Microbiome Data from mice gavaged with different bile acids
Bile acids (BAs) are steroid detergents in bile that contribute to the absorption of fats and fat-soluble vitamins while shaping the gut microbiome due to their antimicrobial properties. A novel mechanism of BA metabolism by the gut microbiota has been identified involving conjugation with various amino acids producing the diverse microbially conjugated bile acids (MCBAs). Here, we show this unique biochemistry is mediated by bile salt hydrolase acting as an aminoacyltransferase (BSH/T). Clostridium perfringens BSH/T rapidly performed acyl-transfer when provided various amino acids and taurocholate, glycocholate or cholate, with an optimum at approximately pH 5.3. Amino acids conjugated by CpBSH/T were pH-dependent and broad in range, though proline and aspartic acid conjugates were not observed. BA conjugation was widespread among gut bacteria, with unique amino acid preferences depending on the organism. Bacteria with closely related BSH/T amino acid sequences displayed similar bile acid conjugation profiles, while horizontal gene transfer of bsh in some species increased conjugation diversity. Tertiary structure mapping of BSH/T from different gut bacteria followed by site-directed mutagenesis showed that the active site structure was responsible for amino acid selectivity. The MCBA products of BSH/T aminoacyltransfer have antimicrobial properties, with hydrophobic conjugates having the most potent activity. The minimum inhibitory concentrations (MIC) of cholate MCBAs on specific gut bacteria reach those measured in the guts of mammals, indicating they may induce a selective pressure on the gut microbiome in vivo. Feeding mice MCBAs showed that they can enter enterohepatic circulation, with the liver and gall bladder concentrations depending on the amino acid conjugated. MCBAs produced by BSH/T are a significant component of the human bile acid pool, reaching equal to and even higher concentrations than secondary and primary bile acids in human feces. MCBA concentrations were reduced in humans after bariatric surgery to treat obesity, indicating they can be altered by changes in GI physiology. Thus, acyltransferase activity is an inherent property of BSH/T that greatly diversifies the bile acid pool, creating a set of previously underappreciated metabolites with the potential to impact the microbiome and human health.