Biology Seminar - Frank Schroeder

Metabolites derived from the intestinal microbiota extensively modulate animal physiology and in particular lipid metabolism; however, to what extent host responses balance the effects of microbiota-derived metabolites remains unclear. I will first discuss an example from C. elegans, where untargeted metabolomics uncovered evolutionarily related endogenous and microbiota-dependent small molecule signals that control expression of the desaturase FAT-7/SCD1 via the nuclear receptor NHR-49/PPARα, conserved gate keepers of fat metabolism.

Similarly, untargeted metabolomics of mouse tissues revealed complementary host and microbial regulation of the farnesoid X receptor (FXR) via bile acid (BA) derivatives. Conjugation of microbiota-derived BAs with methylcysteamine (BA-MCYs) by the host pantetheinase, VNN1/vanin 1, inverts bile acid function in the hepatobiliary system. Whereas microbiota-derived free BAs function as FXR agonists, BA-MCYs act as potent FXR antagonists in vitro and accordingly regulate lipid metabolism in vivo. Taken together, these examples demonstrate how deeply intertwined biosynthetic pathways in metazoan host and associated microbiota converge on nuclear receptor signaling to regulate physiology, and draw attention to the vast space of microbiota-dependent metabolites whose chemical structures, biosyntheses, and physiological functions remain unannotated.