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

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.