Loss of TGR5-activating bile acids is associated with disease activity in inflammatory bowel disease

The gut microbiota communicates extensively with its host through small metabolites, such as bile acids. Primary bile acids are synthesized by the host and secreted into the intestine, where they are actively converted by the microbiota into secondary bile acids. Depending on the resulting bile acid composition, the host's bile acid receptor, Takeda G protein-coupled receptor 5 (TGR5), is activated and mediates immune tolerance. It has been suggested that a disturbed bile acid profile in inflammatory bowel disease (IBD) might lead to inflammation via reduced activation of TGR5. Our study is the first to investigate whether bile acid-induced TGR5 activation differs between healthy individuals and patients with IBD. Bile acid profiles in stool and plasma were quantified by mass spectrometry, and TGR5 bioactivity was assessed from these profiles. In parallel, metagenomic sequencing was performed on fecal samples. We demonstrate that reduced alpha diversity in IBD is associated with a loss of microbial capacity for bile acid transformation, resulting in a significantly decreased secondary-to-primary bile acid ratio (sBA/pBA) in both stool and circulation. TGR5 bioactivity induced by bile acid profiles was substantially reduced in IBD patients, and a lower TGR5 bioactivity correlated with increased inflammatory activity.