<i>Turicibacter sanguinis</i> is a candidate gut microbial pathobiont that promotes metabolic dysfunction-associated steatohepatitis

ABSTRACT Emerging evidence points to the gut microbiota’s involvement in metabolic dysfunction-associated steatohepatitis (MASH), yet the specific causative microbes remain largely unidentified. This study aimed to identify and functionally characterize candidate microbial pathobionts to MASH progression. Differentially abundant microbes were identified by 16S rRNA sequencing in a choline-deficient, L-amino acid-defined, high-fat diet MASH model, validated in other animal MASH models and in public clinical metagenomic data sets, then screened for consistently altered gut taxa. A candidate underwent functional validation via directed oral administration in mice. Mechanisms were explored through bile acid profiling by UHPLC-MS/MS and FXR signaling analysis by qPCR and immunohistochemistry. Additionally, fecal samples from MASH patients before and after treatment were analyzed to correlate microbial abundance with treatment response. Turicibacter sanguinis was consistently enriched in all MASH models and public data sets, with abundance correlating positively with liver injury markers. Its increased abundance exacerbated steatosis, inflammation, and fibrosis in healthy and diseased mice. Mechanistically, Turicibacter sanguinis altered bile acid composition, thereby increasing conjugated and decreasing unconjugated species, and inhibited hepatic FXR signaling, accompanied by suppressed SHP and elevated CYP7A1 and SREBP1c expression, which is consistent with enhanced bile acid synthesis and lipid accumulation. Futhermore, after pharmacotherapy, reduced Turicibater sanguinis levels correlated positively with alanine aminotransferase (ALT) and aspartate aminotransferase (AST) improvements. In conclusion, Turicibacter sanguinis is a clinically relevant microbial pathogen that exacerbated MASH by inducing bile acid dysregulation and suppressing FXR signaling, highlighting its potential as a candidate biomarker for disease monitoring and motivating future evaluation of targeted microbiome interventions. IMPORTANCE Metabolic dysfunction-associated steatohepatitis (MASH) is a growing global health problem with limited treatment options. Although the gut microbiome has been implicated in MASH, the specific bacterial strains that directly drive disease progression remain largely unknown. This study identified Turicibacter sanguinis as a candidate gut microbial pathobiont that promotes MASH, demonstrating its significant enrichment in both animal models and patient samples. By disrupting hepatic metabolic signaling, this bacterium promotes bile acid synthesis and exacerbates liver fat accumulation, inflammation, and fibrosis. Following effective treatment, its abundance decreased significantly in patients. These findings indicate that Turicibacter sanguinis holds promise as a potential target for developing novel microbiome-based diagnostic and therapeutic approaches for MASH.