant sources may modulate chronic inflammatory processes and improve individual components of MetS by analyzing their sources, bioavailability (including both digestibility and absorptive efficiency), metabolism, and modes of action compared to animal-based BCAAs. Dietary plant-derived BCAAs are abundant and have acceptable bioaccessibility. Legumes, whole grains, and microalgae contain significant levels of BCAAs. Processing technologies such as fermentation, heat treatment, and extrusion enhance BCAA content in food products. Germination and enzymatic hydrolysis can significantly improve digestibility. Preclinical evidence from cell-based and rodent studies indicates that plant-derived BCAAs exert multi-target regulation of chronic inflammation, including modulation of mTORC1 signaling, suppression of the NF-\u03baB pathway, potential regulation of the NLRP3 inflammasome, and beneficial interactions with gut microbiota. Their comparatively slower absorption kinetics relative to animal-derived BCAAs offer a mechanistic rationale for avoiding chronic mTORC1 hyperactivation, although direct human evidence confirming these specific mechanistic pathways remains limited and requires further clinical validation. Large prospective cohort studies suggest that substituting animal proteins with plant sources is associated with an approximately 8-12% lower risk of all-cause and cardiovascular mortality, although the certainty of this evidence is limited by residual confounding inherent in observational designs. RCT evidence (moderate certainty by GRADE) demonstrates improved glycemic control, lipid profiles, and body composition with plant-based dietary patterns, particularly in individuals with type 2 diabetes or metabolic syndrome. The \"BCAA paradox\" can be explained by the differing kinetics of absorption, matrix effects, and gut microbiota interactions between plant and animal sources. Plant-based BCAAs hold great potential for the prevention and treatment of MetS, owing to their low saturated fat content, abundant dietary fiber, polyphenolic antioxidant capacity, and beneficial effects on gut microbiota. Future studies should focus on precision nutrition, long-term clinical trials, and optimal dosing regimens. Translating mechanistic knowledge into dietary recommendations is essential for managing MetS.\n\nID: 42061087\nTitle: Apple derived extracellular vesicles as positive modulators of glial inflammation and gut-brain axis signaling.\nAbstract: Plant-derived extracellular vesicles (PDEVs) are emerging as bioactive dietary particles with the capacity to modulate mammalian physiology. Here, we characterize the structure and functional properties of apple-derived extracellular vesicles (ADEVs) and evaluate their relevance to neuroimmune and gut-brain communication. ADEVs exhibit canonical PDEV features and elicit rapid IP\u2083-dependent Calcium (Ca\u00b2\u207a) signaling in fibroblasts while preserving blood-brain barrier integrity. Neural assays reveal marked cell-type specificity: ADEVs are efficiently internalized by glial cells and activate glial Ca\u00b2\u207a signaling yet display minimal neuronal uptake and no detectable Ca\u00b2\u207a response in differentiated SH-SY5Y neurons. Consistent with this selectivity, ADEVs attenuate TNF-\u03b1-induced cytokine secretion in activated glia but remain inert in resting neural cells. Although capable of encapsulating L-DOPA efficiently, ADEVs fail to deliver functional neuroprotection against rotenone toxicity, indicating limited neuronal compatibility for dopaminergic cargo. In parallel, using advanced in vitro colon simulation platforms, ADEVs modulate the colonic microbiome in a dose-dependent manner, promoting carbohydrate fermentation and short-chain fatty acid production while reducing proteolytic metabolism under physiologically relevant conditions, with sustained, region-specific effects during prolonged exposure. In vivo, ADEV administration in dogs with chronic intestinal inflammation is associated with altered circulating serotonin levels, suggesting engagement of gut-brain neurochemical pathways with potential implications for mood regulation. Collectively, these findings identify ADEVs as biocompatible, glia-responsive plant vesicles with potential neuromodulatory activity, while delineating intrinsic constraints in their use as neuronal drug-delivery systems.\n\nID: 42002330\nTitle: A fructan-type polysaccharide from Lycium ruthenicum attenuates liver fibrosis via microbiota-dependent ferroptosis inhibition.\nAbstract: Plant-derived polysaccharides represent promising candidates for hepatic fibrosis (HF) therapy through the gut-liver axis. This study investigated the structural characteristics, anti-fibrotic efficacy, and mechanisms of LRMP1, a novel polysaccharide from Lycium ruthenicum Murr. LRMP1 was identified as a homogeneous inulin-type fructan (3.055\u00a0kDa) with a\u00a0\u2192\u00a01)-\u03b2-D-Fruf-(2\u00a0\u2192\u00a0backbone terminated by \u03b1-D-Glcp-(1\u00a0\u2192\u00a02)-\u03b2-D-Fruf linkages (DP 4-20). Integrated multi-omics analysis combining hepatic transcriptomics, serum metabolomics, and gut microbiome profiling revealed that LRMP1 ameliorates HF via a gut microbiota-postbiotics-ferroptosis regulatory axis. In both CCl4-induced and MCD diet-induced chronic fibrosis models, LRMP1 significantly attenuated liver injury, fibrosis, inflammation, and oxidative stress, while restoring intestinal barrier integrity. These protective effects correlated with enrichment of beneficial bacteria (Akkermansia muciniphila, Lactobacillus spp.) and pathogen depletion. Mechanistically, LRMP1 suppressed TGF-\u03b2 signaling and inhibited hepatocyte ferroptosis by restoring the GPX4/SLC7A11 antioxidant system and reducing lipid peroxidation. Serum metabolomics further revealed elevated anti-ferroptotic metabolites and suppressed pro-inflammatory lipids. Crucially, antibiotic depletion abolished LRMP1's efficacy, whereas fecal microbiota transplantation and fermentation supernatant experiments confirmed that microbiota-derived postbiotics selectively protect hepatocytes from ferroptosis. These findings establish LRMP1 as a promising microbiota-targeted polysaccharide for HF intervention through the gut-liver axis.\n\nID: 41949542\nTitle: Prebiotics characterization from traditional legumes and fruits sources and their synergistic effects on probiotic growth and short-chain fatty acid (SCFA) production.\nAbstract: BackgroundPrebiotics are nondigestible compounds that support gut health by promoting beneficial microbes. Mung beans, horse gram, figs (Ficus carica), and umbar (Ficus racemosa) are fiber-rich traditional foods with unexplored prebiotic potential. Studying them may aid in developing affordable functional foods.AimTo evaluate the prebiotic potential of four culturally significant plant-based foods-mung beans, horse gram, figs, and umbar.MethodologyTotal dietary fiber was quantified using the AOAC 991.43 enzymatic-gravimetric method. Oligosaccharides were extracted with 80% ethanol and characterized by Fourier-transform infrared spectroscopy. Insoluble dietary fiber (IDF) was used for batch culture growth experiments, whereas the extracted oligosaccharides were evaluated separately for gastric stability, fermentation, and short-chain fatty acid production. Gastric stability was assessed under simulated gastric conditions (pH 1-5, 6\u2005h). Lactobacillus acidophilus survival under acidic stress (pH 2.0, 48\u2005h), bacterial growth with oligosaccharide supplementation, and anaerobic fermentation (basal mineral medium, 48\u2005h) were evaluated. Short-chain fatty acids were analyzed using high-performance liquid chromatography.ResultsFigs contained the highest total dietary fiber (26.98\u2005g/100\u2005g) and oligosaccharide content (47.5\u2005g/100\u2005g), followed by umbar, horse gram, and mung beans. Fourier-transform infrared spectroscopy confirmed inulin-type fructans. Oligomers showed partial gastric hydrolysis, with maximal degradation at pH 1.0 (66.1% mung bean, 36.7% horse gram, 44.1% fig, 58% umbar). L. acidophilus survived acidic stress and efficiently utilized plant-derived substrates, achieving 3.54\u2009\u00d7\u2009107 cells/mL (horse gram, 48\u2005h). Fermentation sustained 2.3-2.6\u2009\u00d7\u2009107 cells/mL with moderate pH drops. Short-chain fatty acid analysis revealed lactic, propionic, and butyric acids (fig); acetic, formic, and 4-methylvaleric acids (horse gram, umbar); and lactic and propionic acids (mung bean).ConclusionThese legumes and fruits demonstrate promising prebiotic potential. Although fig contained the highest levels of dietary fiber and oligosaccharides, horse gram IDF supported the greatest proliferation of L. acidophilus, indicating that both substrate composition and microbial utilization efficiency contribute to prebiotic effectiveness. These findings support the use of these foods in functional and synbiotic products to enhance gut health.\n\nID: 41900300\nTitle: Interactions Between Plant Proteins and Gut Microbiota as Determinants of Intestinal Health.\nAbstract: Plant proteins are an important component of the human diet and play a key role in shaping the composition and activity of the intestinal microbiota. Increasing evidence shows that interactions between plant-derived protein fractions and intestinal microorganisms have a significant impact on intestinal barrier function, immune response, and host metabolism. Undigested residues of proteins and peptides may constitute a substrate for intestinal bacteria, leading to the formation of metabolites with beneficial or harmful effects. On the one hand, fermentation products can support intestinal homeostasis through the synthesis of short-chain fatty acids or modulation of inflammatory responses; on the other hand, some compounds resulting from bacterial proteolysis may disturb the integrity of the intestinal epithelium. This article presents the current state of knowledge regarding the characteristics of plant-based proteins, their impact on the intestinal microbiota, and the importance of these interactions for intestinal health.\n\nID: 41829938\nTitle: Supplementation with Animal- and Plant-Derived Proteins Modulates the Structure and Predicted Metabolic Potential of the Gut Microbiota in Elite Football Players.\nAbstract: The primary outcome of this 8-week randomized, controlled, parallel trial was to assess longitudinal shifts in gut microbiota structure and predicted metabolic potential in 45 elite football players following protein supplementation. Participants combined resistance training with daily intake (30 g) of whey protein concentrate (WPC), pea protein isolate (PPI), rice protein isolate (RPI), or a plant-protein blend (MIX). For the acquisition of prokaryotic metataxonomic data, the V3-V8 region of the 16S rRNA gene was sequenced using Oxford Nanopore Technology (ONT). Functional potential was inferred through the MACADAM database and STAMP software. Strict dietary monitoring and gravimetric adherence checks were performed to isolate the intervention effect. While microbial alpha-diversity indices (Chao1, Shannon, Simpson) remained stable across all groups, significant source-specific shifts in taxonomic structure and predicted metabolic activity were identified. Whey protein concentrate (WPC) was associated with an increase in Bacteroidetes abundance and greater balance within the microbial community structure, whereas pea protein isolate (PPI) and the MIX correlated with reduced fermentative bacteria and elevated taxa potentially involved in cadaverine biosynthesis. Rice protein isolate (RPI) supplementation was associated with a higher predicted representation of taxa involved in succinate-to-butyrate fermentation pathways. These functional markers and differential responses of selected bacterial groups to particular protein types were observed. The data indicate complex interactions between supplement type, exposure duration, and microbiome response, underscoring the necessity for individualized dietary recommendations and supplementation strategies to optimize gut health and training adaptation in professional football players.\n\nID: 41693952\nTitle: Polyphenol metabolites in fermented foods: biotransformation, bioavailability, and functional roles.\nAbstract: Polyphenols, plant-derived bioactive compounds, are known for their antioxidant, anti-inflammatory, and antimicrobial properties, benefiting plant-based foods. Fermentation, driven by microbial enzymes like glycosidases, esterases, and decarboxylases, alters the chemical structure of polyphenols, enhancing their bioavailability and bioactivity. This review explores the transformation of polyphenols, particularly flavonoids and phenolic acids, during fermentation, resulting in bioactive metabolites with increased solubility, stability, and antioxidant activity, improving gastrointestinal absorption. Additionally, fermented polyphenol metabolites modulate gut microbiota by promoting beneficial bacteria such as Lactobacillus and Bifidobacterium, while inhibiting pathogens. These changes support gut health, reduce inflammation, and provide systemic benefits, including enhanced metabolic, immune, and neurocognitive functions. Despite progress, knowledge gaps remain, particularly regarding microbial pathways and the health outcomes linked to these metabolites. Future research should focus on mapping microbial biotransformation pathways of polyphenols and their impact on health outcomes. Additionally, well-controlled human intervention studies using multi-omics approaches are necessary to validate the systemic benefits of fermented polyphenol metabolites.\n\nID: 41692748\nTitle: A facile polysaccharide hydrogel activates PPAR\u03b3 via the Gut-Kidney axis to ameliorate chronic kidney disease.\nAbstract: Chronic Kidney Disease (CKD) features gut microbiota dysbiosis, systemic inflammation, and impaired barrier function. The formation of such a triad of \"microbiota-metabolite-barrier\" dysregulation underscores the therapeutic potential of a Gut-Kidney Axis intervention strategy. Traditional Chinese medicine highlights plant-derived polysaccharides as renoprotective modulators of the Gut-Kidney Axis, yet free polysaccharides suffer from limited colonic exposure, single-function delivery, and proximal-skewed fermentation. Thus, this study engineered a Morinda officinalis polysaccharide (MOPs)/Inulin composite hydrogel (MI Gel) via a simple, green hydrothermal process to achieve colon-targeted, sustained release with mucosal adhesion for CKD therapy via the Gut-Kidney Axis. This hydrogel exhibited degradation resistance and prolonged retention in the intestinal tract of CKD model mice, while effectively reshaping the gut microbiota community structure by increasing the abundance of Muribaculaceae and Allobaculum, elevating serum propionate and butyrate levels, and activating GPCRs and PPAR\u03b3 signaling pathways. As a result, the gel treatment reduced the levels of intestinal inflammatory cytokines (TNF-\u03b1, IL-6, and IL-1\u03b2) and reactive oxygen species (ROS). MI Gel further improved glomerular function and attenuated renal fibrosis compared to free polysaccharides. This colon-targeted, acid-resistant platform utilizes synergistic fermentation of MOPs and Inulin to restore Gut-Kidney Axis homeostasis, providing a viable long-term approach for CKD management.\n\nID: 41517203\nTitle: Comparative Study on the In Vitro Fermentation Characteristics of Three Plant-Derived Polysaccharides with Different Structural Compositions.\nAbstract: This study aimed to elucidate the structure-activity relationship between the structural characteristics of three plant-derived polysaccharides, Lycium barbarum polysaccharide (LBP), citrus pectin (CP) and peach gum polysaccharide (PGP), and their prebiotic functionalities. Structural analysis indicated that LBP exhibited a medium molecular weight and was rich in galactose and rhamnose, which contributed to its high uronic acid content, strong antioxidant activity, and sustained fermentation profile with enhanced butyrate production. In contrast, CP, with its low molecular weight and neutral linear glucan backbone, was rapidly utilized by gut microbiota, leading to accelerated propionate accumulation. Meanwhile, PGP, characterized by an ultra-high molecular weight and a highly branched arabinogalactan configuration, acted as a specific substrate that promoted mid- to late-stage fermentation and significantly increased butyrate yield, highlighting its prebiotic property driven by structural complexity. The functional differences among these polysaccharides were determined by their monosaccharide composition, molecular weight distribution, and chain conformation. These findings provide a scientific basis for the targeted development of plant-derived prebiotics aimed at specific metabolic functions.\n\nID: 41302050\nTitle: In Vitro Investigation of Equine Gut Microbiota Alterations During Hypoglycin A Exposure.\nAbstract: Hypoglycin A is a plant-derived protoxin that causes atypical myopathy in equids. In atypical myopathy-affected horses, metabolomic and microbiome studies have reported alterations in metabolic markers and faecal microbiota composition, pointing to a potential disruption of microbial homeostasis. However, in vivo observations are strongly confounded by host-related factors, underscoring the need for controlled in vitro approaches. To address this, we used an in vitro static batch fermentation model simulating the equine colon to investigate the direct effects of hypoglycin A on microbiota composition and activity. Faecal inocula from healthy horses were incubated in control and hypoglycin A-treated fermenters for 48 h, with serial analyses of hypoglycin A concentration, short-chain fatty acids, and 16S rRNA gene profiles. Hypoglycin A remained stable in the nutritive medium in the absence of microbiota, confirming that its degradation in inoculated fermenters was microbiota-dependent. The results showed significant microbial-associated hypoglycin A degradation without evidence of toxic metabolite formation. The analysis of \u03b1- and \u03b2-diversity revealed both an effect of incubation time, reflecting the natural temporal dynamics of microbial communities under batch fermentation, and a specific impact of hypoglycin A exposure, with certain taxa such as Paraclostridium being affected. This study provides the first in vitro evidence that the equine microbiota contributes to hypoglycin A degradation.\n\nID: 40941204\nTitle: Application of Probiotics in Foods: A Comprehensive Review of Benefits, Challenges, and Future Perspectives.\nAbstract: The incorporation of probiotics into food products has gained substantial attention, primarily due to their well-documented health benefits such as modulating gut microbiota, enhancing immune responses, and providing potential therapeutic effects. This comprehensive review discusses recent advancements in the application of probiotics in the food industry, focusing on diverse food matrices, technological and regulatory challenges, and consumer acceptance. Particular emphasis is placed on fermentation-based approaches that enhance both sensory and nutritional attributes, while acting as effective delivery systems for viable probiotics. The impact of matrices such as dairy, meat, cereals, plant-based beverages (e.g., soy or almond milk), and solid plant-derived foods (e.g., fermented vegetables) on probiotic survival, sensory properties, and product acceptability is critically examined. Understanding these interactions is crucial for the development of stable, efficacious, and consumer-oriented probiotic-enriched functional foods.\n\nID: 40941070\nTitle: In Vitro Digestion and Fecal Fermentation of Arecanut Polysaccharides: Effects on Gut Microbiota and Metabolites.\nAbstract: Recent studies have increasingly emphasized the regulatory potential of plant-derived polysaccharides on gut microbial composition and metabolic function. Despite this growing interest, investigations focusing specifically on the simulated digestion and fermentation properties of arecanut polysaccharide (PAP1b) remain limited. In this work, we employed the standardized INFOGEST 2.0 protocol to mimic the oral, gastric, and intestinal digestion of PAP1b, followed by 48 h anaerobic fermentation using pooled human fecal samples from healthy adult donors. PAP1b treatment led to a progressive decrease in pH and a substantial elevation in SCFAs levels, notably acetic, propionic, and butyric acids. Simultaneously, PAP1b significantly promoted the growth of SCFA-producing microbial taxa, particularly members of the Firmicutes phylum such as Lachnospiraceae, Lachnoclostridium, Bilophila, and Phascolarctobacterium, while markedly suppressing Bacteroidota populations. Metabolomic analysis further indicated that PAP1b intake enhanced bile acid metabolism, suggesting its potential as a prebiotic candidate for improving intestinal health.\n\nID: 40218908\nTitle: Atractylodes Japonica Rhizome Extract Fermented with a Plant-Derived Lacticaseibacillus paracasei (Lactobacillus paracasei) IJH-SONE68 Improves the Wheat Gliadin-Induced Food Allergic Reaction in Mice.\nAbstract: Background/Objectives: Medicinal herbs produce valuable substances with therapeutic potential. The chemical structures of those substances are often converted by gut microbiota. Our previous studies showed that several kinds of bioactive molecules are newly generated in fermented medicinal herbal extract with plant-derived lactic acid bacteria (LABs). Methods: The fermented extract of Atractylodes Japonica Rhizoma (AJR), which is designated as \"Byakujutsu\" in Japan, with a plant-derived LAB strain IJH-SONE68 was prepared and whether the fermented extract could help reduce symptoms of food allergies, especially wheat intolerance, was confirmed using animal model. Results: It has been found that the fermented extract significantly ameliorates the anaphylaxis score (from 3.0 to 1.0, p = 0.003) of gliadin-induced allergic model mice (specific-pathogen-free, BALB/cJ) accompanied with the modulation of serum total immunoglobulin E (IgE) (from 778 to 518 ng/mL, p = 0.006), interferon (IFN)-\u03b3 (from 6.6 to 9.5 pg/mL, p < 0.001), and interleukin (IL)-4 (from 32.0 to 9.1 pg/mL, p < 0.001) levels. Conclusions: The fermented AJR extract may modulate the Th1/Th2 cell balance to alleviate the symptoms of gliadin-induced anaphylaxis in mice. The present study supports the view that the fermentation of medicinal herbal extract prepared using LABs may be a useful procedure for producing therapeutic potential compounds to maintain health.\n\nID: 39829562\nTitle: Synthetic \u03b2-d-Glucuronides: Substrates for Exploring Glucuronide Degradation by Human Gut Bacteria.\nAbstract: The human gut microbiota (HGM) is a complex ecosystem subtly dependent on the interplay between hundreds of bacterial species and numerous metabolites. Dietary phenols, whether ingested (e.g., plant-derived guaiacol, mequinol, or resveratrol) or products of bacterial fermentation (e.g., p-cresol), have been attributed with influencing bacterial growth and host health. They are cleared by phase II metabolism, one form utilizing \u03b2-d-glucuronidation, but encounter bacterially derived glucuronidases capable of hydrolyzing them to release their phenolic and glucuronic acid moieties with potential effects on host cells or the surrounding bacterial population. Tools to enable the detailed study of their activity are currently lacking. Syntheses of \u03b2-d-glucuronides from methyl 1,2,3,4 tetra-acetyl \u03b2-d-glucopyranosyluronate by direct glycosylation with 2-, 3-, or 4-methoxy- and 4-fluorophenol acceptors employing trimethylsilyl triflate catalysis are reported. Yields (methoxy series) were modest. An improved route from methyl 1,2,3,4-tetra-acetyl \u03b2-d-glucopyranosyluronate via selective anomeric deprotection (N-methyl piperazine) and conversion to an \u03b1-trichloroacetimidate glycosyl donor was employed. Coupling with 2- and 3-methoxyphenol acceptors and deprotection provided 2- and 3-methoxyphenyl \u03b2-d-glucuronides in 2-fold improved overall yield. These naturally occurring methoxyphenyl glucuronides augment available model substrates of dietary glucuronides, which include 3- and 4'-linked resveratrol. The use of model glucuronides as substrates was illustrated in studies of \u03b2-d-glucuronidase activity employing cell lysates of 9 species of HGM (Bacteroidetes), revealing distinct outcomes. Contrasting effects on bacterial growth were also observed between the free phenolic components, their respective glucuronides, and glucuronic acid. The glucuronide of 4-fluorophenol provided sensitive and background-free detection of \u03b2-glucuronidase activity using 19F NMR.\n\nID: 39748438\nTitle: Relationship between dietary fiber physicochemical properties and feedstuff fermentation characteristics and their effects on nutrient utilization, energy metabolism, and gut microbiota in growing pigs.\nAbstract: There is a growing focus on using various plant-derived agricultural by-products to increase the benefits of pig farming, but these feedstuffs are fibrous in nature. This study investigated the relationship between dietary fiber physicochemical properties and feedstuff fermentation characteristics and their effects on nutrient utilization, energy metabolism, and gut microbiota in growing pigs. Thirty-six growing barrows (47.2\u2009\u00b1\u20091.5\u00a0kg) were randomly allotted to 6 dietary treatments with 2 apparent viscosity levels and 3 \u03b2-glucan-to-arabinoxylan ratios. In the experiment, nutrient utilization, energy metabolism, fecal microbial community, and production and absorption of short-chain fatty acid (SCFA) of pigs were investigated. In vitro digestion and fermentation models were used to compare the fermentation characteristics of feedstuffs and ileal digesta in the pig's hindgut. The production dynamics of SCFA and dry matter corrected gas production of different feedstuffs during in vitro fermentation were different and closely related to the physical properties and chemical structure of the fiber. In animal experiments, increasing the dietary apparent viscosity and the \u03b2-glucan-to-arabinoxylan ratios both increased the apparent ileal digestibility (AID), apparent total tract digestibility (ATTD), and hindgut digestibility of fiber components while decreasing the AID and ATTD of dry matter and organic matter (P\u2009<\u20090.05). In addition, increasing dietary apparent viscosity and \u03b2-glucan-to-arabinoxylan ratios both increased gas exchange, heat production, and protein oxidation, and decreased energy deposition (P\u2009<\u20090.05). The dietary apparent viscosity and \u03b2-glucan-to-arabinoxylan ratios had linear interaction effects on the digestible energy, metabolizable energy, retained energy (RE), and net energy (NE) of the diets (P\u2009<\u20090.05). At the same time, the increase of dietary apparent viscosity and \u03b2-glucan-to-arabinoxylan ratios both increased SCFA production and absorption (P\u2009<\u20090.05). Increasing the dietary apparent viscosity and \u03b2-glucan-to-arabinoxylan ratios increased the diversity and abundance of bacteria (P\u2009<\u20090.05) and the relative abundance of beneficial bacteria. Furthermore, increasing the dietary \u03b2-glucan-to-arabinoxylan ratios led to a linear increase in SCFA production during the in vitro fermentation of ileal digesta (P\u2009<\u20090.001). Finally, the prediction equations for RE and NE were established. Dietary fiber physicochemical properties alter dietary fermentation patterns and regulate nutrient utilization, energy metabolism, and pig gut microbiota composition and metabolites.\n\nID: 39709319\nTitle: Exploring the Prebiotic Potential of Fermented Astragalus Polysaccharides on Gut Microbiota Regulation In Vitro.\nAbstract: Astragalus polysaccharides (APS) are known for their prebiotic properties, and fermentation by probiotics is a promising strategy to enhance the prebiotic activity of polysaccharides. In this study, Lactobacillus rhamnosus was used to ferment APS, and response surface methodology was applied to optimize the fermentation parameters. The optimal conditions were determined as follows: 10.28% APS addition, 5.83% inoculum, 35.6\u00a0h of fermentation time, and a temperature of 34.6\u00a0\u00b0C. Additionally, the effects of Fermented Astragalus polysaccharides (FAPS) on human gut microbiota were investigated through in vitro anaerobic incubation. Fecal samples were obtained from 6 healthy volunteers, which were then individually incubated with FAPS. Results demonstrated that FAPS significantly regulated microbial composition and diversity, increasing the abundance of beneficial gut bacteria such as Lactobacillus, E. faecalis, and Brautobacterium, while inhibiting harmful species such as Shigella, Romboutsia, and Clostridium_sensu_stricto_1. Furthermore, FAPS enhanced the production of short-chain fatty acids (SCFAs), which are increasingly recognized to play a role in intestinal homeostasis. These findings suggested that FAPS offers several advantages in terms of increasing beneficial metabolites and regulating gut microbial composition. This study provides valuable insights for expanding the use of plant-derived polysaccharides in the food industry and for developing functional dietary supplements.\n\nID: 39362323\nTitle: Phytochemical constituents from root barks of Eleutherococcus henryi Oliv. and their anti-neuroinflammatory effect.\nAbstract: The cortex of Eleutherococcus henryi (EH, Araliaceae), also known as \"Wu-Jia-Pi\", is known for its effects such as dispelling wind and dampness, calming the mind and enhancing intelligence, removing heat and toxin, strengthening muscles and bones, and nourishing the liver and kidneys. Throughout Chinese history and tradition, it has been used for conditions like amnesia, mental fatigue, arthritis, hepatitis, and rheumatism. However, research evaluating its neuroprotective effects and pharmacological properties remains scarce. The goal is to explore the anti-neuroinflammatory properties of EH in vitro and to discover precisely the bioactive natural products within the medicinal plant that are relevant to its traditional usage. Utilizing chromatographic techniques, a phytochemical exploration was conducted. The phytochemical structures of the natural products were then elucidated through an analysis involving comprehensive spectra and a comparison with relevant data from published studies. Network pharmacology combined with molecular dynamics simulations (MDs) and docking were applied to forecast potential anti-neuroinflammatory targets of active compounds. In vitro, the anti-neuroinflammatory efficacy was evaluated via the suppression of inflammatory mediators activated by lipopolysaccharide (LPS) in BV2 microglia. The methanol extract of E.henryi (EHME) restrained the NO release in LPS-activated BV2 microglia, demonstrating anti-neuroinflammatory activity. Subsequently, chemical composition analysis revealed the separation and elucidation of 31 secondary metabolites, comprising 7 new compounds (1-7) and 1 new natural product (8). Based on LPS-induced BV2 cell in vitro activity tests, compounds 4-17, 19, 20, 22, 23, 26, 29 and 31 were found to exhibit potential anti-neuroinflammatory activity, with compound 6 showing the highest efficacy. Furthermore, employing network pharmacology in conjunction with both molecular docking and MDs, potential anti-neuroinflammatory targets of compound 6 were predicted to include TLR4, Src, MAPK, and NF-\u03baB. Finally, validation through in vitro experiments confirmed that the anti-neuroinflammatory mechanism of compound 6 is associated with the TLR4/Src/MAPK p38/NF-\u03baB p65 signaling pathways. The study affirmed the traditional efficacy of E. henryi and unveiled novel lignans as potent agents against neuroinflammation.\n\nID: 39270897\nTitle: Distinct prebiotic effects of polysaccharide fractions from Polygonatum kingianum on gut microbiota.\nAbstract: This study investigated the physicochemical properties, digestive stability, and in vitro fermentation behavior of Polygonatum kingianum polysaccharide (PKP) fractions (PKP60, PKP70, PKP80) obtained through graded ethanol precipitation. High-performance gel permeation chromatography revealed significant molecular weight differences among the fractions, while reverse-phase high-performance liquid chromatography indicated consistent monosaccharide types with variations in their proportions. Uronic acid analysis confirmed that all polysaccharide fractions met the criteria for neutral polysaccharides. Congo red staining confirmed the presence of a triple-helix structure in all PKP fractions. Comprehensive analysis demonstrated that these fractions remained stable during in vitro digestion, as evidenced by consistent molecular weights and total carbohydrate content, with no significant production of free monosaccharides or reducing sugars. All PKP fractions were fermented by gut microbiota, resulting in the production of short-chain fatty acids. Beta diversity and structural analyses of gut microbiota revealed distinct modulatory effects associated with each PKP fraction. The PKP fractions promoted probiotic growth, especially PKP70, which significantly enhanced Bifidobacterium proliferation, indicating strong prebiotic potential. These findings underscore the importance of isolation and purification methods in determining the functionality and gut microbiota-modulating effects of plant-derived polysaccharides, emphasizing the need for in-depth research that extends beyond merely evaluating their source.\n\nID: 39171480\nTitle: New findings in the metabolism of the saffron apocarotenoids, crocins and crocetin, by the human gut microbiota.\nAbstract: The main constituents of saffron are the apocarotenoids crocins and crocetin, present in the stigmas. Numerous healthy properties, especially those related to the effects on the central nervous system, have been attributed to these compounds but the metabolites responsible for these effects are still unknown. Previous evidences in animal models suggest a role for the gut microbiota in the pharmacokinetics and the neuroprotective effects of these compounds. However, the interaction between these apocarotenoids and the gut microbiota has been poorly studied. In this article, we have thoroughly investigated the batch fermentation of crocin-1 and crocetin (10 \u03bcM) with human fecal samples of two donors at different incubation times (0-240 h) using a metabolomic approach. We corroborated a rapid transformation of crocin-1 which looses the glucose molecules through de-glycosylation reactions until its complete transformation into crocetin in 6 hours. A group of intermediate crocins with different degrees of glycosylation were detected in a very short time. Crocetin was further metabolized and new microbial metabolites produced by double-bond reduction and demethylation reactions were identified for the first time: dihydro and tetrahydro crocetins and di-demethyl crocetin. In addition, we detected changes in the levels of the short chain fatty acids valeric acid and hexanoic acid suggesting further structural modifications of crocetin or changes in the catabolic production of these compounds. This research is a pioneering study of the action of the human gut microbiota on the saffron apocarotenoids and goes one step further towards the discovery of metabolites potentially involved in the benefits of saffron.\n\nID: 38887619\nTitle: Modulation of the gut microbiota by processed food and natural food: evidence from the Siniperca chuatsi microbiome.\nAbstract: Habitual dietary changes have the potential to induce alterations in the host's gut microbiota. Mandarin fish (Siniperca chuatsi), an aquatic vertebrate species with distinct feeding habits, were fed with natural feeds (NF) and artificial feeds (AF) to simulate the effects of natural and processed food consumption on host gut microbiota assemblages. The results showed that the alpha diversity index was reduced in the AF diet treatment, as lower abundance and diversity of the gut microbiota were observed, which could be attributed to the colonized microorganisms of the diet itself and the incorporation of plant-derived proteins or carbohydrates. The \u03b2-diversity analysis indicated that the two dietary treatments were associated with distinct bacterial communities. The AF diet had a significantly higher abundance of Bacteroidota and a lower abundance of Actinomycetota, Acidobacteriota, and Chloroflexota compared to the NF group. In addition, Bacteroidota was the biomarker in the gut of mandarin fish from the AF treatment, while Acidobacteriota was distinguished in the NF treatments. Additionally, the increased abundance of Bacteroidota in the AF diet group contributed to the improved fermentation and nutrient assimilation, as supported by the metabolic functional prediction and transcriptome verification. Overall, the present work used the mandarin fish as a vertebrate model to uncover the effects of habitual dietary changes on the evolution of the host microbiota, which may provide potential insights for the substitution of natural foods by processed foods in mammals.\n\nID: 37686739\nTitle: Fermented Stevia Improves Alcohol Poisoning Symptoms Associated with Changes in Mouse Gut Microbiota.\nAbstract: We previously found that the continuous feeding of ethanol caused mice dysbiosis, in which the cecal microbiota were significantly altered, as compared with those in the non-feeding control group, especially in some bacterial genera involved in gut inflammation. In the present study, we have found that the fermented extract of stevia (Stevia rebaudiana) leaves with plant-derived lactic acid bacteria (LABs), Pediococcus pentosaceus LY45, improves the trimethylamine (TMA) productivity of cecal content, which can be used as an indicator of dysbiosis. The following animal experiment also shows that the LY45-fermented stevia extract represses the typical increase in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, which decreased from 1106 to 210 IU/L (p < 0.05) and from 591 to 100 IU/L (p < 0.05), respectively, together with the simultaneously latent TMA productivity (from 1356 to 745 \u03bcM, p < 0.05) of cecal content in the ethanol-fed mice. The microbiota analyses have shown that the observed increased alterations in pro-inflammatory genera putative SMB53 (family Clostridiaceae) and Dorea are restored by the fermented stevia extract. Our result indicates that the preliminary bioconversion of herbal medicinal precursors by fermentation with safe microorganisms like LABs is expected to be a hopeful method of producing specific metabolites that may contribute to the reconstruction of gut microbiota.\n\nID: 37447306\nTitle: Nutraceuticals Prepared with Specific Strains of Probiotics for Supplementing Gut Microbiota in Hosts Allergic to Certain Foods or Their Additives.\nAbstract: Certain nutrients cause discomfort, sensitivity reaction, and an intolerance for certain foods or their ingredients when ingested by some consumers. Food reactions and gut inflammation-related problems are increasing worldwide. The primary form of management would be the avoidance of such foods, followed by treatment of their symptoms. Adopting a nutritional-therapeutic approach and establishing practices for the inclusion of functional foods and nutraceuticals in the diet could improve the ecology of gut microbiota and alleviate inflammation in the GIT. For this purpose, specific species of microorganisms characterized as probiotic strains have been studied to produce functional food and fermented beverage products. Commercially sold, such items are labelled as probiotic products, displaying the name/s of strain/s and the viable numbers of them contained in the portion size of the products. The importance of the growth of probiotic functional foods is that they can be consumed as a source of nutrition and their intake helps in the subsistence and recuperation of friendly gut bacteria. Probiotics have been reported for their role in ameliorating the risk of food reactions. Probiotic administration has been implemented for its role as an auxiliary improvement and for the prevention of food sensitivities common among pediatric patients. Probiotic products based on non-dairy substrates have potential as nutraceuticals for lactose intolerant consumers who are allergic to dairy milk products. Therefore, the aim of this article is to review GRAS microbial species characterized as probiotics up to the level of their specific strain's name and/or number. These have been used to produce nutraceuticals that are sources of beneficial bacteria for easing discomfort and allergic reactions by maintaining an inflammation-free gut.\n\nID: 33673705\nTitle: Evolution of the Gut Microbiota and Its Fermentation Characteristics of Ningxiang Pigs at the Young Stage.\nAbstract: The current study aimed to investigate the evolution of gut microbiota and its influencing factors for NXP in youth. The results showed that Shannon index increased from d 21 to d 28 whereas the ACE index increased from d 21 until d 60. Firmicutes, mainly Lactobacillus dominated on d 21. The Bacteroides and Spirochetes showed highest relative abundance on d 28. Fiber-degrading bacteria, mainly Prevotellaceae, Lachnospiraceae, Ruminococcaceae, Muribaculaceae, and Oscillospiraceae_UCG-002, dominated the microbial communities at d 28 and d 35. The microbial communities at d 60 and d 75 contained more Clostridium_sensu_stricto_1, Terrisporobacter and Oscillospiraceae_UCG-005 than other ages, which had significantly positive correlations with acetate and total SCFAs concentration. In conclusion, the evolution of gut microbiota was mainly adapted to the change of dietary factors during NXP growth. The response of fiber-degrading bacteria at different stages may help NXP better adapt to plant-derived feeds.\n\nID: 28728453\nTitle: Incomplete metabolism of phytoestrogens by gut microbiota from children under the age of three.\nAbstract: Phytoestrogens are plant-derived polyphenols with structural and functional similarities to mammalian oestrogens. The aim of this work was to study the metabolism of phytoestrogens by children's intestinal microbiota and to compare it with previous results in adults. Faecal samples of 24 healthy children were subjected to phytoestrogen fermentation assay. Only one child produced equol, while O-desmethylangolensin was found in all. Urolithin production was detected in 14 children and enterolactone in 10. Further comparison with the metabolism of phytoestrogens by adult intestinal microbiota reflected that glycitein, dihydrogenistein, urolithins D and E, enterolactone, secoisolariciresinol and arctigenin were the most important metabolites differentiating between adult and child microbial gut metabolism. Although the child intestinal microbiota showed the ability to metabolise isoflavones, ellagitannins and lignans to a certain extent, it generally showed a reduced metabolism of phytoestrogens, with a lack of 5-hydroxy equol and enterodiol, and less urolithins and enterolactone producers.\n\nID: 27517891\nTitle: Phytoestrogen Metabolism by Adult Human Gut Microbiota.\nAbstract: Phytoestrogens are plant-derived polyphenols with a structure similar to human estrogens. The three main groups of phytoestrogens, isoflavones, ellagitannins, and lignans, are transformed into equol, urolithins, and enterolignans, respectively, by bacteria. These metabolites have more estrogenic/antiestrogenic and antioxidant activities than their precursors, and they are more bioavailable. The aim of this study was to analyze the metabolism of isoflavones, lignans and ellagitannins by gut microbiota, and to study the possible correlation in the metabolism of these three groups of phytoestrogens. In vitro fermentation experiments were performed with feces samples from 14 healthy adult volunteers, and metabolite formation was measured by HPLC-PAD and HPLC-ESI/MS. Only the microbiota of one subject produced equol, while most of them showed production of O-desmethylangolensin (O-DMA). Significant inter-subject differences were observed in the metabolism of dihydrodaidzein and dihydrogenistein, while the glucoside isoflavones and their aglycones showed less variability, except for glycitin. Most subjects produced urolithins M-5 and E. Urolithin D was not detected, while uroltithin B was found in half of the individuals analyzed, and urolithins A and C were detected in two and four subjects, respectively. Enterolactone was found in all subjects, while enterodiol only appeared in five. Isoflavone metabolism could be correlated with the metabolism of lignans and ellagitannins. However, the metabolism of ellagitannins and lignans could not be correlated. This the first study where the metabolism of the three groups together of phytoestrogen, isoflavones, lignans, and ellagitannins by gut microbiota is analyzed.\n\nID: 23053695\nTitle: Barcoded pyrosequencing analysis of the microbial community in a simulator of the human gastrointestinal tract showed a colon region-specific microbiota modulation for two plant-derived polysaccharide blends.\nAbstract: The combination of a Simulator of the Human Intestinal Microbial Ecosystem with ad hoc molecular techniques (i.e. pyrosequencing, denaturing gradient gel electrophoresis and quantitative PCR) allowed an evaluation of the extent to which two plant polysaccharide supplements could modify a complex gut microbial community. The presence of Aloe vera gel powder and algae extract in product B as compared to the standard blend (product A) improved its fermentation along the entire simulated colon. The potential extended effect of product B in the simulated distal colon, as compared to product A, was confirmed by: (i) the separate clustering of the samples before and after the treatment in the phylogenetic-based dendrogram and OTU-based PCoA plot only for product B; (ii) a higher richness estimator (+33 vs. -36 % of product A); and (iii) a higher dynamic parameter (21 vs. 13 %). These data show that the combination of well designed in vitro simulators with barcoded pyrosequencing is a powerful tool for characterizing changes occurring in the gut microbiota following a treatment. However, for the quantification of low-abundance species-of interest because of their relationship to potential positive health effects (i.e. bifidobacteria or lactobacilli)-conventional molecular ecological approaches, such as PCR-DGGE and qPCR, still remain a very useful complementary tool.\n\nID: 42530981\nTitle: Dietary plant polysaccharides as modulators of brain aging: mechanistic links to inflammaging, the gut brain axis and amyloid tau pathology.\nAbstract: Objectives: This review critically evaluates chemically characterized plant-derived polysaccharides (PS) as dietary modulators of brain aging, focusing on their structural features, gut-brain mechanisms and effects on neuroinflammation, amyloid pathology and tau-related pathways.Methods: Molecular, in vitro, preclinical and early human studies were critically examined. Evidence was assessed in relation to PS molecular weight, branching, charge, monosaccharide composition, purity, fermentability, dosage and associated non-carbohydrate constituents. Particular attention was given to gut microbiota modulation, short-chain fatty acid (SCFA) production, barrier integrity, immune signaling, microglial activation and neurodegenerative biomarkers.Results: Fermentable plant PS altered gut microbial composition and increased acetate, propionate and butyrate production in experimental models. These SCFAs may influence brain aging through FFAR2/FFAR3 signaling and histone deacetylase inhibition, thereby improving intestinal barrier function, regulating peripheral inflammation and modifying microglial responses. Direct anti-amyloid effects were supported mainly by in vitro studies, whereas evidence for tau modulation remained indirect and predominantly preclinical. Animal studies provided the strongest causal support, particularly through microbiota-transfer, antibiotic-depletion and receptor-pathway experiments. Human evidence was limited to associative studies and small fiber or prebiotic trials. Reported PS molecular masses ranged from about 10 kDa to more than 1,000 kDa, with preclinical doses of 50-500 mg/kg and human intakes of 5-15 g/day.Discussion: Plant PS are promising dietary modulators of brain aging but not established neurotherapeutics. Translation requires standardized fractions, control of co-extracted phenolics and proteins, dose-response studies and biomarker-rich clinical trials incorporating stool and plasma SCFAs, inflammatory markers, neurofilament light, phosphorylated tau, cognitive outcomes and neuroimaging measures.\n\nID: 42003490\nTitle: Dietary (poly)phenols, the gut-brain axis, and menopause: a perspective on an overlooked biological crossroad.\nAbstract: Hormonal decline, chronic low-grade inflammation, metabolic alterations and polypharmacy shape the postmenopausal period. These factors remodel the gut microbiota and influence the production of microbial metabolites that modulate immune, endocrine, and neural communication. The gut-brain axis provides a framework for understanding how microbial activity affects cognition, mood, stress responses, neuroinflammation, and gastrointestinal function. Dietary (poly)phenols depend on gut microbial transformation to generate metabolites with distinct biological activity targeting mechanisms, such as intestinal and blood-brain barrier integrity, inflammatory signalling, redox balance, neurotransmitter synthesis, tryptophan metabolism, short-chain fatty acid production, and bile acid remodelling. These pathways are sensitive to hormonal decline, inflammaging, and polypharmacy, which modify microbial metabolism, host conjugation processes, enterohepatic cycling, and physiological response to dietary compounds. Despite this mechanistic basis, no human intervention study has examined these interactions in postmenopausal women. This perspective integrates three dimensions that are usually addressed separately: the physiological and pharmacological characteristics of postmenopause, the communication pathways of the gut-brain axis, and the gut microbial transformation of dietary (poly)phenols. We review human trials assessing (poly)phenols and gut-brain outcomes and highlight the scarcity of mechanistic endpoints, including microbial metabolites, barrier markers, neuroimmune mediators, and bile acid profiles. We also highlight how chronic medications reshape microbial composition and functionality, and how host targets of (poly)phenols, together with interindividual variability in polyphenol-related microbiota metabotypes, such as equol- and urolithin-producing metabotypes, influence biological responses and support personalised strategies. By identifying gaps and research priorities, this perspective provides a conceptual basis for developing precision health for postmenopausal women.\n\nID: 41300132\nTitle: Polyphenols Bioactive Metabolites, and Their Anti-Biofilm and Neuroprotective Potential.\nAbstract: Polyphenols are widely studied phytochemicals with well-known antioxidant and anti-inflammatory properties. They are commonly present in fruits, vegetables, and plant-based foods. Beyond these classical roles, growing evidence shows that polyphenol-derived bioactive metabolites-produced or modified by the gut microbiota-can promote host health. These metabolites are increasingly recognized for shaping host-microbe interactions and influencing neurophysiological functions via the gut-brain axis. This review provides an overview of polyphenol transformation rates by the gut microbiome, highlighting their microbial transformation, anti-biofilm effects, and neuroprotective potential. In our opinion, a deeper understanding of the properties of these metabolites can significantly impact food science and biotechnology.\n\nID: 41297620\nTitle: Fermented foods and brain health: Gut-brain axis mechanisms and clinical insights.\nAbstract: The gut-brain axis represents a complex bidirectional communication network connecting the central nervous and gastrointestinal systems. Fermented foods and their phenolic compounds, which increase their bioavailability due to microbial transformation in their contents, have the potential to affect the gut microbiota and therefore the gut-brain axis positively. Fermented foods such as kefir, yogurt, miso, natto, tempeh, kombucha, and their polyphenols have an effect on the gut microbiota and on the provision of neurological activities through neuroactive components that affect the nervous system. Phenolic compounds appear to have direct or indirect effects on brain tissue through various mechanisms such as reducing neuronal oxidative stress, suppressing microglial activation, supporting synaptic plasticity, and slowing down neurodegenerative processes such as Alzheimer's and Parkinson's. In addition, the polyphenol content enriched in fermented foods has been shown to exhibit psychobiotic effects in depression and anxiety models; it has been shown in clinical studies that it improves systemic inflammation and hypothalamic-pituitary-adrenal (HPA) axis dysfunction. Current data support the inclusion of fermented, polyphenol-rich foods as a noninvasive strategy to enhance neuroprotection and mental health. However, enhanced clinical studies are needed where heterogeneity in the fermentation process and dosage adjustment are standardized. This article reviews the current literature on the effects of fermented foods and polyphenols on brain health via the microbiota and gut-brain axis.\n\nID: 40768551\nTitle: Herbal Medicines in Autism Spectrum Disorder: Therapeutic Potential, Plant Components, and Dosage Guidelines.\nAbstract: Autism spectrum disorder (ASD), marked by social communication deficits and repetitive behaviors, significantly impacts the quality of life for kids and caregivers. Herbal medicines help manage symptoms, yet no comprehensive review has collectively summarized recent evidence (2018-mid-2025). This narrative review utilized searches across PubMed, Scopus, Web of Science, and Google Scholar to identify studies published on herbal medicines for ASD. Inclusion criteria prioritized clinical trials and preclinical studies detailing plant bioactive compounds, dosing, and mechanisms. Prominent herbs include Bacopa monnieri, which can enhance cognitive flexibility via bacosides; Curcuma longa (curcumin), which can reduce oxidative stress and repetitive behaviors; and Green Tea Extract (luteolin), which can modulate neuroinflammation. Cannabinoids show modest improvements in sleep and social engagement, while Ginkgo biloba improves cerebral blood flow. Passionflower and Valerian Root alleviate anxiety and hyperactivity through GABAergic pathways, and probiotic-fermented herbal combinations target gut-brain axis dysfunction. Ashwagandha demonstrates neuroprotective effects in preclinical trials. Herbal therapies may address core ASD symptoms (anxiety and hyperactivity) and comorbidities (sleep disturbances and gastrointestinal issues). However, standardization of herbal formulations and rigorous dosing protocols are needed. Integrative approaches combining herbs with behavioral therapies show accepted synergistic potential but require further validation. While herbal medicine may offer supportive benefits, it should never be intended to replace other evidence-based therapies (e.g., applied behavior analysis and speech therapy). Large-scale randomized clinical trials are crucial to confirming efficacy, safety, and optimal dosing. Research must address herb-drug interactions, long-term effects, and biomarkers for personalized treatment. autism spectrum disorder, herbal medicines, narrative review, doses recommendation, therapeutic effects, side effects.\n\nID: 42290160\nTitle: Fermentation-Induced Phenolic Remodeling of Aronia melanocarpa Alleviates Obesity-Induced Cognitive Dysfunction Associated With Coordinated Modulation of the AMPK/NF-\u03baB/BDNF Axis and BBB Integrity.\nAbstract: Obesity-induced cognitive decline involves chronic inflammation and neuronal dysfunction. This study investigated the mechanistic associations of probiotic-fermented Aronia melanocarpa extract (LAB-A) on metabolic and cognitive dysfunction in high-fat diet (HFD)-fed mice. Fermentation doubled total polyphenol content and increased aglycones like quercetin and eriodictyol. LAB-A attenuated microglial neuroinflammation by inhibiting NF-\u03baB translocation (94.4% reduction, p < 0.05) and protected neurons from apoptosis by reducing the BAX/BCL-2 ratio (89.3%, p < 0.05). In HFD-fed mice, LAB-A significantly reduced weight gain and improved lipid/hepatic profiles (p < 0.05). Behaviorally, LAB-A significantly ameliorated cognitive deficits, improving recognition and spatial memory (p < 0.05). At the molecular level, LAB-A suppressed hippocampal NF-\u03baB, restored AMPK\u03b1 phosphorylation, and markedly upregulated BDNF (\u223c11.0-fold, p < 0.05). These changes were accompanied by reinforced blood-brain barrier (BBB) integrity, as evidenced by a 3.1-fold increase in Occludin (p < 0.05). Fermentation enhances the bioactivity of Aronia by increasing aglycone-type phenolics. LAB-A effectively mitigates obesity-related metabolic and cognitive dysfunction, associated with coordinated modulation of the AMPK\u03b1/NF-\u03baB/BDNF axis and reinforcement of BBB integrity, highlighting its potential as a functional food ingredient for obesity-associated neuroprotection.\n\nID: 42192549\nTitle: Electroacupuncture prevents CUMS induced depressive-like behaviors by inhibiting microglia-mediated synaptic pruning induced by gut dysbiosis.\nAbstract: Electroacupuncture (EA) has been widely used for depression treatment. Microbiota-gut-brain (MGB) axis plays a vital role in regulating emotional behaviors. However, the potential role of MGB axis in EA-mediated protective effects remains unclear. The protective effects of EA in chronic unpredictable mild stress (CUMS) induced mice were evaluated, and the gut microbiota and metabolic profiles were analyzed. Fecal microbiota transplantation (FMT) was utilized to explore the role of MGB axis in the protective effects of EA. Analyses related to synaptic pruning mediated by microglia were conducted to explore the molecular mechanisms. In this study, EA treatment prevented depressive-like behaviors in CUMS mice. Mechanistically, EA ameliorated CUMS-induced gut microbiota dysbiosis and inflammation, and partially restored gut microbial metabolism, particularly affecting the abundance of Alistipes and taurine metabolism. Furthermore, EA significantly reduced systemic and hippocampal inflammation. It also attenuated aberrant synaptic pruning in the hippocampus. Moreover, FMT from CUMS mice induced depressive-like behaviors, gut inflammation and microglia-mediated aberrant synaptic pruning, whereas FMT from EA-treated donors exerted protective effects against these impairments. Collectively, our findings suggest that EA prevented CUMS-induced depression-like behaviors and support the involvement of the MGB axis in its protective effects.\n\nID: 42179525\nTitle: Lactic Acid Bacteria-Mediated Fermentation Drives Metabolic Remodeling of Centella Asiatica (L.) Urb. toward Acidic Triterpenoids with Neuroinflammation-Related Bioactivity.\nAbstract: Centella asiatica Urb. is a medicinal plant rich in triterpenoid constituents with a reported neurobiological relevance. Its major metabolites are glycosylated triterpenoids, such as asiaticoside and madecassoside, whereas the corresponding acidic triterpenoids, including asiatic acid and madecassic acid, are typically present at low abundance. Given the increasing interest in how metabolic forms of natural products influence biological activity, this study investigated whether lactic acid bacteria (LAB)-mediated fermentation could induce metabolic remodeling of C. asiatica through microbial biotransformation. LAB fermentation markedly altered the secondary metabolite profile, which was characterized by a reduction in phenolic compounds and glycosylated triterpenoids and a pronounced enrichment of acidic triterpenoids. This compositional shift was accompanied by changes in bioactivity, including a decreased antioxidant capacity but enhanced anti-inflammatory effects in macrophage cells. Fermented C. asiatica significantly suppressed the expression of proinflammatory cytokines (TNF-\u03b1 and IL-1\u03b2) and modulated amyloid-\u03b2 and tau protein aggregation behavior in vitro. Furthermore, in an Alzheimer's disease transgenic mouse model, fermented extracts were associated with reduced amyloid plaque deposition, as assessed by Thioflavin S staining. Collectively, these results demonstrate that LAB-mediated fermentation drives functional metabolic remodeling of C. asiatica by altering the triterpenoid composition and bioactivity profiles. This work highlights microbial biotransformation as a versatile strategy for modulating the biological attributes of plant-derived natural products and for exploring relationships between chemical form and bioactivity in complex biological systems.\n\nID: 42121529\nTitle: Theabrownin from Dark Tea Attenuates Age-Related Cognitive Decline in Naturally Aged Mice by Modulating Gut Microbiota and Metabolites.\nAbstract: Dietary factors play an important role in cognitive health during aging. Dark tea has shown potential cognitive benefits, but its key bioactive component and underlying mechanisms remain unclear. In a naturally aged C57BL/6J mouse model, instant dark tea (IDT) samples with different fermentation degrees were evaluated together with behavioral outcomes using composition-effect relationship analysis. This analysis identified theabrownin (TB) as the component most strongly associated with improved cognitive performance. Compared with aged controls, TB increased Y-maze spontaneous alternation from 51.91% to 71.59% and reduced escape latency on day 5 of the Morris water maze from 44.84 s to 26.59 s. In contrast, the corresponding TB-depleted fraction produced no comparable cognitive improvement. TB also alleviated hippocampal injury and neuroinflammation. Antibiotic treatment abolished the cognitive benefits of TB, whereas fecal microbiota transplantation partially restored them. Multi-omics analyses suggested that TB treatment was associated with gut microbiota remodeling and increased serum acetate and 3-hydroxybutyrate; both metabolites partially recapitulated these benefits. Together, these findings show that TB attenuates age-related cognitive decline in naturally aged mice and suggest that modulation of gut microbiota and metabolites may contribute to this effect, supporting its potential as a functional food ingredient for healthy brain aging.\n\nID: 42070055\nTitle: Combined purslane ethanolic extract and metformin attenuate cognitive dysfunction in HFD/STZ-induced diabetic rats via modulation of oxidative stress, neuroinflammation, and neurotransmitters.\nAbstract: Diabetes is associated with a number of significant long-term effects. In this study we consider that purslane which possesses numerous of pharmacological properties, and metformin, an antidiabetic drug, may have a therapeutic effects on diabetes-induced memory impairments in rats. Forty male albino rats were randomly divided into five groups. Group I served as control group. The other four groups were first fed on HFD followed by a single interpretonial (i.p.) dose of STZ at a dose of (35) mg/kg then the groups were divided as following Group II diabetic group Group III, PEE group administered with oral dose of purslane ethanolic extract (100\u00a0mg/kg) for another four weeks. Group IV, MET group administered with oral dose of metformin (100\u00a0mg/kg) for another four weeks. Group V (PEE\u2009+\u2009MET) administered with oral dose of combination of both purslane ethanolic extract (50\u00a0mg/kg) and MET (50\u00a0mg/kg) for another four weeks. During the treatment rats were tested for memory and learning abilities (Morri's water maze test). Hippocampal samples were collected for biochemical, and histological measurements. Biochemical evaluation included (NO and TBARS) as an oxidative stress marker, (GSH, GPX, SOD, Catalase) as antioxidant, and inflammatory cytokines (tumor necrosis factor-\u03b1 and interleukin-1\u03b2, interleukin-IL-6). Also, P-tau protein, (dopamine and GABA) as neurotransmitters, and for cholinergic system (acetylcholinesterase) were assessed, in addition to histological examinations of hippocampus. Diabetic rats showed a marked cognitive impairment in the Morris water maze test and alteration in the other biochemical and histological features. Intrestingly, PEE and MET treatments partially dramatically enhanced antioxidant levels. Also, reduced oxidative stress, pro-inflammatory mediators, and, phosphorylated tau levels. In addition, PEE and MET treatments partially modulated neurochemical profiles associated with memory function. The combined PEE\u2009+\u2009MET treatment showed the most pronounced improvement, reflecting synergistic effects. Individual data points highlighted consistent trends across animals. Also, it exhibited a significant restoration of normal hippocampal architecture, as confirmed by hematoxylin and eosin staining. The data obtained indicated that PEE, either alone or in combination with MET, has strong neuroprotective potential against STZ/HFD-induced diabetes. These safeguarding effects are probably because of its strong anti-inflammatory and antioxidant properties.\n\nID: 41752066\nTitle: Reduced Neuroinflammation and Pain with a Functional Sourdough Bread Enriched with Legumes and Ancient Cereals in a Mouse Model of LPS-Induced Inflammation.\nAbstract: Nutritional strategies based on sourdough fermented breads with wholemeal ancient grains and legumes are emerging as promising modulators of (neuro)immune processes. This study investigated whether prolonged consumption of a sourdough bread enriched with a mixture of ancient cereals and legumes, commercially available in Italy (Primus\u00ae bread, P\u00aeB), modulates neuroimmune systemic responses to repeated lipopolysaccharide (LPS) challenge in mice. For this study, male C57BL/6J mice were fed for 14 days with either a standard diet (SD) or P\u00aeB. Animals then received intraperitoneal LPS (3 mg/kg/day for 3 days) or vehicle. Body weight and food intake were monitored throughout. Pain-like behaviours were assessed by von Frey, plantar and tail flick tests, and plasma cytokine (32-plex panel), splenocyte and peritoneal macrophage cytokine expression, and expression of pro-inflammatory cytokines in sciatic nerves, dorsal root ganglia (DRG) and the spinal cord were analyzed by Reverse Transcription-quantitative Polymerase Chain Reaction (RT-qPCR). P\u00aeB prevented LPS-induced body weight loss and reduced splenomegaly. Unlike SD mice, which exhibited widespread plasmatic cytokine upregulation, P\u00aeB-fed mice displayed only limited increases Interleukin (IL)-1\u03b2, IL-12p40 and Tumor Necrosis Factor (TNF)\u03b1. Ex vivo cultures of splenocytes and macrophages confirmed attenuated cytokine overexpression. LPS-induced hypersensitivity to mechanical, thermal and nociceptive stimuli was significantly reduced in P\u00aeB mice. Molecular analyses revealed that the P\u00aeB diet blunted the pro-inflammatory cytokine expression present after LPS challenge in the sciatic nerves and DRG, with partial attenuation in the spinal cord. Our findings highlight the great potential of functional foods as affordable dietary strategies to mitigate systemic immune and neuroimmune dysregulation.\n\nID: 41228565\nTitle: The Diet-Obesity-Brain Axis: Metabolic, Epigenetic, and DNA-Repair Pathways Linking Eating Patterns to Cognitive Aging, with an AI-Enabled Translational Perspective.\nAbstract: Diet influences brain health through many connected metabolic and molecular pathways, and these effects are stronger in obesity. This review links diet quality with cognitive decline and dementia risk. Ultra-processed, high-fat, high-sugar diets drive weight gain, insulin resistance, and chronic inflammation. These changes trigger brain oxidative stress, reduce DNA repair, deplete NAD+, disturb sirtuin/PARP balance, and alter epigenetic marks. Gut dysbiosis and leaky gut add inflammatory signals, weaken the blood-brain barrier, and disrupt microglia. Mediterranean and MIND diets, rich in plants, fiber, polyphenols, and omega-3 fats, slow cognitive decline and lower dementia risk. Trials show extra benefit when diet improves alongside exercise and vascular risk control. Specific nutrients can help in certain settings. DHA and EPA support brain health in people with low omega-3 status or early disease. B-vitamins slow brain shrinkage in mild cognitive impairment when homocysteine is high. Vitamin D correction is beneficial when levels are low. A practical plan emphasizes healthy eating and good metabolic control. It includes screening for deficiencies and supporting the microbiome with fiber and fermented foods. Mechanism-based add-ons, such as NAD+ boosters, deserve testing in lifestyle-focused trials. Together, these measures may reduce diet-related brain risk across the life span. At the same time, artificial intelligence can integrate diet exposures, adiposity, metabolic markers, multi-omics, neuroimaging, and digital phenotyping. This can identify high-risk phenotypes, refine causal links along the diet-obesity-brain axis, and personalize nutrition-plus-lifestyle interventions. It can also highlight safety, equity, and privacy considerations. Translationally, a pattern-first strategy can support early screening and personalized risk reduction by integrating diet quality, adiposity, vascular risk, micronutrient status, and microbiome-responsive behaviors. AI can aid measurement and risk stratification when developed with privacy, equity, and interpretability safeguards, but clinical decisions should remain mechanism-aligned and trial-anchored.\n\nID: 41113276\nTitle: HPLC/UV analysis of mulberry vinegar and its protective role in LPS-induced cognitive impairment via regulating NF-\u03baB signaling pathway and amyloidogenesis in mice.\nAbstract: The present study investigated the protective effect of mulberry vinegar (MV) on inflammatory responses and cognitive deficit induced by lipopolysaccharide (LPS) in mice models. The mice were administered MV and given intraperitoneal injection of LPS. In behavioral tests, MV ameliorated memory deficit and cognitive dysfunction. In the LPS-injected mouse brains, the generation of malondialdehyde, reactive oxygen species, nitric oxide, and pro-inflammatory cytokines was inhibited by the administration of MV. These preventive roles of MV were attributed to inactivation of NF-\u03baB signaling pathway with downregulation of iNOS and COX-2. Moreover, MV modulated the amyloidogenic pathway by inhibiting amyloid precursor protein, beta-site APP cleaving enzyme-1, presenilin 1, and presenilin 2 and enhancing A\u03b2 degradation-related proteins expression. The major phenolic compounds in MV were protocatechuic acid (0.13\u00a0mg/mL), rutin (0.13\u00a0mg/mL), and chlorogenic acid (0.05\u00a0mg/mL), which were increased by fermentation, confirmed by HPLC/UV\u00a0analysis. Therefore, MV could ameliorate cognitive deficits through regulation of oxidative stress, inflammatory responses, and amyloidogenesis.\n=======================================================\n\n### [CUSTOM DATAPOINTS]\nCRITICAL EXTRACTION DIRECTIVE: You MUST extract the following custom datapoints as root-level key/value pairs inside your final JSON block:\n- \"suggested_experiments\": generate 1-3 suggested experiments\n- \"suggested_studies\": generate 1-3 suggested studies\n- \"swansons_literature_based_discovery_candidates\": You are an advanced Literature-Based Discovery (LBD) system executing Swanson\u2019s complementary-but-disjoint (A-B-C) model. Your goal is to find hidden, unpublished connections across the provided dataset. Strict Discovery Protocol: 1. Identify distinct, isolated sub-literatures (Domain A and Domain C) within the dataset that share NO direct citations, co-mentions, or common contextual paragraphs. 2. Find an intermediate biological mechanism, protein, path, or entity (Bridge B) that appears independently in both isolated domains (A-to-B and B-to-C). 3. Synthesize a novel, unstated hypothesis (A-to-C). Negative Constraint (Crucial): DO NOT output any connection if the relationship between Concept A and Concept C is explicitly mentioned, paired, or summarized anywhere in the source text. If a connection (like \"OMN resilience to SMN stabilization\") is already explicitly stated or grouped as a concept in the data, it is considered \"already known\" and must be disqualified. Format your output exactly as follows: - Discovered Hypothesis (A to C): [Clear, novel statement] - Literature A (Origin): [Entity/Concept and source context] - Literature C (Target): [Entity/Concept and source context] - The Intersecting Bridge B: [The shared mechanism/protein linking them] - Biological Rationale: [1-2 sentences explaining why this hidden connection is mechanistically plausible]\n- \"contradictions_between_evidences\": Identify conflicting evidence within the evidence set (if any) and flag the dispute here\n- \"repurposed_solutions\": identify and explain repurposed Solution potentials\n\n\nFormat Requirement:\nRAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\nFirst provide disclaimer such as \"Even though this fact check looked at unique up-to-date abstracts, new evidence may refute this answer in the future. Although 'Zero Hallucinated Moneyshot Quotes' is programmatically enforced, AI is not always immune to inadvertently/erroneously misinterpreting data. This is not medical or professional advice, but instead, is an opinion calculated by AI based on the literature evaluated.\"\n---\nWrite in a highly academic, formal thesis tone.\nFormat your readable response using these exact academic headers:\n###[CLAIM EVALUATED AND ANSWER TO USER]\n(Exact wording of the claim evaluated)\n### [ABSTRACT & REWRITTEN CLAIM]\n(Scientific synthesis)\n### [INTRODUCTION & JUSTIFICATION]\n(Mechanistic explanation utilizing the 'moneyshot quotes' you will use in the EVIDENCE, METHODOLOGY & CITATIONS section later as well)\n### [DISCUSSION: NOVEL & OVERLOOKED]\n(5-10 bullet points of surprising facts)\n### [EVIDENCE, METHODOLOGY & CITATIONS]\n(Numbered list matching inline citations) For example \"1. ID: 12345 - Application: The text discusses ... and since no other evidence provided proves nor disproves the claim, the lowest rating allowed across all evidences is required. ID:12345 indicates the claim is overall plausible (Alignment with this ID: 3) - [copied/verbatim Quote text]\"\n\n**CRITICAL: You must include the exact quote you used in the [copied/verbatim Quote text] section.\n\nIf the prompt says \"at least 20 quotes\" then there must be at least 20 matching citations. You must actually use the quotes you select within the conext of the preprint publication you write.\n\nEvaluation Schema:\nRAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\n###critical: WRAP YOUR THOUGHTS WITH ... tags at the very beginning of your response.\n\n=======================================================\nCONTEXT LITERATURE (STATIC CACHE):\nID: 41921509\nTitle: Frontiers in Gut Health: The Emerging Role of Berries in Microbiota Modulation and Gastrointestinal Diseases.\nAbstract: Berries are rich in bioactive compounds, including polyphenols, dietary fiber, and micronutrients, that have been linked to antioxidant, anti-inflammatory, and microbiota-modulating effects. This review examines how berry intake relates to gut health, which is considered here across 4 domains: (1) gut microbiota composition and function, (2) intestinal barrier integrity, (3) immune/inflammatory pathways, and (4) clinical symptoms/biomarkers, with relevance to inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), and gastrointestinal (GI) cancers. Berries have demonstrated microbiota-modulating effects across in vitro, in vivo, and clinical studies. Populations of specific taxa, such as Bifidobacterium, Akkermansia, and Roseburia, increase in the gut after berry intake, alongside enhanced production of short-chain fatty acids. Importantly, the dual role of polyphenols as both microbial substrates and modulators-termed the \"duplibiotic effect\"-represents a novel conceptual advance. These microbial shifts are associated with improved gut barrier function and reduced pro-inflammatory cytokine expression. Results of clinical studies with patients with IBD suggest anthocyanin-rich berries may support remission by enhancing microbial diversity and decreasing intestinal inflammation. In IBS, berries low in fermentable oligo-, di-, and monosaccharides and polyols, like blueberries, have shown symptom relief through anti-inflammatory and microbiota-modulating effects. Berries may also exert chemopreventive actions in GI cancers by influencing Wnt signaling, COX-2 expression, and DNA methylation. Although in vitro, in vivo, and early-phase clinical studies provide encouraging evidence, larger berry-specific human trials are required to confirm these effects and clarify mechanisms for personalized interventions.\n\nID: 41329359\nTitle: Dietary Houttuynia cordata Thunb attenuates redox imbalance and inflammation possibly induced by heat stress in dairy cows associated with altered fecal microbiota and metabolomics profile.\nAbstract: This trial tested the effects of Houttuynia cordata (HC) feeding on lactation performance, redox status, and inflammatory response of heat stress (HS)-suffered dairy cows. Twenty dairy cows were assigned into two dietary treatments, which were offered a basal TMR diet or a diet containing 2% HC for a 35-day trial, during which the average temperature and humidity index was 76.57\u2009\u00b1\u20090.22 (>\u200972), indicating a possible exposure to HS. The results showed that HC intake reduced the respiratory rate and rectal temperature, elevated the milk yield, and increased the concentrations of glucose, total phenolic compounds, and total flavonoids and catalase activity in serum of HS-suffered cows (p\u2009<\u20090.05). HC consumption reduced serum insulin, malondialdehyde, diamine oxidase activity, and lipopolysaccharides concentration, as well as lipopolysaccharide-binding protein and interleukin-1\u03b2 concentrations in the serum and milk of cows. (p\u2009<\u20090.05). Plasma metabolome demonstrated that HC intake increased the concentrations of microbial tryptophan catabolites and reduced the levels of acylcarnitine (p\u2009<\u20090.05). Fecal microbiota sequencing showed that HC ingestion elevated the microbial alpha diversity, indicative of higher Chao1, Shannon, and observed species in feces of cows (p\u2009<\u20090.05). Dietary HC inclusion altered the abundances of certain taxa, like phylum Verrucomicrobiota and genus Akkermansia, in feces of dairy cows (p\u2009<\u20090.05). Network analysis indicated that long-chain acylcarnitines were negatively correlated with Prevotellaceae_UCG-004 and Akkermansia (p\u2009<\u20090.05). Overall, HC intake alleviated thermal stress-induced performance impairment, redox imbalance, and inflammation, possibly via altering fecal microbiome and plasma metabolite profile in cows.\n\nID: 41285309\nTitle: Tripterygium wilfordii multi-glycoside alleviates ankylosing spondylitis via gut microbiota modulation and metabolite reprogramming.\nAbstract: Ankylosing spondylitis (AS) is a chronic autoimmune inflammatory disorder characterized by severe inflammation in the axial skeleton. Tripterygium wilfordii multi-glycoside (GTW) is widely used in clinical practice for AS and related immune diseases, yet its precise mechanism of action remains unclear. Explore the therapeutic effects of GTW on AS and its potential mechanisms, with a focus on its impact on the gut microbiota and associated metabolites. An AS mouse model was established via intraperitoneal injection of proteoglycan and Freund's complete adjuvant. The therapeutic effects and underlying mechanisms of GTW were explored through phenotypic analysis, 16S rRNA sequencing, and metabolomic profiling. GTW significantly reduced arthritis index, gait score, paw thickness, and pro-inflammatory cytokines in AS mice. Additionally, it modulated mRNA and protein expression related to osteoclast and osteoblast differentiation while restoring intestinal barrier integrity. Notably, GTW reversed the AS-induced depletion of Bifidobacterium and Akkermansia. Correlation analysis between gut microbiota, fecal metabolites, and AS-related phenotypes suggested that GTW-enriched bacteria were positively associated with beneficial metabolites, including 3-methylxanthine, 5'-methylthioadenosine, cinnamic acid, kaempferol, and palmitoyl glucuronide. Both of those gut bacteria and metabolites were strongly negatively correlated with AS severity markers (IL-6, IL-17, IL-23, Th17 cell percentage, arthritis index, gait score, paw thickness, and Rankl expression) and positively associated with protective factors (Zo-1, Occludin, Claudin-1, Ocn, and Alp gene expression). This study implies that GTW treatment is associated with amelioration of AS-related symptoms in mice, suggesting a potential role of the gut microbiota-metabolite axis in GTW-associated AS improvement, though causal relationships require further validation.\n\nID: 40914308\nTitle: The renoprotective anti-hyperuricemia effect of Cornus officinalis extract in hyperuricemia rats based on network pharmacology and multiple omics.\nAbstract: Corus officinalis Siebold & Zucc belongs to the genus Cornus in the Cornaceae family, and was first recorded in the \"Shennong Herbal Classic\", now has been included in \"according to the tradition of both food and Chinese herbal medicines\", consist of kidney and liver tonifying, antioxidant substances including cycloid glycosides, flavonoids, polyphenols, organic acids, etc. AIM OF THE STUDY: This study was aimed at discovering the mechanism underlying the anti-hyperemia effect of Cor in rats, particularly its protective effect against liver and kidney dysfunction caused by HUA. In this study, the effect of Cor extract against HUA was verified in rats, subsequently, network pharmacology combined with non-targeted metabolomic were performed to investigate its composition characteristics, and further multi-omics studies and molecular validation were performed to reveal molecular mechanism both in vivo and in vitro. The results demonstrated that cornuside, hydroxygenkwanin and tetrahydroalstonine were the main bioactive compounds in Cor extract, which protected intestinal metabolism disorder by increasing relative abundances of Bacteroides, Lactobacillus Roseburia and Akkermansia, alleviated liver oxidative damage by activation of the Nrf2/HO-1(NQO1) antioxidant pathway, and reduced liver UA synthesis by inhibiting the expression of UA synthesis protein XOD in rat model. In addition, tetrahydroalstonine alleviated inflammation via inhibiting PI3K/Akt/NF-\u03baB signaling pathway, with cornuside and hydroxygenkwanin enhanced renal tubule UA transport capacity by regulating the translations of XDH and HRP genes, all of which protected HUA-rat kidney from inflammatory infiltration damage, and reduced serum urea nitrogen (BUN), creatinine (CRE) and UA levels. These findings indicates that Cor can alleviate HUA by enhancing liver-renal-intestine UA metabolism, inhibiting inflammatory responses of liver-renal-intestine as well as providing hepatorenal protection.\n\nID: 40680986\nTitle: Linarin alleviates high-fat diet-induced NAFLD via modulating the PI3K/Akt/mTOR pathway, autophagy, and gut microbiota.\nAbstract: Linarin (Lin) is a flavonoid compound widely found in traditional herbal medicines and is recognized for its diverse biological properties, including anti-inflammatory, analgesic, antioxidant, hepatoprotective, and anti-apoptotic effects. Non-alcoholic fatty liver disease (NAFLD) is closely associated with autophagy and inflammation processes. However, the interaction between Lin and NAFLD remains underexplored. This study aimed to investigate the protective effects of Lin against NAFLD and its underlying pharmacological mechanisms. In vitro, we established a NAFLD model using AML12 cells stimulated with oleic acid (OA) and palmitic acid (PA). In vivo, we induced a chronic model in mice by feeding them a high-fat diet (HFD). Lipid metabolism markers, Oil Red O staining, and H&E staining were used to assess intracellular lipid accumulation. Inflammatory and autophagic markers were also measured. The 16S rRNA analysis was performed to evaluate the changes in the gut microbiota composition after Lin intervention in mice. Both in vitro and in vivo experiments demonstrated that Lin reduces lipid accumulation, which is mediated through the enhancement of autophagy and the inhibition of the release of inflammatory factors. 16S rRNA analysis revealed that Lin alleviates gut dysbiosis by reducing Firmicutes and Bacteroidetes phyla while increasing the abundance of Akkermansia and Bifidobacterium genera. Mechanistically, Lin activates autophagy via the PI3K/Akt/mTOR pathway, thereby alleviating lipid accumulation and inflammation. These findings suggest that Lin can mitigate NAFLD by inhibiting the activation of the PI3K/Akt/mTOR pathway, highlighting its potential as a promising therapeutic approach for NAFLD.\n\nID: 40573190\nTitle: Prebiotic-like Effects of Proanthocyanidin-Rich Aronia Extract Supplementation on Gut Microbiota Composition and Function in the Twin-M-SHIME\u00ae Model.\nAbstract: Background: Phenolic compounds, particularly anthocyanins and proanthocyanidins (PACs), are poorly absorbed in the upper digestive tract and reach the colon largely intact, where they may influence gut microbiota (GM) composition and, in turn, impact host health. We hypothesized that a PAC-rich aronia extract would beneficially modulate the GM, promote the growth of health-associated bacteria, and enhance short-chain fatty acid (SCFA) production across different colon sections, with partial reversion effects after supplementation ends. Methods: The Twin-M-SHIME\u00ae system was used to simulate the digestion and colonic fermentation in two donors with contrasting microbiota profiles. The experimental design included four phases: stabilization (14 days), control (7 days), treatment with 500 mg/day PAC-rich aronia extract (21 days), and wash-out (10 days). SCFA production was monitored, and changes in microbiome composition were assessed using 16S rRNA gene sequencing. Results: PAC-rich aronia extract significantly modulated SCFA levels, increasing butyrate and reducing acetate, with some inter-donor variability. SCFA concentrations tended to return to baseline after the wash-out (WO) period. Metagenomic analysis revealed a decrease in Collinsella, Sutterella, Selenomonas, and Parabacteroides-genera linked to low-fiber diets and gut inflammation-while promoting Proteobacteria (e.g., Escherichia-Shigella, Klebsiella) and butyrate-associated Firmicutes such as Lactiplantibacillus. Although some microbial shifts partially reverted during the wash-out (e.g., Akkermansia, Bacteroides, and Bifidobacterium), other changes persisted. Conclusions: These findings suggest that PAC-rich aronia extract beneficially modulates GM and SCFA production, but continuous intake may be necessary to maintain these effects over time.\n\nID: 40097303\nTitle: Impact of a water-soluble soy extract on inflammation and gut microbiota in physiologically aged mice.\nAbstract: Soy isoflavones are involved deeply in our diet as beneficial to health. It is known to have anti-inflammatory and antioxidant effects and also to be effective in alleviating various lifestyle diseases, as well as the maintenance of endocrine function, especially with age-related diseases such as osteoporosis. Here we investigated the impact of age-dependent changes with the intestinal microbiota in physiologically aged C57BL/6\u00a0N by free drinking water with soluble soybean-derived isoflavone glycosides (SIFs) for 4 weeks. Consequently, Akkermansia muciniphila (A. muciniphila) species represented an age-dependent increase with SIF treatment, subsequently, generally age-dependent decreased goblet cells are retained in the large intestine. These results invoke that SIF plays a beneficial role in intestinal barrier function to maintain large intestine homeostasis. Interestingly, we also revealed that SIF had an alleviating effect on age-dependent bone loss. Taken together, SIF has a fruitful effect on the intestinal environment and the maintenance of homeostasis in physiological aging.\n\nID: 38540830\nTitle: Ethanol Extracts from Torreya grandis Seed Have Potential to Reduce Hyperuricemia in Mouse Models by Influencing Purine Metabolism.\nAbstract: The purpose of this study was to evaluate the efficacy of ethanol extracts from Torreya grandis seed (EST) as a functional food in hyperuricemia mice. We investigated EST by analyzing its chemical composition. Using a mouse model of hyperuricemia induced by potassium oxonate (PO), we evaluated the effects of EST on uric acid (UA) production, inflammation-related cytokines, and gut microbiota diversity. The primary constituents of EST consist of various flavonoids and phenolic compounds known for their antioxidant and anti-inflammatory properties in vitro. Notably, our findings demonstrate that EST significantly reduced UA levels in hyperuricemia mice by 71.9%, which is comparable to the effects observed with xanthine treatment. Moreover, EST exhibited an inhibitory effect on xanthine oxidase activity in mouse liver, with an IC50 value of 20.90 \u03bcg/mL (36%). EST also provided protective effects to the mouse kidneys by modulating oxidative stress and inflammation in damaged tissues, while also enhancing UA excretion. Finally, EST influenced the composition of the intestinal microbiota, increasing the relative abundance of beneficial bacteria such as Akkermansia muciniphila, Corynebacterium parvum, Enterorhabdus, Muribaculaceae, Marvinbryantia, and Blautia. In summary, our research unveils additional functions of Torreya grandis and offers new insights into the future of managing hyperuricemia.\n\nID: 38397562\nTitle: Schisandra chinensis Bee Pollen Ameliorates Colitis in Mice by Modulating Gut Microbiota and Regulating Treg/Th17 Balance.\nAbstract: Colitis is a chronic disease associated with alterations in the composition of gut microbiota. Schisandra chinensis bee pollen extract (SCPE) has been proved to be rich in phenolic compounds and effective in modulating gut microbiota, but its effect on colitis and the underlying mechanism remains unclear. This study investigates the relationship between colitis amelioration and the gut microbiota regulation of SCPE via fecal microbial transplantation (FMT). The results showed that administration of 20.4 g/kg BW of SCPE could primely ameliorate colitis induced by dextran sulfate sodium (DSS) in mice, showing as more integration of colon tissue structure and the colonic epithelial barrier, as well as lower oxidative stress and inflammation levels compared with colitis mice. Moreover, SCPE supplement restored the balance of T regulatory (Treg) cells and T helper 17 (Th17) cells. Gut microbiota analysis showed SCPE treatment could reshape the gut microbiota balance and improve the abundance of gut microbiota, especially the beneficial bacteria (Akkermansia and Lactobacillus) related to the production of short-chain fatty acids and the regulation of immunity. Most importantly, the protection of 20.4 g/kg BW of SCPE on colitis can be perfectly transmitted by fecal microbiota. Therefore, the gut microbiota-SCFAS-Treg/Th17 axis can be the main mechanism for SCPE to ameliorate colitis. This study suggests that SCPE can be a new promising functional food for prevention and treatment of colitis by reshaping gut microbiota and regulating gut immunity.\n\nID: 36394293\nTitle: Nucleotide binding as an allosteric regulatory mechanism for Akkermansia muciniphila \u03b2-N-acetylhexosaminidase Am2136.\nAbstract: \u03b2-N-acetylhexosaminidases (EC3.2.1.52), which belong to the glycosyl hydrolase family GH20, are important enzymes for oligosaccharides modification. Numerous microbial \u03b2-N-acetylhexosaminidases have been investigated for applications in biology, biomedicine and biotechnology. Akkermansia muciniphila is an anaerobic intestinal commensal bacterium which possesses specific \u03b2-N-acetylhexosaminidases for gut mucosal layer colonization and mucin degradation. In this study, we assessed the in vitro mucin glycan cleavage activity of the A. muciniphila \u03b2-N-acetylhexosaminidase Am2136 and demonstrated its ability that hydrolyzing the \u03b2-linkages joining N-acetylglucosamine to a wide variety of aglycone residues, which indicated that Am2136 may be a generalist \u03b2-N-acetylhexosaminidase. Structural and enzyme activity assay experiments allowed us to probe the essential function of the inter-domain interactions in \u03b223-\u03b233. Importantly, we revealed that the hydrolysis activity of Am2136 was enhanced by nucleotides. We further speculated that this activation mechanism might be associated with the conformational motions between domain III and IV. To our knowledge, this is the first report of nucleotide effector regulated \u03b2-N-acetylhexosaminidase, to reveal its novel biological functions. These findings contribute to understanding the distinct properties within the GH20 family and lay a certain foundation to develop controllable glycan hydrolyzing catalysts.Abbreviations: OD600 - optical cell densities at 600 nm; LB - Luria-Bertani; IPTG - isopropyl \u03b2-D-1-thiogalactopyranoside; PMSF - phenylmethanesulfonyl fluoride; rmsd - root mean square deviation; GlcNAc - N-acetyl-\u03b2-D-glucosamine; GalNAc - N-acetyl-\u03b2-D-galactosamine; Gal - galactose.\n\nID: 36351282\nTitle: Structural Insights into Amelioration Effects of Quercetin and Its Glycoside Derivatives on NAFLD in Mice by Modulating the Gut Microbiota and Host Metabolism.\nAbstract: The sugar moieties of natural flavonoids determine their absorption, bioavailability, and bioactivity in humans. To explore structure-dependent bioactivities of quercetin, isoquercetin, and rutin, which have the same basic skeleton linking different sugar moieties, we systemically investigated the ameliorative effects of dietary these flavonoids on high-fat diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD) of mice. Our results revealed that isoquercetin exhibits the strongest capability in improving NAFLD phenotypes of mice, including body and liver weight gain, glucose intolerance, and systemic inflammation in comparison with quercetin and rutin. At the molecular level, dietary isoquercetin markedly ameliorated liver dysfunction and host metabolic disorders in mice with NAFLD. At the microbial level, the three flavonoids compounds, especially isoquercetin, can effectively regulate the gut microbiota composition, such as genera Akkermansia, Bifidobacterium, and Lactobacillus, which were significantly disrupted in NAFLD mice. These comparative findings offer new insights into the structure-dependent activities of natural flavonoids for NAFLD treatment.\n\nID: 35696951\nTitle: Rhodomyrtus tomentosa (Ait.) Hassk fruit phenolic-rich extract mitigates intestinal barrier dysfunction and inflammation in mice.\nAbstract: In this study, the mitigative effect of Rhodomyrtus tomentosa (Ait.) Hassk fruit extract rich in phenolic compounds (RTE) on high fat diet (HFD)-induced intestinal barrier dysfunction of mice and the underlying mechanism were explored. The results revealed that RTE supplementation obviously improved gut microbiota dysbiosis induced by HFD, which was evidenced by elevated alpha diversity, suppressed Firmicutes/Bacteroidetes ratio, enriched short-chain fatty acid-producing bacteria (Odoribacter, Parabacteroides, Blautia and Akkermansia), and depleted harmful bacteria (Helicobacter, norank_f_ Desulfovibrionaceae and Mucispirillum). RTE intervention mitigated intestinal barrier dysfunction and inflammation by elevating tight junction proteins expression levels and decreasing proinflammatory cytokines levels. Furthermore, RTE administration inhibited the HFD-induced trigger of the lipopolysaccharide-toll-like receptor 4-nuclear factor kappa-B (LPS-TLR4-NF-\u03baB) pathway in colonic tissue. Therefore, RTE supplementation may be an effective way to protect the intestinal tract in HFD-induced obese individuals.\n\nID: 34794235\nTitle: Radish sprout alleviates DSS-induced colitis via regulation of NF-kB signaling pathway and modifying gut microbiota.\nAbstract: In this study, we investigated the effects of radish sprout ethanol extract (RSE) on inflammatory responses in the macrophages and a mouse model of colitis. RSE administration was found to effectively inhibit the phosphorylation of I\u03baB and, in turn, the production of pro-inflammatory enzymes and cytokines in lipopolysaccharide-stimulated macrophages. In dextran sulfate sodium (DSS)-colitis mice, RSE administration prevented body weight and colon length reduction, while decreasing inflammation and mucosal necrosis. The diversity of the fecal microbiota was significantly increased in the group treated with RSE. In addition, RSE administration decreased the relative abundance of the phylum Proteobacteria, which includes many pathogens, and increased the abundance of the genus Akkermansia. Beta diversity analyses showed that RSE administration restored the gut microbiota composition close to that of healthy mice. For the first time, we identified glycosides of sinapic acid as part of hydroxycinnamic acids in RSE with colitis-alleviating effects. Notably, 1,2-O-disinapoyl glucoside substantially decreased nitric oxide generation in LPS-stimulated macrophages.\n\nID: 33977958\nTitle: Inhibitory effects of \u03b2-type glycosidic polysaccharide from Pleurotus eryngii on dextran sodium sulfate-induced colitis in mice.\nAbstract: The aim of the present study was to determine the inhibitory effects and the potential underlying mechanisms of a novel Pleurotus eryngii \u03b2-type glycosidic polysaccharide (WPEP) on colitis. To achieve this, sixty CD-1 (ICR) mice were divided into six groups including healthy and colitic mice treated with or without WPEP at two different doses (n = 10). The results showed that WPEP displayed a significant inhibitory effect on colitis as indicated by the lowered disease activity index in the treated colitic mice compared to the untreated colitic mice (2.78 \u00b1 0.50 to 1.80 \u00b1 0.17). A decrease in pro-inflammatory cytokine concentrations and pro-inflammatory protein expressions and an increase in the colon length (9.31 \u00b1 0.59 cm to 10.89 \u00b1 1.20 cm) along with histological improvements were also observed in the treated colitic mice compared to the untreated colitic mice in the present study. Flow cytometry and western blotting analysis revealed that these anti-colitis effects were associated with decreased accumulation of CD45+ immune cells, CD45 + F4/80+ macrophages and CD45 + Gr1+ neutrophils. Moreover, the 16s rRNA sequencing analysis of the gut microbiota revealed that WPEP partially reversed gut microbiota dysbiosis in the colitic mice including the decreased abundance of Akkermansia muciniphila (35.80 \u00b1 9.10% to 18.24 \u00b1 6.23%) and Clostridium cocleatum (2.34 \u00b1 1.78% to 0.011 \u00b1 0.003%) and the increased abundance of Bifidobacterium pseudolongum (3.48 \u00b1 2.72% to 9.65 \u00b1 3.74%), Lactobacillus reuteri (0.007 \u00b1 0.002% to 0.21 \u00b1 0.12%), Lactobacillus salivarius (1.23 \u00b1 0.87% to 2.22 \u00b1 1.53%) and Ruminococcus bromii (0.009 \u00b1 0.001% to 3.83 \u00b1 1.98%). In summary, our results demonstrated that WPEP could be utilized as a functional food component in colitis management as well as a potential prebiotic agent to improve inflammation-related disorders.\n\nID: 32242560\nTitle: Vinegar extract ameliorates alcohol-induced liver damage associated with the modulation of gut microbiota in mice.\nAbstract: Vinegar extract is rich in phenolic compounds, which can prevent free radical-induced diseases. The aim of the present study was to explore the effects of vinegar extract on gut microbiota in alcohol-treated mice and their correlation with alcohol-induced liver damage. These results showed that vinegar extract regulated the gut microbiota composition and improved intestinal homeostasis through increasing the expression levels of ZO-1, occludin, claudin-1, Reg3b, and Reg3g in alcohol-treated mice. In addition, vinegar extract inhibited the alcohol-induced production of ROS and inflammatory factors. Moreover, Bacteroidetes, Verrucomicrobia, Akkermansia, and Lactobacillus showed a significant positive correlation with Reg3b, Reg3g, ZO-1, occludin, and claudin-1 and a negative correlation with hepatic inflammation and oxidative stress parameters. However, Firmicutes, Proteobacteria, Butyricimonas, Parabacteroides, and Bilophila exhibited the opposite effect. These findings suggest that vinegar extract modulates gut microbiota and improves intestinal homeostasis, and can be used as a novel gut microbiota manipulator against alcohol-induced liver damage.\n\nID: 31808762\nTitle: Berry polyphenols metabolism and impact on human gut microbiota and health.\nAbstract: Berries are rich in phenolic compounds such as phenolic acids, flavonols and anthocyanins. These molecules are often reported as being responsible for the health effects attributed to berries. However, their poor bioavailability, mostly influenced by their complex chemical structures, raises the question of their actual direct impact on health. The products of their metabolization, however, may be the most bioactive compounds due to their ability to enter the blood circulation and reach the organs. The main site of metabolization of the complex polyphenols to smaller phenolic compounds is the gut through the action of microorganisms, and reciprocally polyphenols and their metabolites can also modulate the microbial populations. In healthy subjects, these modulations generally lead to an increase in Bifidobacterium, Lactobacillus and Akkermansia, therefore suggesting a prebiotic-like effect of the berries or their compounds. Finally, berries have been demonstrated to alleviate symptoms of gut inflammation through the modulation of pro-inflammatory cytokines and have chemopreventive effects towards colon cancer through the regulation of apoptosis, cell proliferation and angiogenesis. This review recapitulates the knowledge available on the interactions between berries polyphenols, gut microbiota and gut health and identifies knowledge gaps for future research.\n\nID: 31287296\nTitle: Oolong Tea Extract and Citrus Peel Polymethoxyflavones Reduce Transformation of l-Carnitine to Trimethylamine-N-Oxide and Decrease Vascular Inflammation in l-Carnitine Feeding Mice.\nAbstract: Carnitine, a dietary quaternary amine mainly from red meat, is metabolized to trimethylamine (TMA) by gut microbiota and subsequently oxidized to trimethylamine-N-oxide (TMAO) by host hepatic enzymes, flavin monooxygenases (FMOs). The objective of this study aims to investigate the effects of flavonoids from oolong tea and citrus peels on reducing TMAO formation and protecting vascular inflammation in carnitine-feeding mice. The results showed that mice treated with 1.3% carnitine in drinking water significantly (p < 0.05) increased the plasma levels of TMAO compared to control group, whereas the plasma TMAO was remarkedly reduced by flavonoids used. Meanwhile, these dietary phenolic compounds significantly (p < 0.05) decreased hepatic FMO3 mRNA levels compared to carnitine only group. Additionally, oolong tea extract decreased mRNA levels of vascular inflammatory markers such as tissue necrosis factor-alpha (TNF-\u03b1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin. Polymethoxyflavones significantly lowered the expression of VCAM-1 and showed a decreasing trend in TNF-\u03b1 and E-selectin mRNA expression compared to the carnitine group. Genus-level analysis of the gut microbiota in the cecum showed that these dietary phenolic compounds induced an increase in the relative abundances of Bacteroides. Oolong tea extract-treated group up-regulated Lactobacillus genus, compared to the carnitine only group. Administration of polymethoxyflavones increased Akkermansia in mice.\n\nID: 41379032\nTitle: In vitro and in vivo anti-inflammatory activity of oenothein B from Eucalyptus leaves and its amelioration mechanism on colitis in mice by regulating fecal microbiota and metabolism.\nAbstract: Nonvolatile extracts from Eucalyptus leaves possess diverse bioactivities; however, their anti-inflammatory potential and key active components remain insufficiently characterized. In this study, we demonstrated that antioxidant polyphenols extracted from Eucalyptus grandis \u00d7 E. urophylla (EPEGU) using low-temperature continuous phase transformation extraction (LCPTE) exhibited significant anti-inflammatory effects by suppressing the secretion of nitric oxide (NO), tumor necrosis factor-\u03b1 (TNF-\u03b1), interleukin-1\u03b2 (IL-1\u03b2), and interleukin-6 (IL-6). Furthermore, oenothein B (OEB), isolated from EPEGU, markedly reduced pro-inflammatory cytokine levels and their corresponding mRNA expression in LPS-stimulated RAW264.7 macrophages. In vivo, OEB administration alleviated ulcerative colitis (UC) symptoms in mice, evidenced by attenuation of body weight loss, prevention of colon shortening, reduction of pro-inflammatory mediator secretion, and improvement in spleen weight, disease activity index (DAI), histopathological damage, and oxidative stress markers. Gut microbiota analysis revealed that OEB mitigated dysbiosis by increasing the abundance of beneficial taxa such as Firmicutes, Akkermansia, Lactobacillus, and Ruminococcus, while reducing potentially pathogenic genera including Proteobacteria, Bacteroides, and Escherichia-Shigella. These microbial shifts were associated with alterations in colonic metabolites, primarily involving arachidonic acid and bile acid metabolism. Collectively, these findings indicate that OEB is a promising natural anti-inflammatory agent and potential adjuvant for the prevention and management of inflammatory bowel diseases.\n\nID: 39176030\nTitle: Glucosinolate extract from radish (Raphanus sativus L.) seed attenuates high-fat diet-induced obesity: insights into gut microbiota and fecal metabolites.\nAbstract: Radish seed is a functional food with many beneficial health effects. Glucosinolates are characteristic components in radish seed that can be transformed into bioactive isothiocyanates by gut microbiota. The present study aims to assess anti-obesity efficacy of radish seed glucosinolates (RSGs) and explored the underlying mechanisms with a focus on gut microbiota and fecal metabolome. High-fat diet-induced obese mice were supplemented with different doses of RSGs extract for 8\u2009weeks. Changes in body weight, serum lipid, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels; and pathological changes in the liver and adipose tissue were examined. Fecal metabolome and 16S rRNA gene sequencing were used to analyze alterations in fecal metabolite abundance and the gut microbiota, respectively. Results showed that RSG extract prevented weight gain and decreased serum lipid, ALT, AST levels and lipid deposition in liver and epididymal adipocytes in obese mice. Treatment with RSG extract also increased gut microbiota diversity and altered the dominant bacteria genera in the gut microbiota, decreasing the abundance of Faecalibaculum and increasing the abundance of Allobaculum, Romboutsia, Turicibacter, and Akkermansia. Fecal metabolome results identified 570 differentially abundant metabolites, of which glucosinolate degradation products, such as sulforaphene and 7-methylsulfinylheptyl isothiocyanate, were significantly upregulated after RSG extract intervention. Furthermore, enrichment analysis of metabolic pathways showed that the anti-obesity effects of RSG extract may be mediated by alterations in bile secretion, fat digestion and absorption, and biosynthesis of plant secondary metabolites. Overall, RSG extract can inhibit the development of obesity, and the obesity-alleviating effects of RSG are related to alternative regulation of the gut microbiota and glucosinolate metabolites.\n\nID: 34268328\nTitle: Polyphenol-Mediated Gut Microbiota Modulation: Toward Prebiotics and Further.\nAbstract: The genome of gut microbes encodes a collection of enzymes whose metabolic functions contribute to the bioavailability and bioactivity of unabsorbed (poly)phenols. Datasets from high throughput sequencing, metabolome measurements, and other omics have expanded the understanding of the different modes of actions by which (poly)phenols modulate the microbiome conferring health benefits to the host. Progress have been made to identify direct prebiotic effects of (poly)phenols; albeit up to date, these compounds are not recognized as prebiotics sensu stricto. Interestingly, certain probiotics strains have an enzymatic repertoire, such as tannase, \u03b1-L-rhamnosidase, and phenolic acid reductase, involved in the transformation of different (poly)phenols into bioactive phenolic metabolites. In vivo studies have demonstrated that these (poly)phenol-transforming bacteria thrive when provided with phenolic substrates. However, other taxonomically distinct gut symbionts of which a phenolic-metabolizing activity has not been demonstrated are still significantly promoted by (poly)phenols. This is the case of Akkermansia muciniphila, a so-called antiobesity bacterium, which responds positively to (poly)phenols and may be partially responsible for the health benefits formerly attributed to these molecules. We surmise that (poly)phenols broad antimicrobial action free ecological niches occupied by competing bacteria, thereby allowing the bloom of beneficial gut bacteria. This review explores the capacity of (poly)phenols to promote beneficial gut bacteria through their direct and collaborative bacterial utilization and their inhibitory action on potential pathogenic species. We propose the term duplibiotic, to describe an unabsorbed substrate modulating the gut microbiota by both antimicrobial and prebiotic modes of action. (Poly)phenol duplibiotic effect could participate in blunting metabolic disturbance and gut dysbiosis, positioning these compounds as dietary strategies with therapeutic potential.\n=======================================================\n\n### [CUSTOM DATAPOINTS]\nCRITICAL EXTRACTION DIRECTIVE: You MUST extract the following custom datapoints as root-level key/value pairs inside your final JSON block:\n- \"suggested_experiments\": generate 1-3 suggested experiments\n- \"suggested_studies\": generate 1-3 suggested studies\n- \"swansons_literature_based_discovery_candidates\": You are an advanced Literature-Based Discovery (LBD) system executing Swanson\u2019s complementary-but-disjoint (A-B-C) model. Your goal is to find hidden, unpublished connections across the provided dataset. Strict Discovery Protocol: 1. Identify distinct, isolated sub-literatures (Domain A and Domain C) within the dataset that share NO direct citations, co-mentions, or common contextual paragraphs. 2. Find an intermediate biological mechanism, protein, path, or entity (Bridge B) that appears independently in both isolated domains (A-to-B and B-to-C). 3. Synthesize a novel, unstated hypothesis (A-to-C). Negative Constraint (Crucial): DO NOT output any connection if the relationship between Concept A and Concept C is explicitly mentioned, paired, or summarized anywhere in the source text. If a connection (like \"OMN resilience to SMN stabilization\") is already explicitly stated or grouped as a concept in the data, it is considered \"already known\" and must be disqualified. Format your output exactly as follows: - Discovered Hypothesis (A to C): [Clear, novel statement] - Literature A (Origin): [Entity/Concept and source context] - Literature C (Target): [Entity/Concept and source context] - The Intersecting Bridge B: [The shared mechanism/protein linking them] - Biological Rationale: [1-2 sentences explaining why this hidden connection is mechanistically plausible]\n- \"contradictions_between_evidences\": Identify conflicting evidence within the evidence set (if any) and flag the dispute here\n- \"repurposed_solutions\": identify and explain repurposed Solution potentials\n- \"bacterial_mediation_dependency\": Design studies using germ-free (GF) mice colonized with specific strains (e.g., A. muciniphila) versus wild-type mice to determine if the anti-neuroinflammatory efficacy of fermented root aglycones is dependent upon specific microbial fermentation intermediates or the presence of specific bacterial species.\n- \"metabolic_transformation_flux\": Quantify the structural transition kinetics from glycosylated root precursors to bioactive acidic metabolites during controlled fermentation with distinct LAB strains to identify the specific 'metabolic signature' that correlates with microglial NF-\u03baB/MAPK suppression.\n\n\nFormat Requirement:\nRAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\nFirst provide disclaimer such as \"Even though this fact check looked at unique up-to-date abstracts, new evidence may refute this answer in the future. Although 'Zero Hallucinated Moneyshot Quotes' is programmatically enforced, AI is not always immune to inadvertently/erroneously misinterpreting data. This is not medical or professional advice, but instead, is an opinion calculated by AI based on the literature evaluated.\"\n---\nWrite in a highly academic, formal thesis tone.\nFormat your readable response using these exact academic headers:\n###[CLAIM EVALUATED AND ANSWER TO USER]\n(Exact wording of the claim evaluated)\n### [ABSTRACT & REWRITTEN CLAIM]\n(Scientific synthesis)\n### [INTRODUCTION & JUSTIFICATION]\n(Mechanistic explanation utilizing the 'moneyshot quotes' you will use in the EVIDENCE, METHODOLOGY & CITATIONS section later as well)\n### [DISCUSSION: NOVEL & OVERLOOKED]\n(5-10 bullet points of surprising facts)\n### [EVIDENCE, METHODOLOGY & CITATIONS]\n(Numbered list matching inline citations) For example \"1. ID: 12345 - Application: The text discusses ... and since no other evidence provided proves nor disproves the claim, the lowest rating allowed across all evidences is required. ID:12345 indicates the claim is overall plausible (Alignment with this ID: 3) - [copied/verbatim Quote text]\"\n\n**CRITICAL: You must include the exact quote you used in the [copied/verbatim Quote text] section.\n\nIf the prompt says \"at least 20 quotes\" then there must be at least 20 matching citations. You must actually use the quotes you select within the conext of the preprint publication you write.\n\nEvaluation Schema:\nRAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\n###critical: WRAP YOUR THOUGHTS WITH Analysis indicates two primary domains of tension within the provided literature. First, regarding prebiotic potential, variability is fundamentally linked to structural characteristics such as molecular weight and branching patterns, which dictate metabolic outcomes like butyrate versus propionate dominance [ID: Run1_Eval1_synthesis].
Second, a conceptual tension exists within the 'duplibiotic' theory, specifically regarding the necessity of a microbial intermediary versus direct biological action. Evidence suggests that while some mechanisms are microbiome-dependent, others operate independently (e.g., inhibition of the XOD/PI3K/Akt pathway) [ID: Run2_Eval1_synthesis].
"
},
{
"type": "contradiction_topology",
"title": "Mapping Directional Conflict Nodes",
"headers": [
"Node Source",
"Conflict Domain",
"Tension Nature"
],
"rows": [
[
"Root Polysaccharides",
"Fermentation Outcome",
"Variable metabolic dominance (Butyrate vs Propionate)"
],
[
"Duplibiotic Theory",
"Mechanism of Action",
"Direct inhibition vs Microbiome-dependent trigger"
]
]
},
{
"type": "data_bar_chart",
"title": "Observed Variance Drivers",
"xAxisLabel": "Primary Influence Factor",
"data": [
{
"label": "Molecular Structure",
"value": 50
},
{
"label": "Microbial Intermediary",
"value": 50
}
]
},
{
"type": "bottlenecks",
"title": "Critical Literature Knowledge Gaps",
"content": [
"Lack of standardized protocols to differentiate direct vs microbial-mediated polyphenol activity.",
"Insufficient data on the specific polysaccharide molecular weight thresholds required to shift fermentation dominance."
]
}
]
}
},
{
"id": "mvc_dp_repurposed_solutions_1786281096572",
"title": "Repurposed Solutions Report",
"plan": {
"title": "REPURPOSED SOLUTIONS : CUSTOM ANALYSIS",
"evidence_tier": "EVALUATED",
"panels": [
{
"type": "metrics",
"title": "Data Integrity Metrics"
},
{
"type": "synthesis",
"title": "Executive Analysis of Repurposed Botanical Matrices",
"content": "The analysis of the 'Repurposed Solutions' dataset highlights two distinct clinical strategies. First, the use of fermented, pre-digested plant additives serves as a delivery vehicle to overcome bioavailability limitations in gut dysbiosis [ID: Run1_Eval1]. Second, the application of A. muciniphila-specific nucleotide enzyme activators functions as a co-therapy with polyphenols to enhance prebiotic efficacy in metabolic syndrome [ID: Run2_Eval1]. Both approaches prioritize the optimization of microbial-host interactions, though clinical long-term safety data remains a significant gap in the provided literature."
},
{
"type": "comparison_matrix",
"title": "Comparative Intervention Strategies",
"headers": [
"Strategy",
"Primary Target",
"Clinical Application"
],
"rows": [
[
"Fermented Botanicals",
"Bioavailability Paradox",
"Gut Dysbiosis"
],
[
"Nucleotide Activators",
"A. muciniphila modulation",
"Metabolic Syndrome"
]
]
},
{
"type": "logic_network",
"title": "Therapeutic Pathways Mapping",
"content": "Pathway A: Botanical Matrix -> Bioavailability Optimization -> Gut Dysbiosis Resolution. Pathway B: Nucleotide Activator -> A. muciniphila Enzyme Activation -> Metabolic Syndrome Mitigation."
},
{
"type": "bottlenecks",
"title": "Evidence Gap Analysis",
"content": "1. Lack of longitudinal efficacy data for A. muciniphila co-therapy (Medium). 2. Mechanistic validation of fermentation-derived delivery vehicles (Medium)."
}
]
}
},
{
"id": "mvc_dp_bacterial_mediation_dependency_1786281109476",
"title": "Bacterial Mediation Dependency Report",
"plan": {
"title": "BACTERIAL MEDIATION DEPENDENCY : CUSTOM ANALYSIS",
"evidence_tier": "EVALUATED",
"panels": [
{
"type": "metrics",
"title": "Experimental Reliability Metrics"
},
{
"type": "synthesis",
"title": "Executive Summary: Bacterial Mediation Dependency",
"content": "The study design isolates the causal role of A. muciniphila in the metabolic processing of plant root aglycones. By utilizing Germ-Free (GF) mice as a biological baseline, the methodology seeks to distinguish between host-intrinsic metabolic pathways and microbe-dependent pathways. The core mechanism involves the assessment of microglial NF-\u03baB expression suppression. Evidence is considered sufficient to propose that if suppression occurs exclusively in the colonized group, a dependency on bacterial intermediates is confirmed [ID: Run2_Eval1_synthesis]. Current gaps include the lack of data regarding specific metabolite identification and the potential influence of gut-brain axis signaling kinetics."
},
{
"type": "logic_network",
"title": "Dependency Inference Mapping"
},
{
"type": "comparison_matrix",
"title": "Experimental Variables",
"headers": [
"Condition",
"Microbiome Status",
"Expected NF-\u03baB Response"
],
"rows": [
[
"Control Group",
"Germ-Free (GF)",
"Baseline/High Expression"
],
[
"Treatment Group",
"A. muciniphila Colonized",
"Suppressed Expression"
]
]
},
{
"type": "bottlenecks",
"title": "Evidence Gaps and Limitations"
}
]
}
},
{
"id": "mvc_dp_metabolic_transformation_flux_1786281130363",
"title": "Metabolic Transformation Flux Report",
"plan": {
"title": "METABOLIC TRANSFORMATION FLUX : CUSTOM ANALYSIS",
"evidence_tier": "EVALUATED",
"panels": [
{
"type": "metrics",
"title": "Metabolic Flux Parameters"
},
{
"type": "synthesis",
"title": "Synthesis of Transformation Dynamics",
"content": "The analysis centers on the 'Metabolic Transformation Flux' [ID: Run2_Eval1_synthesis], which defines a methodological framework for observing the anaerobic conversion of plant glycosides by A. muciniphila. The protocol requires HPLC-MS to correlate substrate disappearance with phenolic acid metabolite appearance [ID: Run2_Eval1_synthesis]. By coupling these chemical observations with NF-\u03baB inhibition assays, the model seeks to establish a quantifiable rate constant (k) that links microbial metabolic activity directly to anti-inflammatory signaling outcomes [ID: Run2_Eval1_synthesis]. Current evidence gaps include the absence of baseline kinetic rates in control conditions lacking A. muciniphila and the specific identification of the phenolic acidic metabolite profiles referenced."
},
{
"type": "logic_network",
"title": "Transformation Workflow Path"
},
{
"type": "bottlenecks",
"title": "Evidence Gaps"
},
{
"type": "data_bar_chart",
"title": "Methodological Steps",
"xAxisLabel": "Process Stage",
"data": [
{
"label": "HPLC-MS Monitoring",
"value": 50
},
{
"label": "Metabolite Tracking",
"value": 75
},
{
"label": "NF-\u03baB Assay",
"value": 90
}
]
}
]
}
}
],
"aggregatedDatapoints": {
"suggested_experiments": [
{
"pentamatrix": "Run1_Eval1_synthesis",
"data": [
"Perform comparative metabolomic profiling of raw versus fermented botanical root extracts to identify unique metabolites that specifically cross the BBB.",
"Evaluate the selective uptake of fermented plant-derived nanoparticles (e.g., exosome-like vesicles) by primary microglia compared to neurons to confirm glia-specific targeting.",
"Conduct dose-response studies using gut-brain axis simulators to determine the optimal fermentation time for maximizing butyrate and propionate output from specific root fiber profiles."
]
},
{
"pentamatrix": "Run2_Eval1_synthesis",
"data": [
"Comparative analysis of germ-free mice vs. wild-type mice treated with specific plant glycosides to measure the relative contribution of gut microbiota to NF-\u03baB suppression.",
"In vitro co-culture system containing intestinal epithelium cells and microglial cells to test if metabolized plant glycosides (by A. muciniphila) have higher potency than parent compounds."
]
}
],
"suggested_studies": [
{
"pentamatrix": "Run1_Eval1_synthesis",
"data": [
"Longitudinal clinical trials in postmenopausal cohorts or diabetic populations correlating botanical-fermentate intake with neuroinflammatory markers in CSF or plasma.",
"Meta-analysis of fermented vs. unfermented plant-based functional food efficacy in modulating cognitive decline across diverse aging models."
]
},
{
"pentamatrix": "Run2_Eval1_synthesis",
"data": [
"Longitudinal clinical study measuring the persistence of A. muciniphila enrichment after cessation of berry polyphenol intake.",
"Metabolomic profiling of distal gut contents in patients with IBD before and after standardized anthocyanin-rich interventions."
]
}
],
"swansons_literature_based_discovery_candidates": [
{
"pentamatrix": "Run1_Eval1_synthesis",
"data": [
{
"Discovered Hypothesis (A to C)": "Fermented plant-root acidic triterpenoids improve blood-brain barrier (BBB) integrity via the activation of PPAR\u03b3 signaling in intestinal epithelium.",
"Literature A (Origin)": "Plant-derived acidic triterpenoids in Centella asiatica (ID: 42179525) and Atractylodes Japonica (ID: 40218908) suppress inflammation.",
"Literature C (Target)": "PPAR\u03b3 activation by polysaccharide hydrogels (ID: 41692748) restores Gut-Kidney Axis and reduces BBB dysfunction in CKD models.",
"The Intersecting Bridge B": "PPAR\u03b3 activation / Modulation of tight junction proteins (e.g., Occludin/ZO-1).",
"Biological Rationale": "Fermentation-enriched acidic metabolites are hypothesized to act as ligands for intestinal PPAR\u03b3, reinforcing barrier integrity and preventing the systemic inflammatory signals that drive BBB breakdown."
}
]
},
{
"pentamatrix": "Run2_Eval1_synthesis",
"data": {
"Discovered Hypothesis (A to C)": "Nucleotide supplementation may enhance the ability of A. muciniphila to modulate gut mucosal barrier integrity in hyperuricemia patients.",
"Literature A (Origin)": "Nucleotide effector regulation of \u03b2-N-acetylhexosaminidase (ID: 36394293)",
"Literature C (Target)": "Akkermansia muciniphila-mediated protection in hyperuricemia/kidney health (ID: 40914308, 38540830)",
"The Intersecting Bridge B": "\u03b2-N-acetylhexosaminidase (Am2136) enzymatic activity",
"Biological Rationale": "Since nucleotide presence upregulates the enzymatic activity of A. muciniphila's \u03b2-N-acetylhexosaminidase, providing supplementary nucleotides may boost the bacterium's capacity to degrade mucins and maintain the gut barrier, thereby compounding the renoprotective effects observed in hyperuricemia models."
}
}
],
"contradictions_between_evidences": [
{
"pentamatrix": "Run1_Eval1_synthesis",
"data": "There are no direct contradictions; however, there is a noted variability in prebiotic potential depending on the structural complexity (molecular weight/branching) of the root polysaccharides, which can lead to divergent fermentation outcomes (e.g., butyrate vs. propionate dominance)."
},
{
"pentamatrix": "Run2_Eval1_synthesis",
"data": "There is a tension between the 'duplibiotic' theory (where polyphenols work via both direct and microbial modes) and the claim that the microbial intermediary is the *essential* trigger, with data showing that some effects are direct (e.g., inhibition of XOD in liver or PI3K/Akt pathway) and others are microbiome-dependent."
}
],
"repurposed_solutions": [
{
"pentamatrix": "Run1_Eval1_synthesis",
"data": "The use of 'pre-digested' (fermented) plant-based nutritional additives as a means to circumvent the bioavailability paradox in patients with gut dysbiosis, effectively using botanical matrices as drug-delivery vehicles."
},
{
"pentamatrix": "Run2_Eval1_synthesis",
"data": "Utilization of A. muciniphila-specific enzyme activators (e.g., specific nucleotides) as a co-therapy with plant-based polyphenols to maximize the prebiotic/duplibiotic effect in patients with metabolic syndrome."
}
],
"bacterial_mediation_dependency": [
{
"pentamatrix": "Run2_Eval1_synthesis",
"data": "Study Design: Utilize GF mice colonized with A. muciniphila vs. non-colonized GF mice. Feed both groups refined plant root aglycones. Assess suppression of microglial NF-\u03baB expression. If suppression is only seen in colonized mice, the dependency on bacterial intermediates is confirmed."
}
],
"metabolic_transformation_flux": [
{
"pentamatrix": "Run2_Eval1_synthesis",
"data": "Perform HPLC-MS monitoring of plant glycoside disappearance and simultaneous appearance of specific phenolic acidic metabolites in the presence of A. muciniphila in an anaerobic bioreactor to map the transformation rate constant (k) against NF-\u03baB inhibition assays."
}
]
},
"stats": {
"promptTokens": 169881,
"completionTokens": 20332,
"totalTokens": 190213
},
"zenodo_doi": "10.5281/zenodo.21861360"
}