Abstract
The field of bile acid microbiology in the gastrointestinal tract is going through a current rebirth after a peak of activity in the late 1970s and early 1980s. This renewed activity is a result of many factors, including the discovery near the turn of the century that bile acids are potent signalling molecules and technological advances in next-generation sequencing, computation, culturomics, gnotobiology, and metabolomics. We describe the current state of the field with particular emphasis on questions that have remained unanswered for many decades in both bile acid synthesis by the host and metabolism by the gut microbiota. Current knowledge of established enzymatic pathways, including bile salt hydrolase, hydroxysteroid dehydrogenases involved in the oxidation and epimerization of bile acid hydroxy groups, the Hylemon–Bjӧrkhem pathway of bile acid C7-dehydroxylation, and the formation of secondary allo-bile acids, is described. We cover aspects of bile acid conjugation and esterification as well as evidence for bile acid C3-dehydroxylation and C12-dehydroxylation that are less well understood but potentially critical for our understanding of bile acid metabolism in the human gut. The physiological consequences of bile acid metabolism for human health, important caveats and cautionary notes on experimental design and interpretation of data reflecting bile acid metabolism are also explored.
Key points
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Co-metabolism of bile acids is among the most studied aspects of host–microbiota interactions important for human health, although many mechanistic questions remain unanswered.
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A substantial gap in our knowledge still exists with respect to host synthesis of bile acid A/B-ring trans-isomers, known as allo-bile acids.
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Untargeted metabolomics identified microbially conjugated bile acids, which seem to be generated via bile salt hydrolase enzymes and can signal through PXR and FXR, although their physiological relevance is not fully understood.
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Much of the biochemistry and enzymology of microbial bile acid 7-dehydroxylation is established; however, the enzymology of C3-dehydroxylation and C12-dehydroxylation requires additional work as do host responses to the resultant end-products.
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The oxidation and epimerization of bile acid hydroxyl groups greatly expand the diversity of bile acid metabolites as each hydroxyl toggles among three stable positions (for example, 3α-OH, 3-oxo and 3β-OH).
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Secondary bile acid epimers that have not been measured historically are emerging as potent modulators of the balance between T helper 17-mediated inflammation and immunosuppressive regulatory T cells in the intestine.
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Acknowledgements
The authors express sincere appreciation to Steven Daniel (University of Illinois, USA) for his assistance in editing and offering constructive comments on this review. They acknowledge financial support from National Institutes of Health grants (R01 CA204808-01 (J.M.R. and H.R.G.), R01 GM134423-01A1 (J.M.R.), R01 GM145920-01 (J.M.R.), R03 AI147127-01A1 (J.M.R.)) as well as UIUC Department of Animal Sciences Matchstick grant and Hatch ILLU-538-916 (J.M.R.).
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Ridlon, J.M., Gaskins, H.R. Another renaissance for bile acid gastrointestinal microbiology. Nat Rev Gastroenterol Hepatol 21, 348–364 (2024). https://doi.org/10.1038/s41575-024-00896-2
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DOI: https://doi.org/10.1038/s41575-024-00896-2
