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The changing metabolic landscape of bile acids – keys to metabolism and immune regulation

Abstract

Bile acids regulate nutrient absorption and mitochondrial function, they establish and maintain gut microbial community composition and mediate inflammation, and they serve as signalling molecules that regulate appetite and energy homeostasis. The observation that there are hundreds of bile acids, especially many amidated bile acids, necessitates a revision of many of the classical descriptions of bile acids and bile acid enzyme functions. For example, bile salt hydrolases also have transferase activity. There are now hundreds of known modifications to bile acids and thousands of bile acid-associated genes, especially when including the microbiome, distributed throughout the human body (for example, there are >2,400 bile salt hydrolases alone). The fact that so much of our genetic and small-molecule repertoire, in both amount and diversity, is dedicated to bile acid function highlights the centrality of bile acids as key regulators of metabolism and immune homeostasis, which is, in large part, communicated via the gut microbiome.

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Fig. 1: Diversity of known bile acid chemical modifications.
Fig. 2: Modifications of known bile acids.
Fig. 3: Distribution of bile acids and related transcripts or proteins.
Fig. 4: Proportion of bile acids in humans.
Fig. 5: The known deconjugation and re-conjugation of bile acids by BAAT and BSH enzymes.
Fig. 6: Bile acids and receptor interactions.
Fig. 7: The bile acid encoder–decoder hypothesis.

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Data availability

Structural databases referred to in Fig. 2 and Supplementary Fig. 1 can be accessed and downloaded from https://hmdb.ca/downloads (HMDB), https://gnps-external.ucsd.edu/gnpslibrary (BILELIB19) and https://www.lipidmaps.org/data/structure/download.php (LIPID MAPS). The source code used for generation of Fig. 2 and Supplementary Fig. 1 can be accessed at https://github.com/YasinEl/Bile_Acid_Review_2022; Figs. 3a,b and 4 can be accessed at https://github.com/mohantyipsita/Bile_Acid_Review_2022; Fig. 3c,d can be accessed at https://github.com/callaband/Bile_Acid_Review_2022.

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Acknowledgements

P.C.D. and R.K. acknowledge support from NIH U19 AG063744, and support for the collaborative microbial metabolite centre (1U24DK133658); R.K. also acknowledges DP1AT010885.

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P.C.D., I.M. and C.A. researched data for the article, made a substantial contribution to discussion of content, wrote the article, and reviewed/edited the manuscript before submission. H.M.-R. and Y.E.A. researched data for the article, made a substantial contribution to discussion of content, and reviewed/edited the manuscript before submission. L.R.H. made a substantial contribution to discussion of content, wrote the article, and reviewed/edited the manuscript before submission. R.K. made a substantial contribution to discussion of content and reviewed/edited the manuscript before submission.

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Correspondence to Pieter C. Dorrestein.

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Mohanty, I., Allaband, C., Mannochio-Russo, H. et al. The changing metabolic landscape of bile acids – keys to metabolism and immune regulation. Nat Rev Gastroenterol Hepatol 21, 493–516 (2024). https://doi.org/10.1038/s41575-024-00914-3

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