Host-derived bile acids drive dysbiosis by selecting bile-resistant epimerizing bacteria in inflammatory bowel disease

The gut microbiome is a key regulator of intestinal homeostasis. Although dysbiosis is pervasively reported in inflammatory bowel diseases (IBD), its drivers and impact in disease pathophysiology are not yet fully understood. By integrating public metagenomic and metabolomic datasets from >5000 individuals across 12 ethnically diverse cohorts with independent validation cohorts and using neural-network based feature attribution, we identified epimerized bile acids (BAs) produced by microbial hydroxysteroid dehydrogenases (HSDHs) as a novel hallmark of IBD-associated dysbiosis. This shift occurs alongside previously reported changes including a depletion of microbe-derived C7-dehydroxylated BAs and an accumulation of host-derived C7-hydroxylated BAs. We show that increased levels of host-derived BA lead to epithelial remodelling during disease and are sufficient to recapitulate key features of IBD-related dysbiosis, including reduced microbial diversity and expansion of bile-resistant bacteria such as Mediterraneibacter gnavus and Escherichia coli. HSDHs found in IBD-enriched bacteria facilitate growth under high host-derived BA conditions by converting these molecules into urso- and iso-forms. While epimerized 7α-dehydroxylated BA have established immunoregulatory properties, the function of host-derived BA epimers remain poorly understood. We demonstrate that epimerized host-derived BAs exhibit reduced FXR agonist activity and that increased levels of these metabolites, or the bacteria that produce them, are associated with diminished ileal FXR signaling and altered circulating FGF19 and C4 levels in IBD patients. Our findings identify enhanced BA epimerization as a defining metabolic feature of IBD-associated dysbiosis and reveal a mechanism by which bile-resistant bacteria reshape BA signaling, linking microbial adaptation, impaired host-microbiome feedback regulation, and intestinal inflammation.