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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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.).
The authors declare no competing financial interests.
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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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