Secondary bile acid lithocholic acid ameliorates colitis-like inflammation in a human intestine-on-chip system

Abstract

Inflammatory bowel disease (IBD) is a multifactorial disease of the gastrointestinal tract without curative treatment. Previous studies highlighted that altered fecal bile acid levels correlate with intestinal microbiota composition changes and inflammation in IBD. Lithocholic acid (LCA) is a secondary bile acid (SBA) drastically reduced during active IBD but mediates beneficial effects at the mucosal intestinal barrier during intestinal homeostasis. In a dextran sodium sulfate (DSS)-induced colitis-on-chip model, it was investigated whether the administration of LCA has a protective impact on inflammation-mediated tissue damage. Physiological responses were successfully recapitulated in the human colitis model, enabling the dissection of individual cell responses. Treatment with LCA concentrations similar to healthy human intestinal levels efficiently ameliorated the colitis-like phenotype. LCA treatment stimulated epithelial cell proliferation, thereby maintaining villus morphology, intestinal barrier integrity, and reducing inflammation. The protective effects of LCA were mainly mediated by the activation of the farnesoid X receptor (FXR).