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The microbiota modulates gut immune homeostasis. Bacteria influence the development and function of host immune cells, including T helper cells expressing interleukin-17A (T(H)17 cells). We previously reported that the bile acid (BA) metabolite 3-oxolithocholic acid (3-oxoLCA) inhibits T(H)17 cell differentiation(1). While it was suggested that gut-residing bacteria produce 3-oxoLCA, the identity of such bacteria was unknown, and it was unclear whether 3-oxoLCA and other immunomodulatory BAs are associated with inflammatory pathologies in humans. Here, we identify human gut bacteria and corresponding enzymes that convert the secondary BA lithocholic acid into 3-oxoLCA as well as the abundant gut metabolite isolithocholic acid (isoLCA). Like 3-oxoLCA, isoLCA suppressed T(H)17 differentiation by inhibiting RORγt (retinoic acid receptor-related orphan nuclear receptor γt), a key T(H)17 cell-promoting transcription factor. Levels of both 3-oxoLCA and isoLCA and the 3α-hydroxysteroid dehydrogenase (3α-HSDH) genes required for their biosynthesis were significantly reduced in inflammatory bowel disease (IBD) patients. Moreover, levels of these BAs were inversely correlated with expression of T(H)17 cell-associated genes. Overall, our data suggest that bacterially produced BAs inhibit T(H)17 cell function, an activity that may be relevant to the pathophysiology of inflammatory disorders such as IBD.

Diet is a major factor that shapes the gut microbiome1, but the consequences of diet-induced changes in the microbiome for host pathophysiology remain poorly understood. We conducted a randomized human intervention study using a very-low-calorie diet (NCT01105143). Although metabolic health was improved, severe calorie restriction led to a decrease in bacterial abundance and restructuring of the gut microbiome. Transplantation of post-diet microbiota to mice decreased their body weight and adiposity relative to mice that received pre-diet microbiota. Weight loss was associated with impaired nutrient absorption and enrichment in Clostridioides difficile, which was consistent with a decrease in bile acids and was sufficient to replicate metabolic phenotypes in mice in a toxin-dependent manner. These results emphasize the importance of diet-microbiome interactions in modulating host energy balance and the need to understand the role of diet in the interplay between pathogenic and beneficial symbionts.

The microbiota modulates gut immune homeostasis. Bacteria influence the development and function of host immune cells, including T helper cells expressing interleukin-17A (T