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CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands

Nature Medicine volume 22, pages 598–605 (2016)Cite this article

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Abstract

Complex interactions between the host and the gut microbiota govern intestinal homeostasis but remain poorly understood. Here we reveal a relationship between gut microbiota and caspase recruitment domain family member 9 (CARD9), a susceptibility gene for inflammatory bowel disease (IBD) that functions in the immune response against microorganisms. CARD9 promotes recovery from colitis by promoting interleukin (IL)-22 production, and Card9−/− mice are more susceptible to colitis. The microbiota is altered in Card9−/− mice, and transfer of the microbiota from Card9−/− to wild-type, germ-free recipients increases their susceptibility to colitis. The microbiota from Card9−/− mice fails to metabolize tryptophan into metabolites that act as aryl hydrocarbon receptor (AHR) ligands. Intestinal inflammation is attenuated after inoculation of mice with three Lactobacillus strains capable of metabolizing tryptophan or by treatment with an AHR agonist. Reduced production of AHR ligands is also observed in the microbiota from individuals with IBD, particularly in those with CARD9 risk alleles associated with IBD. Our findings reveal that host genes affect the composition and function of the gut microbiota, altering the production of microbial metabolites and intestinal inflammation.

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Figure 1: CARD9 is involved in recovery from colitis.
Figure 2: The fungal and bacterial microbiota are altered in Card9−/− mice.
Figure 3: Transfer of the microbiota from Card9−/− mice is sufficient to increase susceptibility to colitis and reduce IL-22 production.
Figure 4: Tryptophan metabolism is impaired in the gut microbiota of Card9−/− mice, leading to defective AHR activation and colitis recovery.
Figure 5: Inoculation with lactobacilli that metabolize tryptophan and produce AHR ligands reduces colitis in an AHR-dependent manner.
Figure 6: Reduced tryptophan metabolism and AHR activation in the gut microbiota of individuals with IBD, and its association with the CARD9 genotype.

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Acknowledgements

We thank the members of the ANAXEM germ-free platform, the members of the animal facilities of INRA, and T. Ledent of the animal facilities of Saint-Antoine Hospital for their assistance in mouse care; M. Moroldo and J. Lecardonnel from the CRB GADIE core facility for technical assistance in performing the microarray analyses; S. Dumont for technical help in histology and immunochemistry; and C. Aubry, N.M. Breyner, F. Chain, S. Le Guin, C. Cherbuy, N. Lapaque, and D. Skurnik for fruitful discussions and technical help. We also thank E. Drouet and the Clinical Research Assistant team of Unité de Recherche Clinique de l'Est Parisien for their help in obtaining samples from patients with IBD. Ido1−/− and Il22−/− mice were provided by S. Taleb (INSERM Unit 970) and B. Ryffel (CNRS, UMR7355), respectively. The H1L1.1c2 cell line was provided by M.S. Denison (University of California, Davis). Funding was provided by Equipe ATIP–Avenir 2012 (H.S.), INSERM–ITMO SP 2013 (H.S.) and ECCO grant 2012 (H.S.).

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Authors and Affiliations

  1. Sorbonne University–Université Pierre et Marie Curie (UPMC), Paris, France

    Bruno Lamas, Valentin Leducq, Sarah Jegou, Loic Brot & Harry Sokol

  2. Institut National de la Santé et de la Recherche Médicale (INSERM) Equipe de Recherche Labélisée (ERL) 1157, Avenir Team Gut Microbiota and Immunity, Paris, France

    Bruno Lamas, Valentin Leducq, Sarah Jegou, Loic Brot & Harry Sokol

  3. Centre National de Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR) 7203, Paris, France

    Bruno Lamas, Valentin Leducq, Sarah Jegou, Loic Brot & Harry Sokol

  4. Laboratoire de BioMolécules (LBM), Centre Hospitalo-Universitaire (CHU) Saint-Antoine 27 rue de Chaligny, Paris, France

    Bruno Lamas, Valentin Leducq, Sarah Jegou, Loic Brot & Harry Sokol

  5. Micalis Institute, Institut National de la Recherche Agronomique (INRA), AgroParisTech, Université Paris–Saclay, Jouy-en-Josas, France

    Bruno Lamas, Mathias L Richard, Marie-Laure Michel, Gregory Da Costa, Chantal Bridonneau, Thomas W Hoffmann, Jane M Natividad, Philippe Langella & Harry Sokol

  6. Inflammation–Immunopathology–Biotherapy Department (DHU i2B), Paris, France

    Bruno Lamas, Mathias L Richard, Valentin Leducq, Marie-Laure Michel, Gregory Da Costa, Chantal Bridonneau, Sarah Jegou, Thomas W Hoffmann, Jane M Natividad, Loic Brot, Philippe Langella & Harry Sokol

  7. ILTOO Pharma, Incubateur et Pépinière d'Entreprises Paris–Salpêtrière, Hôpital Pitié Salpêtrière, Paris, France

    Hang-Phuong Pham

  8. INSERM U970, Paris Cardiovascular Research Center, Paris, France

    Soraya Taleb

  9. Université Paris-Descartes, Paris, France

    Soraya Taleb

  10. Laboratory of Experimental and Molecular Immunology and Neurogenetics, UMR 7355 CNRS–University of Orleans, Orleans, France

    Aurélie Couturier-Maillard & Bernhard Ryffel

  11. Department of Gastroenterology, Saint Antoine Hospital, Assistance Publique–Hopitaux de Paris, UPMC, Paris, France

    Isabelle Nion-Larmurier, Philippe Seksik, Anne Bourrier, Jacques Cosnes, Laurent Beaugerie & Harry Sokol

  12. INSERM, UMR S938, Centre de Recherche Saint-Antoine, Plateforme Morphologie du Petit Animal, Paris, France

    Fatiha Merabtene

  13. Institute of Infectious Disease and Molecular Medicine (IDM), University of Cape Town, Cape Town, Republic of South Africa

    Bernhard Ryffel

  14. Department of Biochemistry, INSERM, UMR S942, Lariboisière Hospital, Paris, France

    Jean-Marie Launay

  15. Centre for Biological Resources BB-0033-00064, Lariboisière Hospital, Paris, France

    Jean-Marie Launay

  16. Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, Massachusetts, USA

    Ramnik J Xavier

  17. Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA

    Ramnik J Xavier

  18. Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA

    Ramnik J Xavier

  19. Center for Microbiome Informatics and Therapeutics, MIT, Cambridge, Massachusetts, USA

    Ramnik J Xavier

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  1. Bruno Lamas
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Contributions

B.L., M.L.R., and H.S. conceived and designed the study, performed data analysis, and wrote the manuscript; B.L. designed and conducted all experiments, unless otherwise indicated; V.L. designed and performed the AHR activity experiments; G.D.C., C.B., S.J., T.W.H., J.M.N., L. Brot, F.M., and M.-L.M. provided technical help for the in vitro and in vivo experiments; H.-P.P. conducted the bioinformatics studies and analyzed the microarray experiments; J.-M.L. performed and analyzed HPLC experiments; S.T. provided material from the Ido1−/− mice and discussed the results; A.C.-M. and B.R. provided material from the Il22−/− mice and discussed the results; H.S., J.C., I.N.-L., A.B., L. Beaugerie, and P.S. provided data and samples for the patients with IBD; B.L., M.L.R., R.J.X., P.L., and H.S. discussed the experiments and results.

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Correspondence to Harry Sokol.

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Lamas, B., Richard, M., Leducq, V. et al. CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands. Nat Med 22, 598–605 (2016). https://doi.org/10.1038/nm.4102

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