Bile acid dysmetabolism in inflammatory bowel diseases

Abstract

Aim: To summarize the state-of-the-art data on the molecular mechanisms of bile acid (BA) synthesis and absorption, their impaired absorption and receptor-dependent signaling, as well as on the effects of the gut microbiota on BA metabolism in inflammatory bowel diseases (IBD). Key messages: BA malabsorption is one of the relevant mechanisms in the development of diarrhea in IBD. It may occur due to various disorders of the ileum, such as terminal ileitis, ileocolitis or ileocecal resection in Crohn's disease and ileoanal reservoir in ulcerative colitis. Molecular mechanisms of BA malabsorption in IBD are related to a defect in the BA uptake by the apical sodium dependent bile acid transporter (ASBT), as well as to a decrease in the expression of pregnane X receptor (PXR) and farnesoid X receptor (FXR), whose activation by glucocorticoids results in an increase in the BA reabsorption in the ileum and a decrease in hologenic diarrhea. The metabolic profile of luminal BA in IBD is characterized by an increased content of conjugated and 3-OH-sulfated BA and reduced levels of secondary BA. The decrease in the relative abundance of the Lachnospiraceae and Oscillospiraceae spp. in IBD patients leads to a decrease in the efficiency of microbial biotransformation of BA. Changes in the BA metabolic profile in IBD affect the gut microbiota, and impaired interaction with the FXR, PXR, G protein-coupled bile acid receptor (GPBAR1), retinoid-related orphan receptors (RORs) and vitamin D receptor (VDR) results in a pro-inflammatory response and increased intestinal permeability, bacterial translocation, and IBD progression. BA metabolism in IBD-associated primary sclerosing cholangitis (PSC-IBD) is characterized by a significant decrease in the luminal BA pool, and the microbiota composition is remarkable for an increase in the relative abundance of Fusobacterium and Ruminococcus spp., and a decrease in Veillonella, Dorea, Blautia, Lachnospira and Roseburia. Conclusion: Disordered synergistic interplay of BA with intestinal microbiota results in disruption of the ligand-receptor interaction and BA metabolic transformation, which contributes to the activation of the immune system, formation of a vicious circle of chronic inflammation and IBD progression. Further studies into mutual influence of the gut microbiota, BA metabolism and receptor signaling may promote the development of new methods for the diagnosis and treatment of IBD.