Delineating the impact of gut microbiome-mediated bile acid metabolism upon T helper 17 cells: further insight into inflammatory bowel disease pathogenesis?

Paik D, Yao L, Zhang Y, et al. Human gut bacteria produce T_H17-modulating bile acid metabolites. Nature 2022; 603:907–912. doi: 10.1038/s41586-022-04480-z.

There is a close association between gut microbiome-mediated bile acid metabolism and host immune response, with perturbations of this interaction linked to human diseases including inflammatory bowel disease (IBD). However, pathways underlying these interactions remain only partially understood. Extending on previous work demonstrating that a particular bile acid, 3-oxolithocholic acid (3-oxoLCA), inhibits differentiation of pro-inflammatory T helper 17 (T_H17) cells, Paik et al first screened 990 bacterial isolates derived from human stool for their ability to bioconvert lithocholic acid (LCA) into 3-oxoLCA; 238 isolates with this functionality were identified. A number of these identified strains were also noted to produce isoLCA, an abundant bile acid within the gut. IsoLCA inhibited differentiation of naïve cluster of differentiation 4 (CD4⁺) cells into T_H17 cells as efficiently as 3-oxoLCA; the mechanism for this was via these bile acids directly binding to retinoic acid receptor-related orphan nuclear receptor γt (a major T_H17-promoting transcription factor) and suppressing its transcriptional activity. Bacterial 3a-/b-hydroxysteroid dehydrogenases (HSDHs) were identified as the enzymes responsible for bioconversion of LCA to these derivatives, with close inverse correlation between caecal 3-oxoLCA and isoLCA levels and T_H17 cell frequencies observed in mice. Paik et al also explored the relevance of these findings to humans; both 3-oxoLCA and isoLCA were significantly reduced in Crohn’s patients compared with non-IBD controls, with levels of these bile acids negatively correlating with T_H17/IL-17-related gene expression in Crohn’s patients. 3a-HSDH genes were markedly depleted in IBD patients compared with controls. Collectively, these data give further insight into potential mechanisms as to how disturbance of microbiome-mediated bile acid metabolism may contribute to IBD.

Environmental factors shaping the gut microbiome in a Dutch population

Gacesa R, …