Bacteroides eggerthii ameliorates metabolic dysfunction associated steatotic liver disease through host–microbe signaling and highlights 2-hydroxyisocaproate as a potential effector
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Background/Aims: 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 re main 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. Methods: 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 func tional 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 transcrip tomic analyses were performed. Anti-steatotic effects of B. eggerthii–derived metabolites were validated in vitro. Results: Bacteroides eggerthii supplementation significantly improved liver weight, inflammation, fibrosis, and ste atosis 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. Conclusions: Bacteroides eggerthii ameliorates MASLD via gut-liver axis modulation, including bile acid metabo lism and hepatic lipid signaling. These underscore its therapeutic potential and highlight HICA as a novel microbi ome-derived metabolite with anti-steatotic activity.
Abstract
Background/Aims: 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 re main 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. Methods: 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 func tional 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 transcrip tomic analyses were performed. Anti-steatotic effects of B. eggerthii–derived metabolites were validated in vitro. Results: Bacteroides eggerthii supplementation significantly improved liver weight, inflammation, fibrosis, and ste atosis 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. Conclusions: Bacteroides eggerthii ameliorates MASLD via gut-liver axis modulation, including bile acid metabo lism and hepatic lipid signaling. These underscore its therapeutic potential and highlight HICA as a novel microbi ome-derived metabolite with anti-steatotic activity.