Host metabolism balances microbial regulation of bile acid signalling

Tae Hyung Won; Mohammad Arifuzzaman; Christopher N Parkhurst; Isabella C Miranda; Bingsen Zhang; Elin Hu; Sanchita Kashyap; Jeffrey Letourneau; Wen-Bing Jin; Yousi Fu; Douglas V Guzior; JRI Live Cell Bank; Robert A Quinn; Chun-Jun Guo; Lawrence A David; David Artis; Frank C Schroeder

doi:10.1038/s41586-024-08379-9

Host metabolism balances microbial regulation of bile acid signalling

Nature. 2025 Jan 8. doi: 10.1038/s41586-024-08379-9. Online ahead of print.

Authors

Tae Hyung Won^#^{1

2}, Mohammad Arifuzzaman^#^{3

4}, Christopher N Parkhurst^#³, Isabella C Miranda³, Bingsen Zhang¹, Elin Hu^{3

4}, Sanchita Kashyap^{3

4}, Jeffrey Letourneau⁵, Wen-Bing Jin³, Yousi Fu⁶, Douglas V Guzior^{6

7}; JRI Live Cell Bank; Robert A Quinn⁶, Chun-Jun Guo^{3

4

8}, Lawrence A David^{5

9}, David Artis^{10

11

12

13}, Frank C Schroeder¹⁴

Collaborators

Affiliations

¹ Department of Chemistry and Chemical Biology, Boyce Thompson Institute, Cornell University, Ithaca, NY, USA.
² College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, Pocheon-si, Republic of Korea.
³ Joan and Sanford I. Weill Department of Medicine, Jill Roberts Institute for Research in Inflammatory Bowel Disease, Division of Gastroenterology and Hepatology, Weill Cornell Medicine, Cornell University, New York, NY, USA.
⁴ Friedman Center for Nutrition and Inflammation, Weill Cornell Medicine, Cornell University, New York, NY, USA.
⁵ Department of Molecular Genetics and Microbiology, Duke University, Durham, NC, USA.
⁶ Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, USA.
⁷ Department of Microbiology, Genetics, and Immunology, Michigan State University, East Lansing, MI, USA.
⁸ Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA.
⁹ Program in Computational Biology and Bioinformatics, Duke University School of Medicine, Durham, NC, USA.
¹⁰ Joan and Sanford I. Weill Department of Medicine, Jill Roberts Institute for Research in Inflammatory Bowel Disease, Division of Gastroenterology and Hepatology, Weill Cornell Medicine, Cornell University, New York, NY, USA. dartis@med.cornell.edu.
¹¹ Friedman Center for Nutrition and Inflammation, Weill Cornell Medicine, Cornell University, New York, NY, USA. dartis@med.cornell.edu.
¹² Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA. dartis@med.cornell.edu.
¹³ Allen Discovery Center for Neuroimmune Interactions, Weill Cornell Medicine, Cornell University, New York, NY, USA. dartis@med.cornell.edu.
¹⁴ Department of Chemistry and Chemical Biology, Boyce Thompson Institute, Cornell University, Ithaca, NY, USA. schroeder@cornell.edu.

^# Contributed equally.

PMID: 39779854
DOI: 10.1038/s41586-024-08379-9

Abstract

Metabolites derived from the intestinal microbiota, including bile acids (BA), extensively modulate vertebrate physiology, including development¹, metabolism^2-4, immune responses^5-7 and cognitive function⁸. However, to what extent host responses balance the physiological effects of microbiota-derived metabolites remains unclear^9,10. Here, using untargeted metabolomics of mouse tissues, we identified a family of BA-methylcysteamine (BA-MCY) conjugates that are abundant in the intestine and dependent on vanin 1 (VNN1), a pantetheinase highly expressed in intestinal tissues. This host-dependent MCY conjugation inverts BA function in the hepatobiliary system. Whereas microbiota-derived free BAs function as agonists of the farnesoid X receptor (FXR) and negatively regulate BA production, BA-MCYs act as potent antagonists of FXR and promote expression of BA biosynthesis genes in vivo. Supplementation with stable-isotope-labelled BA-MCY increased BA production in an FXR-dependent manner, and BA-MCY supplementation in a mouse model of hypercholesteraemia decreased lipid accumulation in the liver, consistent with BA-MCYs acting as intestinal FXR antagonists. The levels of BA-MCY were reduced in microbiota-deficient mice and restored by transplantation of human faecal microbiota. Dietary intervention with inulin fibre further increased levels of both free BAs and BA-MCY levels, indicating that BA-MCY production by the host is regulated by levels of microbiota-derived free BAs. We further show that diverse BA-MCYs are also present in human serum. Together, our results indicate that BA-MCY conjugation by the host balances host-dependent and microbiota-dependent metabolic pathways that regulate FXR-dependent physiology.