title: CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands.
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.
authors.affiliation: Sorbonne University-Université Pierre et Marie Curie (UPMC) Paris, France.|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.|Centre National de Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR) 7203, Paris, France.|Laboratoire de BioMolécules (LBM), Centre Hospitalo-Universitaire (CHU) Saint-Antoine 27 rue de Chaligny, Paris, France.|Micalis Institute, Institut National de la Recherche Agronomique (INRA), AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France.|Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Lamas
authors.affiliation: Micalis Institute, Institut National de la Recherche Agronomique (INRA), AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France.|Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France.
authors.forename: Mathias L
authors.initials: ML
authors.lastname: Richard
authors.affiliation: Sorbonne University-Université Pierre et Marie Curie (UPMC) Paris, France.|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.|Centre National de Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR) 7203, Paris, France.|Laboratoire de BioMolécules (LBM), Centre Hospitalo-Universitaire (CHU) Saint-Antoine 27 rue de Chaligny, Paris, France.|Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France.
authors.forename: Valentin
authors.initials: V
authors.lastname: Leducq
authors.affiliation: ILTOO Pharma, Incubateur et Pépinière d'Entreprises Paris-Salpêtrière, Hôpital Pitié Salpêtrière, Paris, France.
authors.forename: Hang-Phuong
authors.identifier: 0000-0002-7896-7401
authors.initials: HP
authors.lastname: Pham
authors.affiliation: Micalis Institute, Institut National de la Recherche Agronomique (INRA), AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France.|Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France.
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Michel
authors.affiliation: Micalis Institute, Institut National de la Recherche Agronomique (INRA), AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France.|Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France.
authors.forename: Gregory
authors.initials: G
authors.lastname: Da Costa
authors.affiliation: Micalis Institute, Institut National de la Recherche Agronomique (INRA), AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France.|Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France.
authors.forename: Chantal
authors.initials: C
authors.lastname: Bridonneau
authors.affiliation: Sorbonne University-Université Pierre et Marie Curie (UPMC) Paris, France.|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.|Centre National de Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR) 7203, Paris, France.|Laboratoire de BioMolécules (LBM), Centre Hospitalo-Universitaire (CHU) Saint-Antoine 27 rue de Chaligny, Paris, France.|Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Jegou
authors.affiliation: Micalis Institute, Institut National de la Recherche Agronomique (INRA), AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France.|Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Hoffmann
authors.affiliation: Micalis Institute, Institut National de la Recherche Agronomique (INRA), AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France.|Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France.
authors.forename: Jane M
authors.initials: JM
authors.lastname: Natividad
authors.affiliation: Sorbonne University-Université Pierre et Marie Curie (UPMC) Paris, France.|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.|Centre National de Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR) 7203, Paris, France.|Laboratoire de BioMolécules (LBM), Centre Hospitalo-Universitaire (CHU) Saint-Antoine 27 rue de Chaligny, Paris, France.|Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France.
authors.forename: Loic
authors.initials: L
authors.lastname: Brot
authors.affiliation: INSERM U970, Paris Cardiovascular Research Center, Paris, France.|Université Paris-Descartes, Paris, France.
authors.forename: Soraya
authors.initials: S
authors.lastname: Taleb
authors.affiliation: Laboratory of Experimental and Molecular Immunology and Neurogenetics, UMR 7355 CNRS-University of Orleans, Orleans, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Couturier-Maillard
authors.affiliation: Department of Gastroenterology, Saint Antoine Hospital, Assistance Publique-Hopitaux de Paris, UPMC, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Nion-Larmurier
authors.affiliation: INSERM, UMR S938, Centre de Recherche Saint-Antoine, Plateforme Morphologie du Petit Animal, Paris, France.
authors.forename: Fatiha
authors.initials: F
authors.lastname: Merabtene
authors.affiliation: Department of Gastroenterology, Saint Antoine Hospital, Assistance Publique-Hopitaux de Paris, UPMC, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Seksik
authors.affiliation: Department of Gastroenterology, Saint Antoine Hospital, Assistance Publique-Hopitaux de Paris, UPMC, Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Bourrier
authors.affiliation: Department of Gastroenterology, Saint Antoine Hospital, Assistance Publique-Hopitaux de Paris, UPMC, Paris, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Cosnes
authors.affiliation: Laboratory of Experimental and Molecular Immunology and Neurogenetics, UMR 7355 CNRS-University of Orleans, Orleans, France.|Institute of Infectious Disease and Molecular Medicine (IDM), University of Cape Town, Cape Town, Republic of South Africa.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Ryffel
authors.affiliation: Department of Gastroenterology, Saint Antoine Hospital, Assistance Publique-Hopitaux de Paris, UPMC, Paris, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Beaugerie
authors.affiliation: INSERM, UMR S942, Department of Biochemistry, Lariboisière Hospital, Paris, France.|Centre for Biological Resources BB-0033-00064, Lariboisière Hospital, Paris, France.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Launay
authors.affiliation: Micalis Institute, Institut National de la Recherche Agronomique (INRA), AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France.|Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Langella
authors.affiliation: Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, Massachusetts, USA.|Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Center for Microbiome Informatics and Therapeutics, MIT, Cambridge, Massachusetts, USA.
authors.forename: Ramnik J
authors.initials: RJ
authors.lastname: Xavier
authors.affiliation: Sorbonne University-Université Pierre et Marie Curie (UPMC) Paris, France.|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.|Centre National de Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR) 7203, Paris, France.|Laboratoire de BioMolécules (LBM), Centre Hospitalo-Universitaire (CHU) Saint-Antoine 27 rue de Chaligny, Paris, France.|Micalis Institute, Institut National de la Recherche Agronomique (INRA), AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France.|Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France.|Department of Gastroenterology, Saint Antoine Hospital, Assistance Publique-Hopitaux de Paris, UPMC, Paris, France.
authors.forename: Harry
authors.initials: H
authors.lastname: Sokol
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics / Q000276:immunology*; D002851:Chromatography, High Pressure Liquid; D003092:Colitis / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D003106:Colon / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D016207:Cytokines / Q000276:immunology; D016264:Dextran Sulfate / Q000633:toxicity; D000069467:Fecal Microbiota Transplantation; D005260:Female; D000069196:Gastrointestinal Microbiome / Q000235:genetics / Q000276:immunology*; D020869:Gene Expression Profiling; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics / Q000276:immunology; D007378:Interleukins / Q000276:immunology*; D007778:Lactobacillus / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D012336:RNA, Ribosomal, 16S / Q000235:genetics; D018336:Receptors, Aryl Hydrocarbon / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014364:Tryptophan / Q000276:immunology / Q000378:metabolism*; D055815:Young Adult; D000097043:Interleukin-22
chemical_list: D053468:CARD Signaling Adaptor Proteins; D016207:Cytokines; D016264:Dextran Sulfate; D007378:Interleukins; D012336:RNA, Ribosomal, 16S; D018336:Receptors, Aryl Hydrocarbon; D014364:Tryptophan; D000097043:Interleukin-22; C513280:Card9 protein, mouse