Through 170 years of bile acid chemistry research, comprising over 40,000 publications, our knowledge of mammalian bile acid conjugation was limited to the amino acids glycine and taurine. By screening organs of germ free (GF) and colonized mice with LC-MS/MS based metabolomics we have discovered unique bile acids made by the microbiome that are produced by acyl-conjugation of cholic acid with alternative amino acids in the gut. These microbially conjugated bile acids (MCBAs) are produced by a multitude of gut anaerobes and we have been characterizing the breadth of their amino acid conjugation and bile acid substrate specificity. These molecules are prevalent in humans, particularly those with Crone’s disease and in infants early in life, but their role in mammalian GI health is poorly understood due to their novelty. MCBA abundance is approximately 10-50-fold lower than the host conjugated taurocholic acid in the murine gut, but there is wide variation in the specific amino acids conjugated in mice. Recently, we demonstrated that the reverse action of the enzyme bile salt hydrolase (BSH) acting as a transferase is responsible for MCBA production. BSH enzymes from various gut bacteria have different amino acid conjugation profiles dictated by the structure of their active site. We have leveraged a novel knockout mouse model that is devoid of host-conjugated bile acids to better understand how gut anaerobe bile acid conjugation alters mammalian GI metabolism. Preliminary data from the mouse model shows that bile acid conjugation is important for early life development in mammals and MCBAs contribute to this. These experiments have also shown that mammalian bile acid conjugation by the liver is itself poorly understood, as the knockout mice had a uniquely shifted bile acid pool containing even more unique conjugations. Although many medical textbooks describe the role of bile acids and bile acid conjugation in GI health, it is clear from recent research, that we poorly understand how our own enzymes and that from our microbiota contribute to bile acid metabolism.

Microbial bile acid conjugation as a new mechanism of host-microbiome crosstalk

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