Investigation of bile salt hydrolase activity in human gut bacteria reveals production of conjugated secondary bile acids

Through biochemical transformation of host-derived bile acids, gut bacteria mediate host-microbe crosstalk and function at the interface of nutrition and host metabolic regulation. Bile acids play a crucial role in human health by facilitating the absorption of dietary lipophilic nutrients, interacting with hormone receptors to regulate host physiology, and shaping gut microbiota composition through antimicrobial activity. Bile acids deconjugation by bacterial bile salt hydrolase has long been recognized as the first necessary bile acid modification required before further transformations can occur. Here, we show that bile salt hydrolase activity is common among human gut bacterial isolates spanning seven major phyla. However, we observed variation in both the extent and the specificity of deconjugation of bile acids among the tested taxa. Unexpectedly, we discovered that certain strains were capable of directly dehydrogenating conjugated bile acids via hydroxysteroid dehydrogenases to produce conjugated secondary bile acids both in vitro and in vivo. These results challenge the prevailing notion that deconjugation is a prerequisite for further bile acid modifications and lay a foundation for new hypotheses regarding how bacteria act individually or in concert to diversify the bile acid pool and influence host physiology.