FXR-Dependent Modulation of the Human Small Intestinal Microbiome by the Bile Acid Derivative Obeticholic Acid

Bile acids play a role in regulating the gut microbiome by inhibiting bacterial growth. Using the FXR agonist obeticholic acid (OCA), we investigated the impact of modulating bile acid synthesis on the human gut microbiome. Suppression of endogenous bile acid synthesis by OCA treatment led to a reversible induction of Gram-positive bacterial taxa that are consumed in the diet, found in the small intestine, and sensitive to growth inhibition by bile acids in vitro. OCA treatment enhanced the representation of genomic pathways involved in DNA synthesis and amino acid metabolism, suggesting greater growth of these bacterial taxa. Indeed, mice fed OCA had reduced endogenous bile acid levels and an increased proportion of Firmicutes, specifically in the small intestine. These results demonstrate the dynamic interplay between bile acids and the human small intestinal microbiome, and suggest opportunities for microbiome biomarker discovery as well as novel modalities to engineer the human microbiome via FXR activation.