ID: 39660634
Title: Ginsenosides From Panax ginseng Improves Hepatic Lipid Metabolism Disorders in HFD-Fed Rats by Regulating Gut Microbiota and Cholesterol Metabolism Signaling Pathways.
Abstract: A high-fat diet (HFD) is often associated with hepatic lipid metabolism disorders, leading to dysfunction in multiple body systems. Ginsenosides derived from Panax ginseng have been reported to possess potential effects in ameliorating lipid metabolism disorders; however, their underlying mechanisms remain insufficiently explored. This study aims to investigate the bioactivities of ginsenosides in combating lipid metabolism disorders and obesity, with a focus on their mechanisms involving the cholesterol metabolism signaling pathway and gut microbiota. Our results demonstrated that ginsenoside treatment significantly reduced overall body weight, body weight changes, liver weight, and eWAT weight, as well as alleviated hepatic steatosis and dyslipidemia in HFD-fed rats, without affecting food intake. These effects were dose-dependent. Furthermore, 16S rRNA sequencing revealed that ginsenosides significantly increased the relative abundance of Akkermansia muciniphila, Blautia, Eisenbergiella, Clostridium clusters XI, XVIII, and III, while decreasing the relative abundance of Clostridium subcluster XIVa and Dorea. In addition, ginsenoside treatment significantly regulated the expression of hepatic genes and proteins involved in the cholesterol metabolism signaling pathway (FXR, CYP7A1, CYP7B1, CYP27A1, ABCG5, ABCG8, Insig2, and Dhcr7), potentially inhibiting hepatic cholesterol biosynthesis while promoting cholesterol transport to HDL and its excretion via bile and feces. Notably, levels of 7-dehydrocholesterol (7-DHC) and 27-hydroxycholesterol (27-OHC) were reduced, while 5β,6β-epoxycholesterol (5,6β-epoxy) levels were elevated following ginsenoside treatment, indicating significant modulation of oxysterols by ginsenosides. Moreover, bile acid enterohepatic circulation was regulated through the enhancement of hepatic FXR-CYP7A1 signaling and intestinal FXR-FGF15 signaling in HFD-fed rats treated with ginsenosides, which was closely linked to gut microbiota composition. Collectively, our findings suggest that ginsenosides alleviate hepatic lipid metabolism disorders by modulating gut microbiota and the cholesterol metabolism signaling pathway in HFD-fed rats.

ID: 40268803
Title: Gut microbiota regulates hepatic ketogenesis and lipid accumulation in ketogenic diet-induced hyperketonemia by disrupting bile acid metabolism.
Abstract: The ketogenic diet (KD) induces prolonged hyperketonemia, characterized by elevated circulating level of β-hydroxybutyrate. However, the KD can negatively affect host metabolic health by altering the gut microbial community. Despite this, the regulatory effect of the gut microbiota on hepatic ketogenesis and triacylglycerol (TAG) accumulation during a KD remains poorly understood. Here, we hypothesized that the commensal bacterium regulates hepatic lipid metabolism in association with KD-induced hyperketonemia. The KD disrupts the remodeling of the gut microbiota following antibiotic-induced depletion. The capacity for ketogenesis and the severity of TAG accumulation in the liver closely correlated with changes in the gut microbial composition and the up-regulation of hepatic farnesoid X receptor (FXR), peroxisome proliferator-activated receptor alpha (PPARα), and diacylglycerol O-acyltransferase 2 (DGAT2), which were modulated by bile acid metabolism through the gut-liver axis. The commensal bacterium Clostridium perfringens type A is particularly implicated in prolonged hyperketonemia, exacerbating hepatic ketogenesis and steatosis by disrupting secondary bile acid metabolism. The increased conversion of deoxycholic acid to 12-ketolithocholic acid represents a critical microbial pathway during C. perfringens colonization. These findings illuminate the adverse effects of the gut microbiota on hepatic adaptation to a KD and highlight the regulatory role of C. perfringens in ketonic states.

ID: 40345144
Title: Walnut-derived peptides combined with intermittent fasting alleviated obesity by modulating gut microbiota and liver metabolome in high-fat-diet-induced obesity mice.
Abstract: This study aimed to investigate the anti-obesity mechanism of walnut-derived peptides (WMP) combined with intermittent fasting (IF) through modulating the gut microbiota-liver metabolism axis in high-fat-diet (HFD)-induced obese mice, providing theoretical support for dietary intervention strategies. Fifty C57BL/6 mice were divided into five groups (n = 10): normal diet, HFD, WMP, IF and WMP + IF, with an 8-week intervention. Biochemical analysis, 16S rRNA sequencing, and untargeted liver metabolomics were employed to explore the underlying mechanisms. WMP + IF significantly alleviated hyperlipidemia, glucose metabolism disorders, insulin resistance, and visceral fat deposition in HFD mice, while suppressing systemic inflammation. Gut microbiota analysis revealed reduced abundance of Firmicutes, Kineothrix, and Dubosiella, along with a decreased Firmicutes/Bacteroidota (F/B) ratio, whereas Bacteroidota and CAG-873 were enriched. Correlation analysis demonstrated positive associations between Firmicutes and obesity-related markers (lipid profiles, liver dysfunction, pro-inflammatory cytokines), while Bacteroidota exhibited negative correlations. Untargeted metabolomics identified upregulated levels of 16-hydroxypalmitic acid and 13-S-hydroxyoctadecadienoic acid (13(S)-HODE), alongside activation of ABC transporters and galactose metabolism pathways. Notably, 13(S)-HODE showed negative correlations with Firmicutes, F/B ratio, and Kineothrix, but positive correlations with Bacteroidota and CAG-873. The synergistic anti-obesity effects of WMP and IF are mediated through restoring gut microbial balance and reprogramming hepatic metabolic pathways. These findings highlight novel mechanisms involving the gut-liver axis, offering innovative strategies for obesity prevention through natural bioactive compounds combined with dietary interventions. © 2025 Society of Chemical Industry.

ID: 41124705
Title: Integrative gut microbiota and metabolomics reveals the mechanism of chicory extract in improving metabolic dysfunction-associated steatotic liver disease via gut-liver axis.
Abstract: Chicory (Cichorium intybus l.) has shown an efficacy anti-metabolic dysfunction-associated steatotic liver disease (MASLD) in basic research and clinical applications, but its pharmacodynamic mechanism remains unclear. This work aims to clarify the pharmacological mechanism of chicory aqueous extract (CE) in improving MASLD from the perspective of gut-liver interaction. MASLD mice induced by a high-fat diet were employed as the in vivo model, while palmitic acid-induced AML12 cells served as the in vitro model. Combined qRT-PCR and Western blot to detect the expression of lipid metabolism-related genes/proteins. 16S rDNA sequencing and gut microbiota depletion experiments were conducted to elucidate the CE-gut microbiota interaction. UPLC-Q-TOF-MS was employed to analyze the chemical components of CE and plasma metabolite profiles. CE significantly inhibited body weight gain, improved hepatic lipid deposition, and down-regulated the expression of SREBP1 and SCD1 in MASLD mice. 16S rDNA sequencing and antibiotic-depleted microbiota experiments showed that CE significantly affected the diversity and community richness of gut microbiota, and its efficacy depended on the presence of gut microbiota. Metabolomics identified plasma taurodeoxycholic acid (TDCA) as a core metabolite of CE intervention, and its level was positively correlated with the abundance of microbial bile salt hydrolase (BSH). Furthermore, in vitro experiments confirmed that TDCA dose-dependently inhibited lipid accumulation in AML12 hyperlipidemic cells. CE exerts an anti-MASLD effect by remodeling the gut microbiota to promote TDCA synthesis, thereby suppressing SREBP1/SCD1 axis. This provides a theoretical foundation for developing gut-liver axis-targeted natural therapies against MASLD.

ID: 41140213
Title: The Role of Lipoprotein and Gut Microbiome in Alzheimer's Disease: A Review of Novel Findings and Potential Applications.
Abstract: Alzheimer's disease (AD), a progressive neurodegenerative disorder, is inadequately comprehended, with hypotheses implicating amyloid-β, tau pathology, mitochondrial dysfunction, and epigenetic factors. Recent research underscores the significance of lipoproteins and the gut microbiota in the etiology of AD. Apolipoprotein E (ApoE), particularly the E4 subtype, emerges as a key genetic risk factor, influencing oxidative stress, synaptic defects, glucose metabolism, and amyloid-β clearance. Lipoprotein receptors, such as LRP-1, also influence the integrity of the blood-brain barrier, indicating potential for therapeutic applications. Novel therapies targeting lipoproteins, such as ALZ-801 and IDOL inhibitors, show promise in preclinical and clinical trials. Concurrently, the gut microbiome's impact on AD is increasingly recognized. Dysbiosis correlates with inflammation, mitochondrial oxidative stress, impaired autophagy, and neurotransmitter imbalances. Gut-derived metabolites, including phenylalanine and isoleucine, promote Th1 cell activation and microglial dysfunction, exacerbating AD pathology. Interventions, like probiotics, GV-971, and polyphenols, demonstrate efficacy in restoring microbial balance and mitigating cognitive decline. Crucially, bidirectional interactions between lipoproteins and the gut microbiome are implicated in AD. ApoE genotypes influence gut microbial composition, while microbiota- derived short-chain fatty acids and endotoxins modulate lipid metabolism and neuroinflammation. These interactions, mediated via the gut-brain axis, highlight novel therapeutic avenues. Current FDA-approved AD drugs face limitations in efficacy and side effects, underscoring the need for innovative strategies targeting lipoprotein-gut microbiome crosstalk. Integrating insights into lipoprotein biology and gut microbiota dynamics may offer transformative potential for AD treatment, emphasizing combinatorial approaches to modulate these interconnected pathways. Further research is warranted to elucidate mechanistic links and translate preclinical findings into clinical applications.

ID: 41146521
Title: Bacteroides eggerthii ameliorates metabolic dysfunction-associated steatotic liver disease through host-microbe signaling and highlights 2-hydroxyisocaproate as a potential effector.
Abstract: Gut microbiome plays a pivotal role in metabolic dysfunction-associated steatotic liver disease (MASLD) pathogenesis, yet, associated functional mechanisms and host responses of specific microbial species remain insufficiently characterized. This study investigated the Bacteroides eggerthii therapeutic effects on MASLD by integrating multi-omics analysis and experimental validation in a Western diet (WD)-induced mouse model. Candidate strains were identified using 16S rRNA gene sequencing of fecal samples from individuals with and without MASLD or obesity. B. eggerthii, a species significantly depleted in both groups, was selected for functional evaluation. Male C57BL/6J mice were fed a WD or WD supplemented with B. eggerthii (WD+B) for 12 weeks. Liver histology, serum biochemistry, fecal microbiome and metabolome profiling, and hepatic and intestinal transcriptomic analyses were performed. Anti-steatotic effects of B. eggerthii-derived metabolites were validated in vitro. Bacteroides eggerthii supplementation significantly improved liver weight, inflammation, fibrosis, and steatosis in WD+B group compared to WD alone. PICRUSt-based LEfSe analysis revealed choloylglycine hydrolase activity enrichment in gut microbiota, and strain-specific qPCR confirmed colonization in mouse colon. Integrated transcriptomic analyses revealed lipid and bile acid signaling pathway restoration, including CD36, FXR, and FGF15. Untargeted metabolomics identified elevated 2-hydroxyisocaproic acid (HICA) as a strain-derived metabolite in feces and B. eggerthii culture supernatants. In vitro, HICA significantly reduced lipid accumulation in free fatty acid-induced steatosis models. Bacteroides eggerthii ameliorates MASLD via gut-liver axis modulation, including bile acid metabolism and hepatic lipid signaling. These underscore its therapeutic potential and highlight HICA as a novel microbiome-derived metabolite with anti-steatotic activity.

ID: 41299593
Title: Gut microbial tyramine facilitates intestinal damage and metabolic dysfunction-associated steatotic liver disease development.
Abstract: Emerging evidence indicates that gut microbiota and intestinal injury are crucial in pediatric metabolic dysfunction-associated steatotic liver disease (MASLD), yet the role of key gut microbial metabolites such as tyramine in pediatric MASLD remains largely unknown. In this study, we aimed to explore the role of gut microbial tyramine in intestinal damage and MASLD development in children. We investigated the functions and mechanisms of previously isolated Enterococcus faecium B6 (E. faecium B6) and its derived tyramine in a mice model of intestinal injury and MASLD development. An integrative analysis of transcriptomics and proteomics was performed on mouse liver to explore the molecular mechanisms of tyramine in MASLD progression. Targeted metabolomics was performed using fecal samples from a hospital-based population (27 MASLD cases and 27 matched controls) to measure tyramine levels. The association of serum tyramine and MASLD risk was then validated in a school-based population, using serum samples of 294 children in the MASLD group and 235 controls. E. faecium B6 and its metabolite tyramine significantly disrupted the intestinal barrier and increased intestinal permeability in mice. Tyramine supplementation promoted MASLD-related metabolic phenotype in mice. Multi-omics analysis indicated that the PPAR signaling pathway played an important role in the molecular mechanisms. Tyramine contributed to lipid accumulation mainly by increasing lipid synthesis and lipid uptake but reducing the β-oxidation processes in the mouse liver, as shown by real-time quantitative polymerase chain reaction and western blot. Furthermore, we demonstrated from the hospital-based cohort that tyramine concentration was significantly higher in the MASLD group than in the control group. Consistently, the school-based cohort demonstrated a higher risk of MASLD in the high-tyramine group compared to the low-tyramine group, with adjusted odds ratios (ORs) and 95% confidence intervals (CIs) of 3.65 (95% CI: 2.66-4.32). These results demonstrated that gut microbial tyramine effectively induced intestinal damage and facilitated MASLD development in mice. Tyramine was positively associated with the risk of MASLD in children. This study offered mechanistic insights into the pathogenesis of MASLD and opened therapeutic opportunities for such metabolic diseases.

ID: 41665239
Title: Integrated Transcriptomic and Metabolomic Analyses Reveal the Protective Mechanism of Icaritin Against High-Fat Diet-Induced Metabolic Dysfunction-Associated Steatotic Liver Disease in Mice.
Abstract: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent chronic liver disease. Icaritin (ICT) has demonstrated potential hepatoprotective effects, while its protective mechanisms on MASLD are still unclear. This study aims to investigate the therapeutic efficacy of ICT against MASLD and elucidate its underlying molecular mechanisms. A MASLD mouse model was established via a high-fat diet (HFD) for 12 weeks, with or without gavage of ICT for 4 weeks. Palmitic acid (PA) was used to induce an in vitro model in AML12 hepatocytes. Histological, biochemical, transcriptomic (RNA-Seq), metabolomic, and lipidomic analyses were employed. Key targets were validated using molecular docking, cellular thermal shift assay (CETSA), and gene knockdown approaches. ICT treatment ameliorated HFD-induced hepatic steatosis, dyslipidemia, and reversed the suppression of reverse cholesterol transport genes. The expression of key genes identified by RNA sequencing was verified by RT-qPCR. Integration of transcriptomics and metabolomics revealed that ICT reshaped transcriptomic and metabolomic profiles, highlighting key pathways in glycogen metabolism, lipid metabolism, and antioxidant responses. Both in vivo and in vitro, ICT reversed the downregulation of GSTA1 expression. Molecular docking and CETSA confirmed a direct binding interaction between ICT and the GSTA1 protein. GSTA1 knockdown in AML12 cells abolished the protective effects of ICT. ICT alleviates MASLD progression by targeting GSTA1-mediated metabolic reprogramming, providing a novel mechanistic foundation for ICT as a promising candidate for MASLD treatment.

ID: 41688737
Title: Supplementation of L-aspartate corrects MASLD and MASH in mice by inhibiting platelet-hepatocyte interaction-mediated mitochondrial fragmentation via the ATP-P2X7-NEK7-DRP1 axis.
Abstract: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a worldwide prevalent metabolic disorder with increasing demands for therapeutic agents. L-aspartate is a nonessential amino acid that has great potential for curing liver disease. However, the therapeutic potential of L-aspartate against MASLD and its severe form metabolic dysfunction-associated steatohepatitis (MASH), as well as its metabolic regulation mode, are not well documented. Here we found that plasma and liver L-aspartate levels were decreased and negatively correlated with the severity of MASLD in mice and humans. L-aspartate supplementation in mice reversed the manifestations of both MASLD and MASH and these were correlated with improvements in hepatic mitochondrial quality and oxidation. The results of joint transcriptome and metabolomics analyses revealed that the metabolite cGMP and platelet activation were highly annotated after a single L-aspartate treatment. Notably, L-aspartate treatment increased cGMP levels in platelets and blocked platelet activation and aggregation, thereby suppressing activated platelet-derived ATP secretion and its mediated P2X7-NEK7-DRP1 axis hyperactivation in hepatocytes. Correspondingly, L-aspartate addition reversed the ATP-induced increases in oleatic acid-induced mitochondrial fragmentation and lipid accumulation. Interestingly, treatment with either the antiplatelet agent aspirin or the P2X7 inhibitor or NEK7 knockdown corrected oleatic acid + ATP-induced exacerbations of mitochondrial fragmentation and lipid accumulation in hepatocytes or ameliorated MASLD in mice. Notably, the L-aspartate increased cGMP levels in platelets was correlated with reductions in the plasma level of its inducers, including ADP and thrombin. These data together indicate that activated platelet-mediated mitochondrial fragmentation in hepatocytes is a pivotal driving force for MASLD and MASH. Blocking platelet activation underlies the therapeutic potential and metabolic regulation of L-aspartate against MASLD and MASH.

ID: 41751076
Title: Fermented Rice Bran Enhances Rabbit Meat Quality and Nutritional Value via Metabolic Reprogramming and Enriched Nutrient Profiles.
Abstract: The valorization of sustainable feed ingredients such fermented de-oiled rice bran meal (FDRBM) is crucial; however, the molecular mechanisms driving its benefits remain unclear. This study addresses this gap by investigating FDRBM as a dietary substitute for maize in rabbits to determine its effects on meat quality and underlying gut-liver axis communication. In an eight-week trial, New Zealand White rabbits were assigned to a control diet or the basal diet with a 20% substitution of either unfermented de-oiled rice bran (UFDRBM) or FDRBM. Post-trial, the researchers analyzed carcass traits, meat quality, and nutritional composition. A multi-omics approach integrates gene expression data from the ileum and muscle with liver metabolomics to model coordinated biological responses. Although growth performance was similar, the FDRBM diet significantly improved meat quality by enhancing water-holding capacity and increasing essential amino acids (p < 0.05). Mechanistically, these improvements were associated with the upregulation of genes associated with oxidative muscle fiber (Tnnc1) and lipid metabolism. Analysis of the gut-liver axis revealed that FDRBM enhanced ileum antioxidant capacity, which coincided with profound reprogramming of liver metabolism (p < 0.01 *), identifying C17-sphinganine as a differential metabolite. This study provides novel insights into the mode of action of FDRBM, suggesting that it enhances rabbit meat quality in part by modulating metabolic gene expression and is associated with coordinated molecular changes across the gut-liver axis.

ID: 41771387
Title: Integrated metabolomic and transcriptomic analyses reveal Radix Bupleuri alleviates MASLD induced by a high-fat diet and circadian disruption via the DCA/HCA-TGR5-GLP-1 axis.
Abstract: The coexistence of unhealthy diets and circadian rhythm disturbances contributes to the rising prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), for which effective therapies are still lacking. Radix Bupleuri (BR) is a traditional Chinese medicine recognized for its hepatoprotective and lipid-modulating effects. However, the precise mechanisms by which it exerts therapeutic benefits in MASLD are not fully elucidated. This study aimed to clarify the protective effects of BR alleviates MASLD in rats and to thoroughly explore its possible action pathways and molecular mechanisms. To establish MASLD models, rats underwent combined high-fat diet feeding and chronic circadian rhythm disruption (HFD-CRD) via a phase-delaying light-dark cycle (12 h light/12 h dark, with an 8 h delay in light onset every 48 h), followed by 6-week oral administration of BR fractions of varying polarities. Positive controls included Bicyclol and Melatonin. Physiological and biochemical assessments included body weight, liver and epididymal fat mass, locomotor activity, fasting blood glucose, oral glucose tolerance, serum lipid profile, and liver function markers. Hepatic steatosis was evaluated by H&E staining. Mechanistic insights were obtained via hepatic transcriptomics, untargeted metabolomics, targeted bile acid profiling, and qPCR validation. BR treatment, particularly the high polarity fraction of BR (BH), significantly reduced body weight gain, hepatic steatosis, serum ALT and AST levels, and improved glucose tolerance, lipid metabolism, and locomotor activity. Metabolomics revealed BH-mediated normalization of 25 dysregulated liver metabolites, particularly bile acid derivatives. Transcriptomics demonstrated that BH reversed HFD-CRD-induced transcriptional alterations, primarily enriching in bile secretion and insulin signaling pathways. Integrated metabolomic-transcriptomic correlation analyses demonstrated that bile acid and glucolipid related genes were closely linked with metabolic phenotypes. Targeted bile acid quantification confirmed that BH comprehensively restored the dysregulated bile acid pool, with the DCA/HCA pair emerging as the most sensitive biomarker of metabolic remodeling. Functional validation further showed that BH reversed aberrant expression of bile acid secretion and glucose metabolism genes and activated hepatic and intestinal TGR5/GLP-1 signaling, thereby improving bile acid homeostasis, glucose metabolism, and gut barrier integrity. BR ameliorates HFD-CRD-induced MASLD by restoring bile acid homeostasis, modulating glucolipid metabolism, and activating the TGR5/GLP-1 axis, expanding the pharmacological basis of BR for liver disorders and offering novel insights into multi-target MASLD therapeutics.

ID: 41797191
Title: Xiayuxue decoction alleviates MASH by regulating gut microbiota, bile acid metabolism, and m6A modification.
Abstract: Metabolic dysfunction-associated steatohepatitis (MASH) has emerged as a worldwide health challenge with few therapeutic options. Xiayuxue Decoction (XYXD), a classical herbal formula from the Synopsis of the Golden Chamber (Jin Gui Yao Lue), a classic by Zhang Zhongjing, comprises Prunus persica (Linn.) Batsch, Rheum palmatumLinn., and Eupolyphaga sinensis Walker. While clinically employed for the treatment of chronic liver diseases, including MASH, its precise molecular mechanisms remain undefined. This study aims to clarify the therapeutic mechanisms underlying the effects of XYXD in MASH, with a particular focus on investigating its roles in gut microbiota remodeling, bile acid (BA) metabolism, N6-methyladenosine (m6A) transcriptional modification, and arachidonic acid (AA) metabolism. A MASH model was induced by using a methionine-choline-deficient (MCD) diet, and the therapeutic effect of XYXD was evaluated by analyzing lipid profiles, liver function parameters, and histopathological changes. Gut microbiota composition was characterized via 16S rRNA gene sequencing. Meanwhile, the metabolomic profiling of BA metabolites in the liver, serum, and feces, as well as AA derivatives in the liver, was performed by using LC-MS/MS. Additionally, the expression profiles of relevant mRNAs and proteins, including those related to BA metabolism, lipid homeostasis, inflammatory response, and m6A modification, were determined. Deoxycholic acid (DCA) and XYXD-containing serum were used to treat RAW264.7 macrophage cells to verify further their regulatory effects on inflammation, m6A modification, and AA metabolism in vitro. XYXD exhibits therapeutic efficacy against MASH through the dual regulation of inflammatory pathways and lipid metabolic homeostasis. It effectively reverses MCD diet-induced microbiota imbalance and maintains BA homeostasis by activating the farnesoid X receptor (FXR)-small heterodimer partner (SHP) pathway, with a particular role in reducing Clostridium abundance and DCA levels. Further investigations revealed that DCA mediates the upregulation of methyltransferase-like 13/14 mRNA, which in turn enhances m6A modification and influences AA metabolism. This integrated regulation of inflammatory, metabolic, and epigenetic pathways underscores XYXD's systemic therapeutic potential. XYXD alleviates MASH via the following multifaceted regulatory mechanism: it modulates gut microbiota dynamics, activates the FXR-SHP axis to maintain BA homeostasis, and ultimately regulates m6A transcriptional modification to influence AA metabolism. This coordinated network establishes functional crosstalk between microbiota and metabolic pathways in disease intervention.

ID: 41800297
Title: Gut-Derived Hippuric Acid Alleviates Hepatic Lipid Metabolism via UGDH/FOXK1/CD36 Axis in Obese Mice.
Abstract: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of chronic liver disease globally, creating an urgent need to elucidate its pathogenesis and develop effective therapeutic strategies. In this study, we established obese mouse models using distinct dietary patterns. We then employed 16S rRNA sequencing and metabolomics to profile gut microbiota composition and identify differential metabolites in serum and intestinal contents. Using Limited proteolysis mass spectrometry, co-immunoprecipitation mass spectrometry and luciferase reporter assays were used to identify the downstream molecular mechanisms. Our findings revealed that the abundance of hippuric acid (HA) was significantly decreased in the serum and gut of obese C57BL/6 mice, and it positively correlated with the abundance of Akkermansia and Alistipes. Notably, HA supplementation effectively reduced body weight and alleviated hepatic lipid accumulation in obese mice. Mechanistically, we found that HA directly binds to UDP-glucose dehydrogenase (UGDH), enhancing its interaction with forkhead box protein K1 (FOXK1) in the cytoplasm, thereby preventing FOXK1 nuclear translocation. This event suppresses Cd36 transcription and mitigates hepatic lipid accumulation. Furthermore, silencing Ugdh attenuated the inhibitory effect of HA on FOXK1-mediated regulation of Cd36 transcription. We demonstrate a novel mechanism for regulating hepatic lipid metabolism through HA/UGDH/FOXK1/CD36 pathway. This study provides evidence supporting the potential of HA as a therapeutic metabolite for MASLD. Moreover, these results are derived from preclinical murine models, and further clinical studies are warranted to validate the efficacy of HA.

ID: 41809269
Title: High-dose taurine supplementation exacerbates alcohol-associated liver disease by inducing gut microbiota dysbiosis and bile acid dysregulation in mice.
Abstract: β-aminoethanesulfonic acid (taurine) is a conditionally essential amino acid that plays critical roles in bile acid (BA) conjugation, antioxidative defence and metabolic regulation. Previous studies showed that faecal taurine level was reduced in patients with alcohol-associated liver disease (ALD), suggesting that taurine supplementation may have beneficial effects. This study aimed to determine whether oral taurine supplementation prevents the development of ALD in mice and to elucidate the underlying mechanisms. A total of 8-week-old male mice were subjected to a chronic-plus-binge ALD model. Taurine was administered orally via the diet for ten days before and during ethanol exposure. Faecal 16S ribosomal RNA metagenomic analysis, liver RNA sequencing and BA profiling were performed. High-dose taurine supplementation (3 g/kg body weight/day) was associated with worsened ethanol-induced liver injury, as indicated by increased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, hepatic steatosis, apoptosis and inflammation. At the molecular level, high-dose taurine treatment was associated with reduced Cpt1a expression, altered expression of genes involved in fatty acid β-oxidation and lipogenic gene Fasn, and decreased expression of Baat, accompanied by changes in taurine-conjugated BA profiles. These alterations were accompanied by changes in BA composition and intestinal FXR-associated gene expression. Taurine supplementation was also associated with shifts in gut microbial composition, including enrichment of hydrogen sulfide-producing bacteria, increased microbial H2S production, impaired intestinal barrier-related parameters and increased bacterial translocation to the liver, paralleling enhanced hepatic inflammatory responses. In contrast, low-dose taurine supplementation (0.2 g/kg body weight/day) was associated with improved liver phenotypes, including reduced steatosis, lower serum ALT and AST levels, decreased Fasn expression and enhanced BA conjugation. Collectively, these results indicate a dose-dependent association between taurine supplementation and ALD-related outcomes. Our findings suggest that high-dose taurine supplementation is associated with unfavourable alterations in gut microbiota composition, intestinal barrier integrity, BA metabolism and hepatic taurine-related pathways in ALD, coinciding with exacerbated liver injury. In contrast, low-dose taurine supplementation was associated with improved hepatic outcomes. These results highlight the importance of dose considerations in taurine supplementation and support the concept that taurine may exert divergent effects on ALD depending on the administered dose.

ID: 41895417
Title: Mucin alleviates HFD-induced obesity and MASLD via an Akkermansia muciniphila-associated mucin-Neu5Ac-PPARα signaling axis.
Abstract: Mucin is known to modulate the gut environment; however, its specific mechanisms and downstream metabolites in alleviating obesity and hepatic steatosis remain unclear. In this study, we investigated the beneficial effects of mucin in a high-fat diet (HFD) mouse model and explored the underlying mechanisms. Our results showed that mucin supplementation significantly reduced weight gain, improved glucose tolerance, and alleviated hepatic steatosis and fibrosis in HFD-fed mice. These benefits were abolished by antibiotic treatment, indicating a microbiota-dependent mechanism. Fecal 16S rRNA gene sequencing and metabolomics revealed that mucin specifically enriched the abundance of Akkermansia muciniphila, which enzymatically liberates N-acetylneuraminic acid (Neu5Ac) from mucin O-glycan via glycoside hydrolases, leading to elevated fecal and serum Neu5Ac levels. Direct administration of Neu5Ac successfully recapitulated the protective effects of mucin, reducing obesity, improving insulin sensitivity, and preserving colonic mucosal integrity. Mechanistically, mucin and Neu5Ac improve lipid homeostasis by promoting fatty acid oxidation via the PPARα/CPT1A pathway. In conclusion, our findings demonstrate that mucin alleviates HFD-induced metabolic syndrome and metabolic dysfunction-associated steatotic liver disease (MASLD) by enriching A. muciniphila and subsequent Neu5Ac production. The Neu5Ac-PPARα/CPT1A axis represents a promising therapeutic target for treating obesity and associated liver pathologies.

ID: 41918527
Title: Er-Chen Decoction ameliorates metabolic dysfunction-associated steatotic liver disease via gut microbiota-barrier axis-driven hepatic metabolic reprogramming.
Abstract: Metabolic dysfunction-associated steatotic liver disease (MASLD) constitutes a critical global health challenge, with gut-liver axis dysfunction and metabolic endotoxemia serving as key drivers. The traditional Chinese medicinal formula Er-Chen Decoction (ECD) has proven effective in treating metabolic disorders, yet the specific mechanisms by which it modulates gut-liver crosstalk have not been fully elucidated. A mouse model of MASLD was established via a high-fat diet (HFD). The therapeutic effects of ECD were evaluated using the glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide (SE) as a positive control. A comprehensive analysis of the underlying mechanisms of ECD treatment was conducted by integrating fecal metagenomic sequencing, untargeted serum metabolomic profiling, hepatic transcriptomic analysis, and molecular biology assays. Treatment with ECD markedly ameliorated hepatic steatosis, insulin resistance, and hyperlipidemia, demonstrating a therapeutic efficacy comparable to that of SE. Fecal metagenomic analysis indicated that whereas SE predominantly enriched the genus Akkermansia, the relative abundance of Bifidobacterium and Lactobacillus was markedly and specifically elevated following ECD treatment. Serum metabolomic profiling revealed that ECD specifically activated the tryptophan-indole metabolic pathway, as evidenced by elevated concentrations of indoleacrylic acid and indole-3-acetic acid. Correlation analyses established a strong positive correlation between these indole derivatives and the bacterial genera enriched by ECD. Mechanistically, our findings suggest that elevated indoles activate the aryl hydrocarbon receptor (AHR) in the colon, upregulating tight junction proteins ZO-1 and Occludin and restoring intestinal barrier integrity, thereby significantly reducing serum lipopolysaccharide (LPS) levels. In hepatic tissue, the diminished LPS influx alleviated the suppression of DNA methyltransferase 3B (DNMT3B), thereby promoting the epigenetic silencing of the lipid droplet fusion protein CIDEA and inhibiting pathological hepatic lipogenesis. Our findings elucidate a novel mechanism through which ECD may ameliorate MASLD via the distinctive "gut microbiota-indole-barrier" axis. In contrast to SE, ECD modulates gut microbiota composition to boost indole production and subsequently activate AHR signaling. This activation inhibits endotoxin translocation and induces hepatic DNMT3B-mediated epigenetic reprogramming to reverse hepatic steatosis. These results offer scientific evidence supporting the potential of ECD as an effective therapeutic strategy for MASLD.

ID: 41935802
Title: Gut microbial extracellular vesicles modulate the development of metabolic dysfunction-associated steatohepatitis through the gut-liver axis.
Abstract: Metabolic dysfunction-associated steatohepatitis (MASH) represents a growing global health challenge due to its propensity to progress to irreversible hepatic disorders, including fibrosis, cirrhosis, and carcinoma. This study aimed to investigate the role of gut microbiota in the pathogenesis of MASH. We identified Romboutsia hominis as a key contributor to MASH progression, exacerbating hepatic lipid accumulation and inflammation via the tumor necrosis factor-α (TNF-α) signaling pathway. Conversely, Akkermansia muciniphila and its extracellular vesicles (EVs) mitigated MASH by reducing hepatic lipid deposition through lipid biosynthesis-related genes downregulation. Furthermore, by integrating gut microbiota profiles and serum biomarkers using a machine learning approach, we achieved over 90% accuracy in noninvasive MASH diagnosis. These findings elucidate critical mechanisms within the gut-liver axis and suggest novel therapeutic and diagnostic strategies targeting gut microbiota and their functional EVs for MASH.

ID: 41990467
Title: Inhibition of miR-320 alleviates hepatic steatosis and dyslipidemia via suppressing the transcription of APOE in MASLD.
Abstract: Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by hepatic steatosis with cardiometabolic disorders. Due to the complicated pathophysiological processes, current therapeutic strategies for MASLD remain limited. Previous studies revealed that miR-320 was a regulator of systemic lipid metabolism with multi-targets. However, whether treatments against miR-320 would be benefit to MASLD was unclear. Mice with MASLD were induced by high-fat diet (HFD) treatment. Tough Decoy or sponge against miR-320 was delivered by recombinant adeno-associated virus (serotype 8) vectors in vivo. Hepatic steatosis and plasma lipids were assessed by histopathology, biochemical assays and LC-MS. Moreover, LC-MS, Western blotting, real-time PCR, immunofluorescence and luciferase reporter were performed to investigate the underlying mechanisms. Knockdown of miR-320 attenuated HFD-induced MASLD by alleviating hepatic lipid accumulation and hyperlipidemia. Mechanistically, palmitic acid (PA) combined with oleic acid (OA) treatment promoted the translocation of miR-320 from the cytoplasm into the nucleus of hepatocytes. Especially, increased nuclear miR-320 activated the transcription of APOE by targeting its promoter, which in turn aggravated triglyceride accumulation and secretion in hepatocytes. Our study revealed that treatments against miR-320 attenuated hepatic steatosis and hyperlipidemia simultaneously, which might be a potential strategy of MASLD.

ID: 42039609
Title: Dietary Oxysterols Reprogram Hepatic Lipid Metabolism and Reshape the Gut Metabolome-Microbiome Interface.
Abstract: Dietary oxysterols are biologically active cholesterol oxidation products ubiquitous in Western diets, yet their systemic effects on host metabolism and the gut microbiome remain largely unexplored. Here, we employed an integrated multi-omics approach - shotgun metagenomics, quantitative proteomics, untargeted metabolomics, and bulk RNA-seq - to characterize the impact of DOxS exposure on the gut-liver axis in rats fed a Western diet (WD vs. WD-DOxS). Hepatic proteomics revealed near-complete suppression of the mevalonate/cholesterol biosynthesis pathway, particularly in males, while de novo lipogenesis enzymes (Scd1, Fasn, Plin2) were paradoxically upregulated, consistent with dual oxysterol signaling through SREBP inhibition and LXR activation. Bile acid synthesis was concurrently suppressed, confirmed by metabolomics. Strikingly, RNA-seq across liver, heart, and brain detected virtually no differentially expressed genes, establishing that DOxS act predominantly through post-transcriptional mechanisms. In the gut, DOxS increased microbial α-diversity while depleting Limosilactobacillus reuteri, with concomitant loss of the barrier-protective metabolite 3-indoleacrylic acid. Tissue-specific responses were widespread, with liver and colon frequently mounting opposing metabolic and immune responses to the same dietary challenge. Cross-omics integration revealed convergent microbiome-metabolite axes connecting microbial remodeling to both hepatic lipid reprogramming and colonic barrier disruption. These findings reposition dietary oxysterols from food-quality markers to active modulators of the gut-liver axis, with implications for metabolic disease and intestinal barrier integrity.

ID: 42051491
Title: Loss of immunometabolic adaptability in MASH: gut-derived signals drive macrophage reprogramming and fibrosis.
Abstract: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive inflammatory subtype of metabolic dysfunction-associated steatotic liver disease (MASLD), characterized by hepatocellular steatosis, persistent inflammation, and varying degrees of fibrosis. Although multiple therapeutic strategies targeting inflammatory or metabolic pathways have entered clinical development, their overall efficacy remains limited, suggesting that the mechanisms driving sustained disease progression remain incompletely understood. Previous studies have largely focused on inflammatory cascades, whereas the role of immune cell energy metabolism in sustaining inflammation and promoting fibrosis has received comparatively less attention. Recent work has increasingly shifted toward immunometabolic reprogramming, indicating that metabolic signals derived from the gut microbiota may contribute to the establishment and maintenance of the hepatic immune microenvironment. In this context, reductions in short-chain fatty acids and secondary bile acids, together with increased succinate and endotoxin levels, may alter the energy metabolism of Kupffer cells and infiltrating macrophages through signaling pathways involving FXR/TGR5 and mTOR/AMPK, thereby favoring a pro-inflammatory phenotype. This metabolic shift is associated with enhanced inflammatory signaling linked to HIF-1α, increased NLRP3 inflammasome activity, and paracrine effects that may promote hepatic stellate cell activation during fibrotic progression. Overall, current evidence supports a model in which MASH progression is associated with a gradual loss of immunometabolic adaptability in the setting of metabolic dysregulation along the gut-liver axis. Reduced metabolic flexibility may limit the ability of immune cells to transition between functional states, thereby hindering resolution of inflammation and contributing to pathological tissue remodeling. Within this framework, single-target interventions may be insufficient to fully restore immunometabolic homeostasis, whereas strategies that concurrently address gut microbial function and key metabolic signaling pathways may be more mechanistically sound. Considering MASH as a model of systemic immunometabolic dysregulation may also provide insight into other metabolism-associated inflammatory diseases, although extrapolation should remain cautious.

ID: 42075815
Title: Rebamipide Reprograms Hepatic Networks to Prevent and Reverse Metabolic-Dysfunction-Associated Steatotic Liver Disease: Multi-Omics Insights and Histological Validation.
Abstract: Background: Metabolic-dysfunction-associated steatotic liver disease (MASLD) is a growing global health burden, yet no approved pharmacological therapy currently exists. Purpose: The purpose of this study is to investigate the prophylactic and therapeutic potential of Rebamipide, a mucosal-protective and anti-inflammatory drug, in a high-fat diet (MHFD)-induced MASLD rat model, integrating quantitative liver proteomics, network analysis, and histopathology. Methods: Male Wistar rats were fed MHFD for 16 weeks and treated with Rebamipide either prophylactically (Reb T1, co-administered with diet) or therapeutically (Reb T2, administered post-NASH onset). Label-free LC-MS/MS proteomics combined with principal component analysis (PCA), partial squares discriminant analysis (PLS-DA), and enrichment analyses (including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Reactome via g: Profiler, network mapping, and Rat Genome Database (RGD) mining) revealed that MHFD had the following impacts: it induced the profound suppression of mitochondrial chaperones (Hspa9), microsomal triglyceride transfer protein (Mttp), and cytochrome P450 isoforms (Cyp2c6); it disrupted lipid trafficking, oxidative stress defense, and xenobiotic metabolism. Results: Rebamipide prophylaxis preserved lipid-handling proteins, prevented glycogen loss, and maintained antioxidant defenses. In contrast, therapeutic administration reversed established steatosis and remodeled metabolic pathways, enhancing fatty acid β-oxidation, detoxification, and mitochondrial protein import. Nine shared proteins across all comparisons, including MTTP and multiple Stress-70 mitochondrial isoforms, mapped to three core genes (Mttp, Cyp2c6, Hspa9) central to lipid transport, protein import, and metabolic stress adaptation. KEGG and Reactome analyses highlighted Rebamipide's modulation of bile acid synthesis, ceramide and phosphatidylcholine metabolism, lipoprotein remodeling, and MAPK signaling. Histopathological evaluation confirmed Rebamipide's efficacy, showing reduced steatosis and the normalization of the hepatocyte structure, with near-complete restoration in the therapeutic (Reb T2) group compared to partial protection in the Reb T1 group. Conclusions: These findings demonstrate Rebamipide's dual-phase, multi-targeted mechanism: early protection against diet-induced metabolic injury and robust reversal of established MASLD pathology. The identified protein triad (Mttp, Cyp2c6, Hspa9) and associated pathways provide novel biomarker candidates and mechanistic insight supporting Rebamipide's repurposing as a therapeutic for metabolic liver disease.

ID: 42146077
Title: Raspberry aqueous extract ameliorates MAFLD in mice by regulating gut microbiota and purine metabolism.
Abstract: Metabolism-associated fatty liver disease (MAFLD) has emerged as a severe worldwide public health burden with insufficient available clinical therapeutic strategies, which underscores the urgent demand for safe, natural dietary interventions. Raspberry (Rubus idaeus L.), a typical food-medicine homologous fruit abundant in diverse bioactive components including anthocyanins, flavonoids and polysaccharides, possesses prominent nutritional and medicinal potential. In this study, raspberry aqueous extract (RE) was prepared to comprehensively investigate its ameliorative effects and underlying molecular mechanisms against MAFLD. MAFLD animal model was established in C57BL/6 mice via 12-week high-fat diet (HFD) feeding. From the 9th week, model mice were intragastrically administered with RE at doses of 1 g/kg/d and 2 g/kg/d for continuous intervention. Integrated multi-omics analyses including 16S rRNA microbial sequencing, serum/hepatic biochemical detection, histopathological examination, in vivo microbial colonization assay, and in vitro cellular and metabolomic experiments were performed to systematically clarify the regulatory mechanism. RE treatment markedly improved the core pathological phenotypes of MAFLD mice, and significantly mitigated hepatic steatosis and hepatocellular injury. 16S rRNA sequencing demonstrated that RE remodeled the gut microbial dysbiosis, specifically elevating the abundance of beneficial genus Ileibacterium and suppressing pathogenic microbial taxa. Meanwhile, RE strengthened intestinal mucosal barrier integrity by upregulating tight junction protein expression, and activated hepatic purine metabolic reprogramming to boost the levels of critical metabolites including inosine and ADP. Spearman correlation analysis verified the significantly positive correlation between Ileibacterium abundance and hepatic inosine content, and both factors were closely correlated with the remission of MAFLD pathological indicators. In vivo colonization experiments further validated that Ileibacterium intervention alone remarkably alleviated hepatic lipid deposition and liver damage in MAFLD mice. In vitro strain metabolomics confirmed that Ileibacterium could directly biosynthesize and secrete inosine extracellularly. Furthermore, in vitro AML12 hepatocyte experiments revealed that 100 μM inosine remarkably relieved palmitic acid-induced lipotoxicity via reducing intracellular lipid overload, reactive oxygen species (ROS) accumulation and mitochondrial dysfunction, alongside modulating the expression of lipid metabolism, inflammatory and autophagy-related genes. Collectively, our results elucidate that raspberry aqueous extract alleviates experimental MAFLD through the gut microbiota-purine metabolism-inosine regulatory axis, in which Ileibacterium and inosine act as the core synergistic mediators. This study provides solid preclinical experimental evidence for the development and application of raspberry as a promising functional food for the prevention and nutritional intervention of MAFLD.

ID: 42168694
Title: The Gut-Liver Axis in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): Mechanisms, Microbiome Interactions and Therapeutic Targets.
Abstract: Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognized as a multifactorial condition in which the gut-liver axis plays a central pathogenic role. While a large body of literature has described associations between gut microbiota alterations and MASLD, a critical synthesis of the mechanistic pathways linking microbial activity to liver injury remains lacking. This review specifically focuses on gut-derived microbial metabolites as key mediators of disease progression. We examine how short-chain fatty acids, bile acids, lipopolysaccharide (LPS), trimethylamine-N-oxide (TMAO) and microbially derived ethanol influence hepatic lipid metabolism, inflammation and fibrogenesis through defined molecular pathways, including FXR signaling, TLR4 activation and immune-metabolic crosstalk. Importantly, we highlight inconsistencies in human microbiome studies, limitations in establishing causality and the challenges in translating preclinical findings into effective therapies. Although microbiome-targeted interventions such as probiotics, bile acid modulators and fecal microbiota transplantation show promise, their clinical efficacy remains variable due to interindividual heterogeneity and lack of mechanistic precision.By integrating current mechanistic evidence with translational insights, this review identifies critical knowledge gaps and proposes future directions for metabolite-focused therapeutic strategies. A more precise understanding of gut-derived signaling pathways will be essential to move from associative microbiome research toward targeted and personalized interventions in MASLD.

ID: 42207914
Title: Akkermansia muciniphila-derived L-norleucine modulates FABP1-dependent fatty acid transport.
Abstract: Fatty acids undergo re-esterification to form triglycerides or are directly oxidized for energy production following absorption. Fatty acid binding protein 1 (FABP1), a key transporter highly expressed in both hepatic and intestinal tissues, directs the metabolic fate of absorbed fatty acids. Although its role in facilitating fatty acid transport and lipogenesis in the liver is well established, the functional mechanisms of intestinal FABP1 remain poorly understood due to the complexity of the intestinal microenvironment. In this study, using animal models with intestinal-specific FABP1 knockout and gut microbiota depletion, we demonstrate that intestinal FABP1 directly facilitates the absorption of dietary fatty acids, and that gut microbiota regulate FABP1-mediated dietary fatty acid absorption through metabolites. Notably, the abundance of Akkermansia muciniphila exhibits an inverse correlation with FABP1-dependent obesity progression in an arachidonic acid-induced model. Supplementation with A. muciniphila markedly alleviates this obese phenotype. Through FABP1 protein-based metabolite enrichment coupled with untargeted metabolomics, we identified L-norleucine as a competitive FABP1 inhibitor despite its smaller molecular size relative to long-chain fatty acids. L-norleucine possesses a hydrophobic alkyl chain structurally analogous to fatty acids and a hydrophilic amino acid moiety, which may explain its binding to FABP1. Critically, L-norleucine constitutes a major metabolite in the gut, which may play an underappreciated role in regulating lipid homeostasis. Collectively, this study uncovers a previously unrecognized gut microbiota-FABP1 axis governing lipid homeostasis, offering therapeutic insights for metabolic disorders.

ID: 42240574
Title: Camellia diacylglycerol oil attenuates atherosclerosis and NAFLD by modulating gut microbiota and lipid metabolism in ApoE-/- mice.
Abstract: Camellia diacylglycerol oil (CDO), produced by enzymatic glycerolysis of camellia oil, is widely consumed as a functional food ingredient; however, its cardiovascular benefits remain insufficiently characterized. This study investigated the effects of CDO on high-fat diet (HFD)-induced atherosclerosis and non-alcoholic fatty liver disease in ApoE-/- mice, with a particular focus on alterations in gut microbiota and metabolomic profiles. Compared with the vehicle group, CDO supplementation (3 and 6 mL kg-1) reduced aortic plaque area by approximately 50% without significantly affecting body weight in the mice. CDO treatment significantly decreased serum triglycerides (TG), total cholesterol (TC) and low-density lipoprotein cholesterol, at the same time as increasing high-density lipoprotein cholesterol. Notably, CDO administered at 3 mL kg-1 demonstrated greater efficacy than camellia oil in improving TG and high-density lipoprotein cholesterol levels (P < 0.05). Furthermore, CDO supplementation significantly alleviated hepatic histopathological injury, reduced Oil Red O-positive lipid deposition and lowered hepatic TG and TC levels compared to the vehicle group. Gut microbiota analysis revealed a decreased Firmicutes/Bacteroidetes ratio and increased relative abundances of Roseburia and Faecalibaculum in CDO-treated mice. Metabolomic profiling further identified ether lipid metabolism and bile acid-related pathways as potential mediators of the metabolic improvements-induced by CDO. CDO was more effective than camellia oil in mitigating HFD-induced atherosclerosis and non-alcoholic fatty liver disease in ApoE-/- mice, most likely through coordinated modulation of the gut-liver-vascular axis. These findings support the potential of CDO as a functional food ingredient for cardiovascular risk reduction and warrant further validation in human studies. © 2026 Society of Chemical Industry.

ID: 42242027
Title: Bifidobacterium longum alleviation of metabolic dysfunction-associated steatotic liver disease: A multi-omics landscape of microbiota and metabolome reconfiguration.
Abstract: The gut microbiome-host metabolism axis plays a critical role in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). Although the probiotic Bifidobacterium longum (B. longum) shows promise in ameliorating metabolic disorders, its functional impact on the microbiome-metabolome interplay in MASLD remains elusive. Herein, we established a MASLD mouse model using a high-fat, high-fructose (HFHF) diet and conducted integrated multi-omics analyses, including liver transcriptomics, gut metagenomics, and serum metabolomics, following B. longum intervention. B. longum supplementation effectively attenuated systemic metabolic dysfunction, hepatic steatosis, and intestinal barrier impairment in MASLD. This amelioration was driven by a two-pronged functional reorganization: the restoration of intestinal integrity and a profound remodeling of the hepatic transcriptome, featuring the downregulation of crucial mediators within the CD14-TLR4-NF-κB signaling cascade, including Cd14 and Runx1. Such functional reorganization coincided with a reconfigured gut microbiota, characterized by an increased abundance of beneficial taxa (e.g., Parabacteroides distasonis, Muribaculum intestinale) and suppression of opportunistic pathobionts (e.g., Ruminococcus gnavus, Clostridioides difficile). Furthermore, these microbial shifts were intrinsically linked to a reconfigured serum metabolome, highlighted by the enrichment of protective tryptophan-derived metabolites (e.g., indole-3-propionic acid) and the reduction of detrimental ones (e.g., 17α-methyltestosterone, 7-HDoHE). Collectively, our results suggest that B. longum mitigates MASLD through modulation of the gut microbiota and host serum metabolome, supporting its potential as a probiotic candidate for the management of metabolic health.

ID: 42259828
Title: Faecalibacterium-derived spermidine mediates the amelioration of fatty liver hemorrhagic syndrome by inulin in laying hens.
Abstract: Fatty liver hemorrhagic syndrome (FLHS) is a critical disease threatening the laying hen industry. Inulin, a widely used prebiotic, has shown promise in alleviating metabolic disorders, but its role in mitigating FLHS in laying hens is not fully understood. Here, we investigated the effects and underlying mechanisms of inulin-mediated alleviation of FLHS in a high-carbohydrate low-protein diet (HCD)-induced laying hen model. We found that inulin supplementation significantly ameliorated HCD-induced hyperlipidemia, hyperglycemia, hepatic steatosis, liver injury, and oxidative stress. These phenotypic improvements were accompanied by enhanced fatty acid oxidation and suppressed lipid synthesis and inflammation. Microbiota analysis revealed that inulin reshaped the HCD-perturbed cecal microbiota, with Faecalibacterium identified as the only dominant genus substantially depleted by HCD and restored by inulin. Targeted metabolomics showed that inulin elevated cecal spermidine levels, which strongly correlated with Faecalibacterium abundance and improved metabolic traits. Fecal microbiota transplantation (FMT) from inulin-treated donors replicated the protective effects, confirming the causal role of gut microbiota in mediating inulin's anti-FLHS activity. Further mechanistic investigation using the representative species Faecalibacterium prausnitzii demonstrated that inulin enhanced spermidine production through transcriptional activation of the spermidine biosynthetic pathway. Spermidine, in turn, upregulated hepatic ALDH1A2 expression, enhancing retinoic acid synthesis and activating the AMPK-SIRT1 axis, thereby reducing lipid accumulation in hepatocytes. Collectively, these findings establish a novel Faecalibacterium-spermidine-ALDH1A2-retinoic acid-AMPK-SIRT1 axis through which inulin alleviates FLHS, highlighting inulin as a dietary intervention targeting the gut-liver axis and offering novel therapeutic avenues for preventing this disorder in laying hens.

ID: 42275581
Title: Gut microbiota-derived indole-3-propionic acid alleviates endoplasmic reticulum stress by regulating FMO2 in MASLD.
Abstract: Metabolic dysfunction-associated steatotic liver disease (MASLD) has become a global health challenge for which there are currently no approved drugs. Indole-3-propionic acid (IPA), as one of the primary metabolites of gut microbiota, can influence the development of liver diseases through the gut-liver axis, but how it contributes to liver diseases remains unclear. The present study was conducted to explore the possible molecular mechanisms of IPA in the development of MASLD. Metabolomic analysis compared serum and fecal metabolite profiles between MASLD and normal mice. The effects of microbial metabolite IPA on MASLD were evaluated through the utilization of a mouse model and cell models. Transcriptome data analysis was used, and further validation was conducted through flow cytometry, western blotting, RNA interference, and immunoprecipitation. Serum and fecal IPA levels in high-fat diet-fed mice were significantly decreased compared with those of normal chow diet-fed mice. IPA supplementation reduced hepatic lipid accumulation and alleviated insulin resistance, liver damage, and steatosis development in high-fat diet-fed mice, while gut microbiota dysbiosis was restored. Mechanistic analysis suggested that IPA promoted FMO2 expression, enhancing the interaction between FMO2 and protein kinase R-like endoplasmic reticulum kinase (PERK) and inhibiting the PERK/eIF2α/ATF4/CHOP signaling cascade, then mitigating endoplasmic reticulum (ER) stress, such as reducing hepatocyte apoptosis and reactive oxygen species levels, ultimately improving MASLD. IPA can promote the expression of FMO2, which binds to PERK within the ER of hepatocytes. This binding process inhibits the phosphorylation of PERK, thereby affecting PERK-mediated ER stress, and subsequently leading to a reduction in hepatocyte apoptosis and oxidation. This study puts forward the IPA/FMO2/PERK axis as a potential therapeutic target in ER stress for MASLD.

ID: 42288145
Title: Gut microbiota reshaped by exercise improved glycolipid metabolism in obese mice via increasing the production of medium and long chain fatty acids: a multi-omics study.
Abstract: Exercise is effective in combating obesity and regulating the composition of the gut microbiota. However, the molecular mechanism by which exercise alters gut microbiota and its metabolites to exert weight loss has not been fully elucidated. In this study, the mechanism of gut microbiota and microbial metabolites reshaped by exercise in weight loss were investigated by macrogenomic sequencing, metabolomics analysis and fecal microbiota transplantation (FMT). The results showed that exercise significantly increased the abundance of beneficial bacteria such as Oscillibacter, Lachnoclostridium, and unclassified_f__Lachnospiraceae, and decreased the abundance of Lactobacillus and Desulfovibrio. Meanwhile, exercise significantly increased medium- and long-chain fatty acid (MCFA and LCFA) content, as well as butyric acid, and decreased fructose levels. These metabolites were associated with fatty acid degradation, and unsaturated fatty acid synthesis pathways. In addition, FMT from exercised mice significantly reduced high-fat diet (HFD)-induced obesity and lipid accumulation, increased insulin sensitivity, and improved glucose homeostasis, with decreased the levels of serum lipids and lipopolysaccharide (LPS). FMT also attenuated hepatic and pancreatic dysfunction, as well as hepatic steatosis. Notably, FMT from exercised mice significantly increased the content of MCFAs and LCFAs in the intestines of HFD-treated mice and upregulated the expression of genes related to glycolipid metabolism and the secretion of Glucagon-like Peptide-1 (GLP-1). Finally, caprylic, lauric, cardamic and stearic acids can significantly increase GLP-1 levels in Caco-2 cells. Taken together, the mechanism by which exercise suppresses obesity may inhibit appetite by optimizing the intestinal microbiota, promoting the synthesis of MCFAs and LCFAs, and up-regulating GLP-1 secretion.

ID: 42300613
Title: Coordinated changes in microbiota features, short-chain fatty acids, and peripheral clocks accompany fructo-oligosaccharide-associated metabolic improvement.
Abstract: Metabolic disorders induced by a high-fat diet (HFD) are closely linked to disruptions in the circadian regulation of glucose and lipid metabolism. This study evaluated the metabolic benefits and chrono-nutritional potential of the prebiotic fructo-oligosaccharides (FOS) in a mouse model of HFD-induced obesity using 24 hour time-series analysis. FOS supplementation not only reduced weight gain, insulin resistance, and hepatic steatosis, but also restored the diurnal oscillations of key metabolic genes (Srebp1c, Pparα) and core circadian clock genes (Bmal1, Clock) in metabolic tissues. Notably, FOS reshaped gut microbiota composition by enriching beneficial genera and was accompanied by improved temporal organization of microbial metabolites, particularly the rhythmic production of short-chain fatty acids (SCFAs). Correlation analyses revealed strong temporal associations between FOS-induced microbial rhythmicity and improved host metabolic parameters. These findings suggest that FOS improves circadian metabolic homeostasis, accompanied by changes in gut microbiota rhythmicity and SCFAs rhythmicity, supporting its potential as a chrono-nutritional strategy in metabolic disorders.

ID: 42314883
Title: Hyaluronan exerts unique microbiome and metabolic effects compared with pectin: a multi-omics study of dietary polysaccharides.
Abstract: Dietary polysaccharides are increasingly recognized as modulators of host metabolism through intestinal interactions, yet not all exert comparable systemic effects. In this context, dietary hyaluronan (HA) is distinguished by its clinical efficacy on connective tissues. We investigated whether oral HA modulates the small-intestinal microbiome, systemic metabolome, and lipid metabolism, and compared its effects with pectin. Using a healthy murine model, we combined 16S rRNA sequencing, metabolomics, lipidomics, and correlation analyses. Oral HA triggered profound and previously undescribed shifts in the small-intestinal microbiome, while pectin's effects were markedly weaker. Both supplements increased microbial diversity, with HA specifically enriching taxa such as Turicibacter, Clostridium, and Lachnoclostridium. HA was also associated with elevated systemic metabolites, enhancing redox status. Hydroxybutyrate and related metabolites increased, consistent with enhanced lipolysis. HA was linked to reduced glycogen degradation without effects on synthesis, whereas pectin was related to lowered glycogen synthesis without alterations in degradation. Notably, HA was associated with modulated plasma and hepatic lipid metabolism. Specifically, lipid mediators playing roles in organismal homeostasis, inflammation, and pain modulation were altered. Collectively, these findings indicate that oral HA exerts a unique effect on the intestinal microbiome, systemic metabolome, and lipidome compared to pectin.

ID: 42354872
Title: Oleanolic Acid Modulates the Gut-Liver Axis to Alleviate High-Fat Diet-Induced Hepatic Lipid Deposition in Nile Tilapia (Oreochromis niloticus).
Abstract: This study examined the protective mechanisms of oleanolic acid (OA) against high-fat diet (HFD)-induced hepatic steatosis and intestinal dysbiosis in Nile tilapia. Fish were allocated to four groups: normal diet (ND), HFD, and OA-supplemented HFD (50 and 250 mg/kg). After 42 days, physiological, biochemical, and histological assessments demonstrated that OA markedly reduced hepatic lipid accumulation, mitochondrial injury, and intestinal shortening. Transcriptomic analysis revealed that OA alleviated lipid dysregulation by inhibiting de novo lipogenesis and promoting lipid trafficking and β-oxidation, effectively reversing HFD-induced changes in the PPAR, MAPK, mTOR, and autophagy-lysosome signaling pathways. 16S rRNA sequencing indicated that OA increased microbial alpha diversity, suppressing HFD-associated taxa (e.g., Nordella) while enriching beneficial genera such as Clavibacter, Bosea, and Bdellovibrio. Importantly, OA treatment restored HFD-induced depletion of intestinal butyric acid and suppressed hepatic pro-inflammatory cytokines (tnf-α, il-1β), while upregulating growth-related factors (igf1). Correlation analysis confirmed strong associations between microbial alterations (Nordella and Phreatobacter) and hepatic lipid metabolism and inflammatory gene expression. Overall, OA mitigates metabolic stress in Nile tilapia by reconfiguring the gut-liver axis, integrating microbial restoration with precise regulation of hepatic nutrient-sensing and inflammatory pathways, providing a potential therapeutic strategy for lipid metabolism disorders in aquaculture.

ID: 42358289
Title: Fecal metabolomics and gut microbiota profiling uncover the protective role of probiotic-rich traditional fermented sour soup (Guizhou Hongsuantang) against alcoholic liver damage.
Abstract: This study investigates the metabolic mechanisms underlying the hepatoprotective effects and mitigation of alcohol-induced impacts of bacterial strains (Lactobacillus plantarum LP and Lactobacillus paracasei H2) isolated from "Guizhou Hongsuantang." In order to identify changes in microbial composition, fecal metabolites and metabolic pathways linked to probiotic intervention, the study uses integrated gut microbiota analyses and metabolomics such as 16S rDNA sequencing, UHPLC-MS and functional predictions. Pathway enrichment analysis revealed significant modulation of key metabolic pathways, particularly those associated with lipid metabolism such as steroid hormone biosynthesis and arachidonic acid metabolism as well as amino acid metabolism, membrane transport and bile secretion. These pathways are critical for regulating inflammation, oxidative stress and detoxification processes, which are commonly impaired during liver injury or alcohol-induced stress. Further metabolite classification identified a predominance of lipids, fatty acids, and organic acids with remarkable enrichment in subclasses such as fatty acyls, eicosanoids, isoprenoids and glycerophospholipids all of which are implicated in liver protection, energy metabolism and cellular repair. The intervention was associated with levels of microbial-derived metabolites and secondary bioactive compounds, including flavonoids and macrolides, suggesting an interaction between host metabolism and gut microbiota. Differential analysis across experimental groups revealed dose-dependent effects, with high-dose intervention (Group G) is correlated with the most substantial metabolic shifts. These findings clarify the gut-liver axis-related metabolic mechanisms of probiotic-rich "Guizhou Hongsuantang" in protecting against alcoholic liver damage. These findings provide a scientific basis for the development of probiotic-based functional fermented foods derived from traditional ethnic foods and offer a promising approach to reducing alcohol-induced hepatic injury and advancing the modernization of traditional ethnic fermented foods.

ID: 42358979
Title: Gut microbiota metabolites in inflammatory bowel disease: advances in mechanistic insights.
Abstract: Inflammatory bowel disease (IBD), primarily comprising Crohn's disease and ulcerative colitis, represents a group of chronic, relapsing intestinal inflammatory conditions mediated by immune dysregulation. Emerging evidence has established the gut microbiota and its metabolic products as central players in IBD pathogenesis. The human gut microbiota constitutes a vast and dynamic micro-ecosystem whose metabolic activities generate a diverse array of small molecules, including short-chain fatty acids, bile acids, and tryptophan-derived metabolites. These metabolites collectively form a "gut microbiota-metabolite-immune axis" that is deeply involved in maintaining intestinal homeostasis, and their dysregulation is closely linked to IBD initiation and progression. Patients with IBD typically exhibit significant alterations in gut microbial composition and function, with key metabolic perturbations characterized by reduced levels of SCFAs and secondary bile acids, as well as imbalances in specific amino acid-derived metabolites. SCFAs not only serve as essential energy substrates for colonic epithelial cells but also modulate immune responses and enhance barrier integrity through G protein-coupled receptors and inhibition of histone deacetylases. Bile acids contribute to barrier function and immune balance via activation of nuclear receptors such as the farnesoid X receptor and the G protein-coupled bile acid receptor 1. Tryptophan, metabolized by both host enzymes and the gut microbiota into kynurenine, serotonin, and various indole derivatives, participates in immunoregulation through pathways involving the aryl hydrocarbon receptor. These examples underscore the pivotal roles of gut microbial metabolites in both the pathogenesis and treatment of IBD. This review aims to synthesize recent advances in understanding the functions and molecular mechanisms of key gut microbial metabolites in IBD, with a focus on how they orchestrate the initiation and perpetuation of intestinal inflammation through complex immunoregulatory networks and modulate intestinal barrier function. By providing new insights into the mechanisms underlying IBD pathogenesis and intervention, this review seeks to establish a theoretical foundation for the development of novel diagnostic and therapeutic strategies targeting microbial metabolites.

ID: 42359775
Title: Blue light exposure exacerbates Western diet-induced hepatic lipid accumulation and injury via suppression of the SIRT1-NR1D1 axis.
Abstract: Excessive exposure to artificial blue light has been associated with circadian disruption and metabolic disorders; however, its role in hepatic lipid metabolism under dietary stress remains poorly defined. This study investigated how blue light exposure modulates Western diet-induced nonalcoholic fatty liver disease (NAFLD) and the underlying molecular mechanisms involving the NR1D1-SIRT1 metabolic axis. Male C57BL/6J mice were fed either a control or Western diet and exposed to blue light or sham illumination for 12 weeks. Hepatic morphology was evaluated by hematoxylin-eosin and Masson's trichrome staining, whereas macrophage infiltration and expression of NR1D1 and SIRT1 were assessed by immunohistochemistry. Untargeted LC-TOFMS-based metabolomic profiling and pathway enrichment analysis were conducted to characterize global metabolic alterations across experimental groups. The results showed that blue light exposure markedly aggravated Western diet-induced hepatic steatosis, ballooning, and lobular inflammation without evidence of fibrosis. Immunohistochemical staining revealed increased F4/80 positive macrophages and downregulation of NR1D1 and SIRT1 in blue light exposed, Western diet-fed (WDBL) mice, suggesting impaired mitochondrial homeostasis. Metabolomic profiling identified 113 hepatic metabolites, revealing distinct clustering by diet and light exposure. Blue light synergistically amplified Western diet-driven accumulation of long-chain and unsaturated acylcarnitines and polyunsaturated fatty acids, indicative of incomplete β-oxidation and oxidative lipid remodeling. Pathway enrichment analysis highlighted disruptions in glycerophospholipid, sphingolipid and bile acid metabolism, accompanied by reduced antioxidant cofactors (retinol and tocopherols). In conclusion, chronic blue light exposure accelerates Western diet-induced NAFLD progression by suppressing the SIRT1-NR1D1 axis, disrupting mitochondrial lipid oxidation, and promoting redox imbalance and macrophage-mediated inflammation. These findings identify environmental blue light as a metabolic stressor that synergizes with dietary lipid overload to drive hepatic injury, offering new mechanistic insight into light-associated metabolic liver disease.

ID: 42364635
Title: Integrated multi-omics analyses reveal potential inflammatory, hepatic, and endocrine risks of the overlooked BPA isomer o,p'-BPA.
Abstract: 2,4'-Isopropylidenediphenol (o,p'-BPA), a structural isomer and byproduct of bisphenol A (BPA) synthesis, is frequently detected in food and human samples, yet its toxicological effects remain insufficiently characterized. In this study, the toxicological profiles of BPA and o,p'-BPA were systematically compared in male Sprague-Dawley rats exposed to 50 μg/kg/day for 28 days. Hematological parameters, metabolomic profiles, and gut microbiota composition were integrated to construct a microbiota-metabolite-host interaction framework. Both compounds significantly elevated inflammation-related markers (e.g., white blood cell count) and liver function indicators (e.g., alanine aminotransferase) by 11-42% (ANOVA, p = 0.0018-0.037). Multi-omics analysis revealed that BPA toxicity involved Romboutsia dysbiosis and disruptions in purine metabolism, lipid metabolism, and pantothenate/CoA biosynthesis. In contrast, o,p'-BPA exposure was associated with changes in both Romboutsia and Escherichia_Shigella populations and with alterations in glutathione metabolism and steroid hormone biosynthesis-related pathways. These findings suggest that o,p'-BPA may induce a distinct pattern of microbiota and metabolic perturbations compared with BPA, highlighting the importance of considering potential isomer-specific responses in chemical safety evaluations.

ID: 42365696
Title: Apigenin ameliorates methionine-choline deficient diet-induced metabolic-associated fatty liver disease through modulation of gut microbiota-liver axis.
Abstract: Apigenin, a naturally occurring flavone widely present in the plant kingdom, possesses antioxidant, anti-inflammatory, and metabolic regulatory activities. Metabolic-associated fatty liver disease (MAFLD), a chronic liver disorder driven by metabolic stress, currently lacks effective pharmacological therapies. Given these pharmacological properties, apigenin may represent a promising candidate for MAFLD intervention. This study aimed to evaluate the therapeutic potential of apigenin in MAFLD and to elucidate the underlying mechanisms linking the gut microbiota and host lipid metabolism. A methionine-choline deficient (MCD) diet-induced mouse model of MAFLD, combined with lipidomic profiling, microbiota analysis, and metabolite assessment, was used to determine the beneficial effects of apigenin. Apigenin markedly ameliorated hepatic steatosis in MCD-fed mice, as demonstrated by reduced hepatic triglyceride accumulation, improved liver function markers, and alleviated hepatic inflammation and oxidative stress. Lipidomic profiling showed decreased hepatic saturated and polyunsaturated fatty acids accompanied by an increase in monounsaturated fatty acids and their related lipid species. Apigenin remodeled the gut microbiota, characterized by increased Lactobacillus abundance and decreased Akkermansia abundance. Further analyses identified homocysteine (HCY) as a key microbiota-associated metabolite that induced oxidative stress and reproduced the lipid dysregulation observed in MAFLD, thereby linking microbial alterations to hepatic lipid metabolism. These findings demonstrate that apigenin alleviates MAFLD by remodeling the gut microbiota-metabolite network, lowering HCY levels, and subsequently improving hepatic function, lipid metabolism, and oxidative stress, highlighting its potential as a phytochemical-based therapeutic strategy.

ID: 42365823
Title: Redox coupling of lactate and β-hydroxybutyrate: An inter-organ circuit linking metabolic flexibility, mitochondrial adaptation, and disease.
Abstract: Lactate and β-hydroxybutyrate (βHB), once regarded mainly as metabolic byproducts or alternative fuels, are now increasingly recognized as redox-active metabolites that regulate energy partitioning, mitochondrial function, and adaptive stress responses. Here, we propose a unifying framework in which lactate and βHB form a redox-coupled inter-organ circuit linking the liver, kidney, heart, and skeletal muscle. Through coordinated LDH- and BDH1-dependent reactions and monocarboxylate transport, the lactate-βHB axis integrates carbohydrate and lipid metabolism, supports dynamic fuel switching, and links distinct cytosolic and mitochondrial NAD+/NADH redox states during fasting, exercise, hypoxia, and metabolic stress. Disruption of this circuit contributes to mitochondrial dysfunction, impaired metabolic flexibility, and maladaptive redox signaling in disorders including metabolic dysfunction-associated steatotic liver disease, type 2 diabetes, chronic kidney disease, heart failure, and sarcopenia. Beyond their bioenergetic roles, lactate and βHB also act as signaling metabolites that influence transcriptional, epigenetic, post-translational, and stress-response pathways, including protein lysine lactylation and β-hydroxybutyrylation, thereby linking metabolic state to cellular adaptation, tissue resilience, and long-term remodeling. Importantly, interventions including exercise, ketogenic or low-carbohydrate diets, SGLT2 inhibition, ketone-based strategies, and NAD+-enhancing approaches may help restore lactate-βHB coupling and improve redox homeostasis. This framework positions the lactate-βHB axis as a systems-level mechanism of inter-organ redox communication and provides a redox-biological basis for therapeutic targeting in metabolic and degenerative disease.

ID: 42365932
Title: PPARδ in neurological diseases: Mechanisms and therapeutic prospects.
Abstract: Peroxisome proliferator-activated receptors (PPARs) are a class of nuclear receptors that play a pivotal role in diverse physiological processes, including lipid metabolism, energy homeostasis, and immune responses, through the regulation of gene expression. Among the PPAR subtypes, PPARδ (also referred to as PPARβ/δ) has garnered growing attention in the research of neurological disorders, attributed to the recent discovery of its high expression level in the nervous system. Accumulating evidence demonstrates that PPARδ exerts multiple beneficial effects, such as inhibiting neuroinflammation, enhancing mitochondrial function, maintaining cellular energy balance, and exerting neuroprotective activities. Neurological diseases, encompassing neurodegenerative disorders, cerebrovascular diseases, and neuroinflammatory conditions, impose a substantial burden on global health. The purpose of this review is to summarize the latest research advances in PPARδ, analyze and delineate the specific molecular mechanisms underlying its protective effects against neurological diseases, and discuss the current challenges and future prospects in this field, thereby providing a theoretical basis for the development of novel therapeutic strategies. Additionally, this review highlights several compounds and PPARδ-targeted drug development strategies that have been investigated for ameliorating the pathological progression of these neurological disorders.

ID: 42381483
Title: ODC1-Mediated Ornithine Metabolism Exacerbates Obesity by Disrupting AMPK/ACC Pathway.
Abstract: Ornithine (OR) is a key intermediate metabolite; however, its molecular role in obesity remains unclear. This study aimed to investigate the effects of OR and its rate-limiting enzyme, ornithine decarboxylase 1 (ODC1), on lipid metabolism using high-fat diet (HFD)-induced obese C57BL/6 mice and C3H10T1/2 cell models. The results showed that OR supplementation and ODC1 overexpression exerted similar effects, including significantly aggravated HFD-induced obesity, elevated serum polyamine levels, impaired glucose tolerance, reduced oxygen consumption, and hepatic steatosis. Transcriptomic analysis combined with protein validation indicated that ODC1-promoted lipid deposition is associated with suppression of the AMPK/ACC pathway. In vitro, ODC1 overexpression promoted adipocyte proliferation and differentiation, accompanied by elevated levels of polyamines, including putrescine, spermidine, and spermine. Increased polyamine turnover further induced polyamine catabolic enzymes spermidine/spermine N1-acetyltransferase 1 (SAT1) and polyamine oxidase (PAOX), resulting in increased reactive oxygen species (ROS) accumulation, lipid peroxidation, and mitochondrial dysfunction. These changes were associated with suppression of the AMPK/ACC pathway, resulting in increased intracellular triglyceride (TG) accumulation. Conversely, treatment with the ODC1 inhibitor DFMO or knockdown ODC1 markedly alleviated oxidative stress and lipid accumulation. Furthermore, OR supplementation failed to reverse oxidative stress and adipogenesis following ODC1 knockdown, indicating that its metabolic effects are largely dependent on ODC1 activity. Taken together, our findings reveal that ODC1-mediated polyamine synthesis links SAT1/PAOX-associated ROS production to AMPK/ACC and increased lipid accumulation, highlighting ODC1 as a potential therapeutic target for obesity and lipid metabolic disorders.

ID: 42395006
Title: Microbiome-mediated pharmacology of ginseng: Mechanistic insights into metabolic regulation and therapeutic potential.
Abstract: Ginseng, a traditional medicinal herb with a favorable safety profile, has long been used to promote systemic health. Recent studies reveal that many of its beneficial effects are mediated through interactions with the gut microbiota. Microbial enzymes convert parent ginsenosides into more absorbable and bioactive metabolites such as compound K, while ginseng reciprocally remodels the microbial community and metabolite composition by promoting the growth of beneficial taxa including Akkermansia, Bifidobacterium, and Lactobacillus. These bidirectional interactions modulate host metabolic, immune, and intestinal barrier functions. The ginseng-microbiome interplay regulates microbial and host-derived metabolites such as short-chain fatty acids, bile acids, and indole derivatives, which in turn activate key signaling pathways including FXR/TGR5, FFAR, AMPK, and Nrf2. Through these mechanisms, ginseng improves lipid metabolism, enhances insulin sensitivity, alleviates low-grade inflammation, and ameliorates metabolic abnormalities such as obesity, insulin resistance, and nonalcoholic fatty liver disease (NAFLD). This review provides a comprehensive synthesis of the ginseng-microbiota metabolic axis, focusing on its mechanistic basis in metabolic regulation and related disorders. We also highlight the therapeutic convergence between ginseng and probiotics possessing ginsenoside-hydrolyzing enzymes, discuss strategies for strain selection and co-administration, and outline future directions in precision, microbiome-informed formulations and clinical trial design. Collectively, current evidence supports the ginseng-microbiota interactions as a promising therapeutic platform for restoring metabolic homeostasis and managing metabolic diseases.

ID: 42395018
Title: Ginsenoside Rb1 mitigates senescence-associated hepatic steatosis in mice through enhanced lysine degradation.
Abstract: The liver is the central organ for metabolism and detoxification, and its function gradually declines with age, often accompanied by pathological changes such as lipid metabolism disorders, inflammatory responses, and fibrosis, significantly increasing the risk of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). Ginsenoside Rb1 (Rb1) is a major active constituent of ginseng. However, its regulatory mechanism on hepatic lipid metabolism and MASLD/MASH-related phenotypes during natural aging remains unclear. To explore the effects of Rb1 on liver aging phenotypes, lipid deposition, inflammation, fibrosis, and related metabolic pathways in naturally aged mice, and to further elucidate the underlying regulatory mechanisms. Naturally aged male C57BL/6J mice (72-week-old) were used and divided into the Old group and the Rb1 treatment group (Old + Rb1). Young mice (6-week-old) served as controls. Therapeutic effects were evaluated through histopathology (H&E, Masson trichrome, Oil Red O staining), immunofluorescence (p21, FASN, FABP1, PPARα), immunohistochemistry (PCNA, F4/80), RT-qPCR analysis of lipid metabolism-related genes. Additionally, untargeted metabolomics analyses of both serum and liver tissues, as well as liver transcriptome sequencing, were performed to investigate the underlying mechanisms. Rb1 alleviated hepatocellular senescence, as evidenced by reduced p21 expression and increased PCNA-positive cells. It ameliorated age-related hepatic pathological damage, as evidenced by reduced inflammatory infiltration (F4/80) and collagen deposition (Masson staining), along with improved hepatocellular vacuolation and lipid accumulation (Oil Red O staining). Rb1 regulated hepatic lipid metabolism through three mechanisms: inhibiting lipid synthesis (Fasn, Acaca, Srebf1), modulating lipid transport (Fabp1, Slc27a2), and promoting lipid oxidation (Pparα, Fgf21). Serum and hepatic metabolomics consistently revealed that Rb1 activated the lysine degradation pathway, accompanied by an increase in the key intermediate metabolite trimethyllysine (TML). Liver transcriptome sequencing further indicated an increasing trend in the numbers of genes associated with the biological process of metabolic process and the molecular functions of transporter activity and transcription regulator activity. Additionally, enrichment of the biological process of lipid export from the cell was observed in the comparison between the Old and Old+Rb1 groups. Rb1 ameliorates age-related hepatic lipid accumulation and pathological damage in naturally aged mice by promoting the lysine degradation pathway and comprehensively remodeling lipid metabolic homeostasis. These findings provide a potential target and theoretical basis for intervention in aging-related MASLD/MASH.

ID: 42398618
Title: Dihydroberberine in metabolic disorders: Bioavailability, molecular mechanisms, toxicology, and future perspectives.
Abstract: The global prevalence of metabolic diseases, including obesity, type 2 diabetes mellitus (T2DM), and metabolic dysfunction-associated steatotic liver disease (MASLD), continues to rise, representing a major global health threat and economic burden. Dihydroberberine (DHB), a reduced derivative of berberine (BBR), has recently garnered attention due to its superior lipophilicity and intestinal absorption. Pharmacokinetic studies suggested that DHB achieves significantly higher blood concentrations compared to BBR at equivalent doses. This review systematically synthesized the current preclinical evidence regarding the metabolic regulatory mechanisms of DHB. Key pharmacological targets identified in cell and animal models included the activation of AMP-activated protein kinase (AMPK) and glucokinase (GCK), modulation of lipid metabolism, and attenuation of inflammatory and oxidative stress pathways. Furthermore, DHB interacted extensively with the gut microbiota, acting both as a microbial metabolite of BBR and a modulator of microbial composition. Toxicological assessments indicated a favorable safety profile, although potential risks such as hERG channel inhibition required careful evaluation. Importantly, while in vitro and animal studies demonstrated significant metabolic benefits, human clinical trials assessing direct disease outcomes remained highly limited. This review highlighted the pharmacokinetic advantages of DHB and outlined the critical translational gaps that must be addressed in future research.

ID: 42434567
Title: Multi-omics reveal soil microbial dysbiosis and metabolite toxicity as drivers of blueberry continuous cropping obstacles.
Abstract: Blueberry (Vaccinium spp.) are one of the most economically important fruit trees globally. However, due to continuous cropping have limited the industry's ability to produce consistently over the long term, and the mechanism underlying the development of this continuous cropping problem is not yet fully understood. In this study, we applied metagenomic and metabolomic to systematically detect changes in microbial community structure, function and metabolic profiles in rhizosphere and non-rhizosphere soils after different years of continuous blueberry cultivation (0, 2, 4, and 6 years) in Dalian (China). The results showed that continuous cultivation significantly reduced overall microbial diversity and the bacterial and fungal Shannon index, with the decrease being more significant in the rhizosphere soils (P < 0.05). The β diversity analysis showed that the microbial community structure was distinctly separated between cultivation periods, with the most prominent differences in the rhizosphere soils (PERMANOVA, P < 0.01). The increased cultivation duration led to a decrease in the relative abundance of beneficial functional taxa in the microbial community, while the depletion-tolerant and stress-adapted taxa were gradually enriched. Functional annotation analysis showed that KEGG pathways related to stress response, amino acid degradation, and energy metabolism significantly increased, while functions related to nutrient transformation and plant-microbe interactions were weakened (FDR < 0.05). The metabolomic results further showed that 6 years of continuous cultivation significantly reshaped the rhizosphere metabolite composition. This was evidenced by the accumulation of various secondary metabolites in the rhizosphere soil, including metabolites related to potential self-toxicity (e.g., ferulic acid, 3-hydroxyphenylacetic acid, and 2-hydroxycinnamic acid), mainly involved in the pathways of amino acid metabolism, lipid metabolism, and secondary metabolite synthesis. In conclusion, continuous cultivation of blueberry induced pronounced shifts in rhizosphere microbial community structure, function, and metabolite composition, suggesting that these changes may contribute to the development of continuous cropping obstacles (CCO).

ID: 42436161
Title: Dietary glucoraphenin ameliorates obesity and steatotic liver disease associated with gut dysbiosis induced by a Western diet in mice.
Abstract: Western-style diets promote obesity, gut dysbiosis, and metabolic dysfunction-associated steatotic liver disease (MASLD). In this study, glucoraphenin (GRE), the major glucosinolate in radish (Raphanus sativus L.) greens and sprouts, was evaluated for its effects on Western diet (WD)-induced metabolic derangements and gut dysfunction in mice. Intaking of 1 mg/kg body weight of GRE with WD for 8 weeks caused significant reductions in adipogenesis indicators such as body weight gains, adipocyte hypertrophy, and serum leptin level. This result was further proved by significant changes in lipogenesis and lipolysis-related protein expressions in adipocyte. Administration of GRE also suppressed development of MASLD, which was observed through reductions in serum ALT and AST and suppressions the expression of FAS, SREBP1, mTOR, SCD1, ACC, and ChREBP in liver tissues. GRE administration effectively prevented the decrease in the gut microbial richness and diversity caused by WD and recovered serum branched-chain amino acids and microbiota-derived purine metabolites (inosine and hypoxanthine). These findings indicate that GRE mitigates WD-induced obesity and MASLD via coordinated regulation of lipid metabolism and the gut-liver axis.

ID: 42436400
Title: Association of TNNI3 and MYBPC3 variants with clinical phenotype and metabolic disorders in patients with hypertrophic cardiomyopathy.
Abstract: Hypertrophic cardiomyopathy is an inherited cardiovascular disease with heterogeneous presentation. However, the metabolic changes resulting from mutations and their relationship to the phenotype remain unclear. To investigate the association between TNNI3 and MYBPC3 variants and both clinical phenotype and metabolic disorders in HCM patients. 34 newly diagnosed HCM patients, 51 healthy individuals, and 23 unaffected family members were included. Clinical information and plasma samples were collected and analyzed. Whole-exome and Sanger sequencing were used for variant identification. Non-targeted metabolomics was performed using ultra-high-performance liquid chromatography-high-resolution mass spectrometry. TNNI3 and MYBPC3 variants were identified in familial HCM cases, which exhibited earlier onset and increased interventricular septum thickness. Metabolomics revealed lower L-valine and higher free fatty acid levels in HCM patients. Patients with TNNI3 variants showed dysregulation of lyso-phosphatidylcholines and lyso-phosphatidylethanolamines, along with disturbances in glutamic acid-related pathways. MYBPC3 variants were linked to dysregulation in energy metabolism. Correlation analysis highlighted associations between specific lipid metabolites and cardiac structure and function. Significant metabolic alterations, particularly in amino acid and lipid metabolism, are prevalent in HCM. These findings enhance our understanding of HCM pathogenesis and suggest potential biomarkers and therapeutic targets for this genetic heart disease.