Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapieDec 10, 2024

Microbial bile acid may reduce inflammation in inflammatory bowel disease by activating GPBAR1 and blocking RORγt

Circadian Biology Weekly Brief ↗PubMed ↗DOI ↗

Updated Mar 31, 2026

Abstract

Inflammatory bowel disease (IBD) is associated with elevated excretion of primary bile acids and decreased levels of secondary bile acids.

IBD patients show increased levels of primary bile acids while secondary bile acids are reduced.
Changes in bile acid levels correlate with disease severity and immune responses, including pro-inflammatory cytokine expression.
Five specific bile acids—3-oxo-DCA, 3-oxo-LCA, allo-LCA, iso-allo-LCA, and 3-oxo-UDCA—are observed to have decreased excretion in IBD patients and colitic mice.
These bile acids act as agonists for GPBAR1 and inverse agonists for RORγt, influencing immune cell behavior.
Administering 3-oxo-DCA in a murine model reverses colitis development and improves gut microbiota composition.

Simplified

The interplay between the dysbiotic microbiota and bile acids is a critical determinant for development of a dysregulated immune system in inflammatory bowel disease (IBD). Here we have investigated the fecal bile acid metabolome, gut microbiota composition, and immune responses in IBD patients and murine models of colitis and found that IBD associates with an elevated excretion of primary bile acids while secondary, allo- and oxo- bile acids were reduced. These changes correlated with the disease severity, mucosal expression of pro-inflammatory cytokines and chemokines, and reduced inflow of anti-inflammatory macrophages and Treg in the gut. Analysis of bile acids metabolome in the feces allowed the identification of five bile acids: 3-oxo-DCA, 3-oxo-LCA, allo-LCA, iso-allo-LCA and 3-oxo-UDCA, whose excretion was selectively decreased in IBD patients and diseased mice. By transactivation assay and docking calculations all five bile acids were shown to act as GPBAR1 agonists and RORγt inverse agonists, skewing Th17/Treg ratio and macrophage polarization toward an M2 phenotype. In a murine model of colitis, administration of 3-oxo-DCA suffices to reverse colitis development and intestinal dysbiosis in a GPBAR1-dependent manner. In vivo administration of 3-oxo-DCA to colitic mice also reverses disease severity and RORγt activation induced by a RORγt agonist and IL-23, a Th17 inducing cytokine. These results demonstrated that intestinal excretion of 3-oxoDCA, a dual GPBAR1 agonist and RORγt inverse agonist, is reduced in IBD and in models of colitis and its restitution protects against colitis development, highlighting a potential role for this agent in IBD management.

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Microbial bile acid may reduce inflammation in inflammatory bowel disease by activating GPBAR1 and blocking RORγt

Abstract

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