Enterotoxigenic Bacteroides fragilis exacerbates alcoholic liver disease progression through kynurenine mediated AMPK signaling inhibition and retinoic acid depletion

ABSTRACT:

Abstract Background & Aims: Alcoholic liver disease (ALD) pathogenesis involves gut microbiota dysbiosis, but specific pathobionts and mechanisms remain unclear. This study investigated the role of patient-derived enterotoxigenic Bacteroides fragilis (ETBF) in ALD progression and its underlying molecular mechanisms. Methods: We recruited 25 healthy controls (HC) and 49 ALD patients. Fecal and serum samples underwent metagenomic and metabolomic analyses. Mechanistic validation employed fecal microbiota transplantation (FMT), ETBF monocolonization, and metabolite interventions in ethanol-fed mice, complemented by in vitro studies. Results:ALD patients exhibited dysbiosis characterized by marked ETBF enrichment and depletion of SCFA-producing bacteria (Faecalibacterium prausnitzii, Fusicatenibacter saccharivorans). Fecal SCFAs were significantly decreased and inversely correlated with liver injury markers. Serum metabolomics identified 128 dysregulated metabolites, including elevated pro-inflammatory 9,10-DHOME and decreased hepatoprotective lysophosphatidylcholines. Metagenomic and metabolomic data achieved high diagnostic accuracy and predicted disease progression (AUC=0.89). FMT from ALC patients or ETBF monocolonization exacerbated alcohol-induced liver injury, steatosis, inflammation, and fibrosis in mice. Mechanistically, ETBF upregulated hepatic and colon IDO1 via inflammatory cytokines TNF-α, increasing stool and hepatic kynurenine levels. Kynurenine exerted dual hepatotoxic effects: (1) inhibiting AMPK phosphorylation in hepatocytes, promoting lipid accumulation; and (2) inducing CYP26A1, accelerating retinoic acid (RA) catabolism. RA deficiency derepressed PPARγ transcription, activating hepatic stellate cells and driving fibrogenesis. Exogenous kynurenine recapitulated these effects, while RA supplementation attenuated Lipid formation and fibrogenic in ALD mice. Exogenous Anti-TNF-α or Talarozole alleviates ETBF-induced Lipid formation and fibrogenic in ALD mice. Conclusions: ETBF is associated with ALD progression through IDO1/kynurenine/CYP26A1/RA/PPARγ cascade, representing a novel pathogenic mechanism and offering multiple therapeutic targets.

INSTRUMENT(S): Liquid Chromatography MS - alternating - reverse-phase

PROVIDER: MTBLS15572 | MetaboLights | 2026-09-07

REPOSITORIES: MetaboLights