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Host metabolism balances microbial regulation of bile acid signalling

Nature (2025)Cite this article

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Abstract

Metabolites derived from the intestinal microbiota, including bile acids (BA), extensively modulate vertebrate physiology, including development1, metabolism2,3,4, immune responses5,6,7 and cognitive function8. However, to what extent host responses balance the physiological effects of microbiota-derived metabolites remains unclear9,10. 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.

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Fig. 1: Identification of MCY conjugates of BAs.
Fig. 2: Microbiota dependence and biosynthesis of BA–MCY conjugates.
Fig. 3: Host-dependent production of BA–MCYs and microbial deconjugation.
Fig. 4: BA–MCY conjugates are FXR antagonists.
Fig. 5: BA–MCYs regulate BA biosynthesis in vivo and a model for the role of BA–MCYs in BA metabolism.

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Data availability

Source data for Figs. 2–5 and Extended Data Figs. 2, 3 and 5–12 are provided with this paper. Raw sequencing reads were uploaded to the Sequence Read Archive under accession number BioProject PRJNA761331, and mass spectrometry data for all mouse metabolome samples analysed in this study are available on the GNPS website (https://massive.ucsd.edu) under MassIVE ID number MSV000090974. Source data are provided with this paper.

Code availability

The custom Fiji script used for the analysis of liver lipid accumulation imaging is available on Zenodo69 (https://doi.org/10.5281/zenodo.14031611).

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Acknowledgements

We thank members of the Schroeder and Artis laboratories for discussion and critical reading of the manuscript; B. Fox for assistance with mass spectrometry; and all contributing members of the JRI IBD Live Cell Bank consortium, which is supported by the Jill Roberts Institute for Research in IBD, the Jill Roberts Center for IBD, Cure for IBD, the Rosanne H. Silbermann Foundation, the Sanders Family, and the WCM Division of Pediatric Gastroenterology and Nutrition. The schematics in Fig. 1a were created using BioRender (https://biorender.com). All chemical structures were created with ChemDraw. This work was supported by the Crohn’s & Colitis Foundation (to M.A.), the Thomas C. King Pulmonary Fellowship, the WCM Fund for the Future, the Sackler Brain and Spine Institute Research Grant, and a Brain and Behavior Research Foundation (NARSAD) Young Investigator Award (all to C.N.P.), Office of Naval Research grant N00014-18-1-2616 (to L.A.D.), the Howard Hughes Medical Institute (to F.C.S.), Kenneth Rainin Foundation and the W. M. Keck Foundation (all to C.-J.G.), The Global Grants for Gut Health co-supported by Yakult and Nature Research (to R.A.Q.), the AGA Research Foundation, the WCM-RAPP Initiative, Cure for IBD, the Jill Roberts Institute for Research in IBD, the Kenneth Rainin Foundation, the Sanders Family Foundation, the Rosanne H. Silbermann Foundation, the Glenn Greenberg and Linda Vester Foundation, the Allen Discovery Center Program, a Paul G. Allen Frontiers Group advised program of the Paul G. Allen Family Foundation (all to D.A.), and the US National Institutes of Health (K99AI173660 to M.A., K08MH130773 and NIAID Mucosal Immunology Studies Team Young Investigator Award to C.N.P., GM131877 to F.C.S., DK116187 to L.A.D., DK140854 to R.A.Q., DP2 HD101401 and DK135816 to C.-J.G., and DK126871, AI151599, AI095466, AI095608, AR070116, AI172027 and DK132244 to D.A.).

Author information

Author notes

  1. Tae Hyung Won

    Present address: College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, Pocheon-si, Republic of Korea

  2. These authors contributed equally: Tae Hyung Won, Mohammad Arifuzzaman, Christopher N. Parkhurst

Authors and Affiliations

  1. Department of Chemistry and Chemical Biology, Boyce Thompson Institute, Cornell University, Ithaca, NY, USA

    Tae Hyung Won, Bingsen Zhang & Frank C. Schroeder

  2. 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

    Mohammad Arifuzzaman, Christopher N. Parkhurst, Isabella C. Miranda, Elin Hu, Sanchita Kashyap, Wen-Bing Jin, Randy Longman, Gregory F. Sonnenberg, Ellen Scherl, Robbyn Sockolow, Dana Lukin, Vinita Jacob, Laura Sahyoun, Michael Mintz, Thomas Ciecierega, Aliza Solomon, Arielle Bergman, Kimberley Chein, Elliott Gordon, Kenny Joselin Castro Ochoa, Lily Barash, Victoria Ribeiro de Godoy, Adriana Brcic-Susak, Dario Garone, Caitlin Mason, Chloe Scott, Lexi Tempera, Chun-Jun Guo & David Artis

  3. Friedman Center for Nutrition and Inflammation, Weill Cornell Medicine, Cornell University, New York, NY, USA

    Mohammad Arifuzzaman, Elin Hu, Sanchita Kashyap, Randy Longman, Gregory F. Sonnenberg, Ellen Scherl, Robbyn Sockolow, Dana Lukin, Victoria Ribeiro de Godoy, Adriana Brcic-Susak, Dario Garone, Chloe Scott, Lexi Tempera, Chun-Jun Guo & David Artis

  4. Department of Molecular Genetics and Microbiology, Duke University, Durham, NC, USA

    Jeffrey Letourneau & Lawrence A. David

  5. Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, USA

    Yousi Fu, Douglas V. Guzior & Robert A. Quinn

  6. Department of Microbiology, Genetics, and Immunology, Michigan State University, East Lansing, MI, USA

    Douglas V. Guzior

  7. Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA

    Randy Longman, Gregory F. Sonnenberg, Chun-Jun Guo & David Artis

  8. Program in Computational Biology and Bioinformatics, Duke University School of Medicine, Durham, NC, USA

    Lawrence A. David

  9. Allen Discovery Center for Neuroimmune Interactions, Weill Cornell Medicine, Cornell University, New York, NY, USA

    David Artis

  10. Department of Pediatrics, Division of Gastroenterology, Hepatology, & Nutrition, Weill Cornell Medicine, Cornell University, New York, NY, USA

    Robbyn Sockolow, Thomas Ciecierega, Aliza Solomon, Arielle Bergman, Kimberley Chein, Elliott Gordon, Kenny Joselin Castro Ochoa & Lily Barash

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Consortia

JRI Live Cell Bank

  • David Artis
  • , Randy Longman
  • , Gregory F. Sonnenberg
  • , Ellen Scherl
  • , Robbyn Sockolow
  • , Dana Lukin
  • , Vinita Jacob
  • , Laura Sahyoun
  • , Michael Mintz
  • , Thomas Ciecierega
  • , Aliza Solomon
  • , Arielle Bergman
  • , Kimberley Chein
  • , Elliott Gordon
  • , Kenny Joselin Castro Ochoa
  • , Lily Barash
  • , Victoria Ribeiro de Godoy
  • , Adriana Brcic-Susak
  • , Dario Garone
  • , Caitlin Mason
  • , Chloe Scott
  •  & Lexi Tempera

Contributions

D.A. and F.C.S. supervised the study. T.H.W. carried out the metabolomics and chemical synthesis and analysed most of the data. C.N.P. and M.A. conducted all animal experiments. W.-B.J. and C.-J.G. provided the bacterial strains and helped with the monocolonization experiments. S.K., E.H. and I.C.M. helped with the mouse experiments and various other assays. B.Z. assisted with the metabolomic analyses and conducted the VNN1 assays. J.L. and L.A.D. provided the human samples. Y.F., D.V.G. and R.A.Q. provided the Baat-knockout mouse metabolome samples and data analysis, as well as microbial analyses. The JRI Live Cell Bank contributed to clinical sample acquisition, annotation, processing and evaluation. T.H.W., M.A., C.N.P., D.A. and F.C.S. analysed the data and wrote the manuscript with input from all co-authors.

Corresponding authors

Correspondence to David Artis or Frank C. Schroeder.

Ethics declarations

Competing interests

D.A. has contributed to scientific advisory boards at Pfizer, Takeda, Nemagene and the Kenneth Rainin Foundation. F.C.S. is a cofounder of Ascribe Bioscience and Holoclara Inc., and a member of the scientific advisory board of Hexagon Bio. The other authors declare no competing interests.

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Nature thanks the anonymous reviewers for their contribution to the peer review of this work. Peer reviewer reports are available.

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Extended data figures and tables

Extended Data Fig. 1 MS2 spectra of MCY conjugates of BAs.

a-e, MS2 spectra of CA-MCY (a), CDCA-MCYO (b), CA-MCYO (c), 7KDCA-MCYO (d), and CA-MCYO2 (e). The listed BA-MCY conjugates in each panel produced MS2 spectra very similar to the shown examples. Blue arrows indicate inferred fragmentation. MS2 fragments and structure parts highlighted in red represent MCY groups. Green fragments are derived from water loss.

Extended Data Fig. 2 Microbiota dependent production of BA-taurine and BA-MCY conjugates.

a, Relative abundances of BA-MCYO conjugates of less abundant BAs in serum of SPF (n = 11) and GF (n = 12), and mice that received FMT (n = 10, the three donors are represented by triangles, circles, and crosses, n = 3-4 for each donor). b,c, Relative abundances of CA-MCY conjugates (b) and βMCA-MCY conjugates (c) as well as the corresponding free BAs in feces of SPF mice (n = 3), GF mice (n = 3), and mice that received FMT (n = 10, the three donors are represented by triangles, circles, and crosses, n = 3-4 for each donor). N.D., not detected. d, Relative abundances of BA-MCYO conjugates of less abundant BAs in feces of SPF (n = 3) and GF (n = 3), and mice that received FMT (n = 10, the three donors are represented by triangles, circles, and crosses, n = 3-4 for each donor). e, Relative abundances of BA-taurine conjugates in serum or feces of SPF (n = 11 for serum and n = 3 for feces) and GF (n = 12 for serum and n = 3 for feces), and mice that received FMT (n = 10, the three donors are represented by triangles, circles, and crosses, n = 3-4 for each donor). f,g, Relative abundances of free BAs in serum (f) or feces (g) of SPF (n = 11 for serum and n = 3 for feces) and GF (n = 12 for serum and n = 3 for feces), and mice that received FMT (n = 10, the three donors are represented by triangles, circles, and crosses, n = 3-4 for each donor). Data are mean ± s.e.m. P values were calculated using unpaired two-sided Student’s t-test with Welch’s correction.

Source Data

Extended Data Fig. 3 Relationship between abundances of free BAs and BA-MCY conjugates.

a,b, Relative abundances of CA-MCY (a) and βMCA-MCY conjugates (b) as well as corresponding free BAs in serum of mice fed control (n = 8) or inulin fiber diet (n = 7). c, Relative abundances of BA-MCYO conjugates as well as corresponding free BAs in serum of mice fed control (n = 8) or inulin fiber diet (n = 7). d, Relationship between abundances of free BAs and BA-MCY conjugates in feces of SPF mice used as control for the FMT study (n = 25), FMT mice (n = 10), SPF mice fed a control diet for the inulin fiber diet study (n = 6), and inulin fiber diet fed SPF mice (n = 8). e, Relationship between abundances of free BAs and BA-MCY conjugates in serum of SPF as control for the FMT study (n = 11), FMT mice (n = 10), SPF mice fed a control diet for the inulin fiber diet study (n = 8), and inulin fiber diet fed SPF mice (n = 7). f,g, Relative abundances of free BAs (f) and corresponding BA-MCY conjugates (g) in serum of human (n = 19). Data are mean ± s.e.m. P values were calculated using unpaired two-sided Student’s t-test with Welch’s correction.

Source Data

Extended Data Fig. 4 Analysis of stable-isotope feeding experiments.

a, Administration of taurine-d4 in SPF mice resulted in deuterium incorporation in all detected taurine conjugates, but not in any MCY conjugates. Shown are EICs for the m/z of molecular ions of unlabeled (black) and deuterium-labeled versions (red) of the different conjugates in serum of mouse fed taurine-d4. b, Administration of deuterium-labeled L-cysteine (L-cys-d2) in SPF mice resulted in deuterium incorporation in the MCY conjugates of BAs. Shown are EICs for the m/z of the molecular ions of the unlabeled (black) and the deuterium-labeled versions of BA-MCY conjugates (red) detected in serum of mice fed L-cys-d2. c,d, Administration of deuterium-labeled L-cysteine (L-cys-d2) in SPF mice (see Fig. 2i) resulted in deuterium incorporation in taurine conjugates of BAs (c) and pantetheine (d). EICs for molecular ion peaks (black) and deuterium isotope peaks (red) of taurine conjugates of BAs (c) and pantetheine (d) in serum of mouse fed L-cys-d2.

Extended Data Fig. 5 Analysis of Baat−/− mice.

a-d, Extracted ion chromatograms (EICs) of BA-MCY and BA-MCYO conjugates (a,b,c) and BA-MCYO2 conjugates (d) in liver of Baat−/− mice and comparison with synthetic standards analyzed in ESI + . e,f, Relative abundances of BA-MCY conjugates (e) and corresponding free BAs (f) in liver of WT (n = 4) or Baat−/− (n = 5) mice. Data are mean ± s.e.m. P values were calculated using unpaired two-sided Student’s t-test with Welch’s correction. N.D., not detected.

Source Data

Extended Data Fig. 6 Abundances of BA-MCY conjugates in different tissues.

a,b, Abundances of CA-MCY conjugates, TCA and CA (a), and βMCA-MCY conjugates, TβMCA and βMCA (b) in liver, small intestine, and cecum of SPF (n = 11) and GF (n = 12 for liver and n = 13 for small intestine and cecum) mice. Data are mean ± s.e.m. c–f, Abundances of UDCA-MCY conjugates and UDCA (c), CDCA-MCY conjugates and CDCA (d), DCA-MCY conjugates and DCA (e), and 7-KDCA-MCY conjugates and 7-KDCA (f) in liver, small intestine, and cecum of SPF (n = 11) and GF (n = 12 for liver and n = 13 for small intestine and cecum) mice. Data are mean ± s.e.m. P values were calculated using unpaired two-sided Student’s t-test with Welch’s correction. N.D., not detected.

Source Data

Extended Data Fig. 7 The role of VNN1 in production of BA-MCY conjugates.

a, Steady-state kinetic analysis of CA-pant and pantetheine hydrolysis catalyzed by recombinant human VNN1 (ΔN490aa truncated) revealed both reactions follow saturation kinetics. The steady-state kinetic parameters Km and Vmax are determined by HPLC-HRMS for pantothenic acid formation to be 39.78 ± 20.31 μM and 1.53 ± 0.20 min−1 for CA-pant, and 74.07 ± 41.52 μM and 2.13 ± 0.37 min−1 for pantetheine. The reaction mixtures contain 0.01 μM VNN1. Number of independent assays using the same batch of enzyme (n = 3). Data are mean ± s.d. b, EICs of CA-CY in ileum of Baat−/− mice, extracts of in vitro reaction of VNN1 hydrolyses CA-pantetheine, and comparison with a synthetic standard analyzed in ESI + . c, EICs of CA-pant in small intestine of Vnn1−/− mice and comparison with a synthetic standard analyzed in ESI + . d, Relative abundances of CA-pant in small intestine, feces, liver, and serum of WT (n = 5) and Vnn1−/− (n = 5) mice. Data are mean ± s.e.m. P values were calculated using unpaired two-sided Student’s t-test with Welch’s correction. N.D., not detected.

Source Data

Extended Data Fig. 8 Microbial deconjugation of BA-MCYs in SPF, GF, and ABX mice.

a, Ratio of total BA-taurine or BA-MCY conjugates to corresponding free BAs in feces of SPF (n = 14) and GF (n = 16) mice. Data are mean ± s.e.m. P values were calculated using unpaired two-sided Student’s t-test with Welch’s correction. b,c, Total amounts of free BAs (b) or BA-MCY conjugates (c) in feces of SPF (n = 14) and GF (n = 16) mice. Data are mean ± s.e.m. P values were calculated using unpaired two-sided Student’s t-test with Welch’s correction. d, Total amounts of free BAs and BA-MCY conjugates in feces of GF (n = 16) mice. Data are mean ± s.e.m. P values were calculated using paired two-sided Student’s t-test. e, HRMS analysis of feces of mice fed CDCA-d5-MCY revealed deconjugation of supplemented CDCA-d5-MCY, represented by peaks in the CDCA mass spectrum highlighted in red. Endogenously produced CDCA can be distinguished, highlighted in green. CA remained unlabeled. f–h, Total amounts of labeled free BAs (f), BA-MCY conjugates (g), and BA-taurine conjugates (h) in feces of SPF (n = 14), ABX (n = 15), and GF (n = 3) mice administered CDCA-d5-MCY. i, Volcano plot of differential metabolites detected in liver of SPF mice administered control (corn oil) (n = 4) or CDCA-d5-MCY (n = 5). Bubble sizes reflect peak areas. See Supplementary Table 4 for compounds derived from supplemented CDCA-d5-MCY. P values were calculated using unpaired two-sided Student’s t-test. j–l, Total amounts of labeled free BAs (j), BA-MCY conjugates (k), and BA-taurine conjugates (l) in liver of SPF (n = 5) and ABX (n = 5) mice administered CDCA-d5-MCY. m, Volcano plot of differential metabolites detected in liver of ABX mice administered control (corn oil) (n = 4) or CDCA-d5-MCY (n = 5). Bubble sizes reflect peak areas. See Supplementary Table 4 for compounds derived from supplemented CDCA-d5-MCY. P values were calculated using unpaired two-sided Student’s t-test.

Source Data

Extended Data Fig. 9 Microbial deconjugation of BA-MCYs in vitro and gnotobiotic mice.

a,b, Deconjugation of CA-MCY conjugates in fecal suspensions obtained from SPF mice (a) (n = 3) and cultured gut bacteria (b) (n = 3). c, Relative abundances of CDCA-d5-MCY conjugates and corresponding free BA in feces of GF monocolonized with WT (n = 3) or BSH-deficient B. ovatus (n = 3) (WT Bo and Δbsh Bo, respectively). Data are mean ± s.e.m. P values were calculated using unpaired two-sided Student’s t-test with Welch’s correction.

Source Data

Extended Data Fig. 10 FXR-related activity of known ligands and BA-MCYs.

a, βMCA-MCY was tested against a cell-based protein-protein interaction assays in both agonist and antagonist modes. βMCA-MCY showed strong FXR antagonistic effects to GW4604-mediated activation of FXR. βMCA-MCY showed no FXR agonistic effects in the assay. Assays were performed in duplicate for each concentration. b, FXR agonistic effect of CDCA as measured in the protein-protein interaction assays. Data were normalized to the maximal and minimal response observed in the presence of control compound (GW4064) and vehicle (DMSO), respectively. Assays were performed in duplicate for each concentration. c,d, CDCA-MCY showed FXR antagonistic effects to obeticholic acid (25 μM) (c) or CDCA (25 μM) (d) mediated activation of FXR. Data were normalized to the maximal and minimal response observed in the presence of control compound (DY268) and vehicle (DMSO), respectively. Assays were performed in duplicate for each concentration. e–g, Cytotoxicity assays for CDCA-MCY (e), CDCA-MCYO (f), and CDCA (g) in a cell-based assay on human primary hepatocytes. Assays were performed in duplicate for each concentration. h, TβMCA did not show FXR antagonistic effects in protein-protein interaction assays at the tested concentrations. DY268 a synthetic FXR antagonist was used as a positive control. Data were normalized to the maximal and minimal response observed in the presence of control compound (DY268) and vehicle (DMSO), respectively. Assays were performed in duplicate for each concentration.

Source Data

Extended Data Fig. 11 Regulation of BA biosynthesis by BA-MCYs in vivo.

a,b, Abundances of endogenously produced BAs in feces of mice administered CDCA-MCY or CDCA-d5-MCY daily for 14 days. Shown are individual amounts of CDCA-derived BAs (a) and CA-derived BAs (b) in feces. Data are mean ± s.e.m. with control (corn oil) (n = 7) and CDCA-MCY fed mice (n = 7 for CDCA-derived pathway and n = 3 for CA-derived pathway). P values were calculated using unpaired two-sided Student’s t-test with Welch’s correction. c, Total endogenously produced BAs in feces of ABX mice administered CDCA-d5-MCY. Shown are total amounts of BAs (n = 13 for control and n = 14 for CDCA-MCY fed mice). Data are mean ± s.e.m. P values were calculated using unpaired two-sided Student’s t-test with Welch’s correction. d,e, Abundances of CDCA-derived BAs (d) and CA-derived BAs (e) in liver of mice administered CDCA-MCY or CDCA-d5-MCY daily for 14 days. Data are mean ± s.e.m. with control (corn oil) (n = 6) and CDCA-MCY fed mice (n = 3 for CDCA-derived pathway and n = 7 for CA-derived pathway). P values were calculated using unpaired two-sided Student’s t-test with Welch’s correction. f,g, Abundances of CDCA-derived BAs (f) and CA-derived BAs (g) in serum of mice administered CDCA-MCY or CDCA-d5-MCY daily for 14 days. Data are mean ± s.e.m. with control (corn oil) (n = 6) and CDCA-MCY fed mice (n = 3 for CDCA-derived pathway and n = 7 for CA-derived pathway). P values were calculated using unpaired two-sided Student’s t-test with Welch’s correction.

Source Data

Extended Data Fig. 12 FXR-related activity of BA-MCYs in vivo.

a,b, Abundances of total BAs in liver (a) and serum (b) of WT and Nr1h4−/− mice administered CDCA-d5-MCY daily for 14 days. Data are mean ± s.e.m. with control (corn oil) (n = 4) and CDCA-d5-MCY fed mice (n = 4). P values were calculated using unpaired two-sided Student’s t-test with Welch’s correction. c, Representative photomicrographs of oil red O staining of liver sections of mice treated with the indicated conditions. Mice were fed control (n = 4 for vehicle and n = 4 for CDCA-MCY) or high cholesterol diet (HCD) (n = 4 for vehicle and n = 4 for CDCA-MCY). CDCA-MCY was delivered by oral gavage at a rate of 5 mg/kg body weight per day for two weeks. Scale bar, 100 μm. d, Average measured oil red O area of liver sections of mice in c. Data are mean ± s.e.m. P values were calculated using one-way ANOVA with Tukey’s correction.

Source Data

Supplementary information

Supplementary Information

This file contains Supplementary Methods, Supplementary Tables 2 and 5, Supplementary Figs 1–5, Supplementary Note, and descriptions for Supplementary Tables 1, 3, and 4 (tables supplied separately).

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Supplementary Table 1

MS features whose production is microbiota-dependent in serum.

Supplementary Table 3

Abundance of BA-taurine, BA-MCY conjugates, and free BAs in serum, feces, liver, small intestine, and cecum of SPF, GF mice, and mice that received FMT.

Supplementary Table 4

MS features that were derived from supplemented CDCA-d5-MCY in SPF and ABX mice.

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Won, T.H., Arifuzzaman, M., Parkhurst, C.N. et al. Host metabolism balances microbial regulation of bile acid signalling. Nature (2025). https://doi.org/10.1038/s41586-024-08379-9

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