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Nat Med. 2016 Jun;22(6):598-605. doi: 10.1038/nm.4102. Epub 2016 May 9.

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

Lamas B1,2,3,4,5,6, Richard ML5,6, Leducq V1,2,3,4,6, Pham HP7, Michel ML5,6, Da Costa G5,6, Bridonneau C5,6, Jegou S1,2,3,4,6, Hoffmann TW5,6, Natividad JM5,6, Brot L1,2,3,4,6, Taleb S8,9, Couturier-Maillard A10, Nion-Larmurier I11, Merabtene F12, Seksik P11, Bourrier A11, Cosnes J11, Ryffel B10,13, Beaugerie L11, Launay JM14,15, Langella P5,6, Xavier RJ16,17,18,19, Sokol H1,2,3,4,5,6,11.

Author information

1
Sorbonne University-Université Pierre et Marie Curie (UPMC) Paris, France.
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.
3
Centre National de Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR) 7203, Paris, France.
4
Laboratoire de BioMolécules (LBM), Centre Hospitalo-Universitaire (CHU) Saint-Antoine 27 rue de Chaligny, Paris, France.
5
Micalis Institute, Institut National de la Recherche Agronomique (INRA), AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France.
6
Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France.
7
ILTOO Pharma, Incubateur et Pépinière d'Entreprises Paris-Salpêtrière, Hôpital Pitié Salpêtrière, Paris, France.
8
INSERM U970, Paris Cardiovascular Research Center, Paris, France.
9
Université Paris-Descartes, Paris, France.
10
Laboratory of Experimental and Molecular Immunology and Neurogenetics, UMR 7355 CNRS-University of Orleans, Orleans, France.
11
Department of Gastroenterology, Saint Antoine Hospital, Assistance Publique-Hopitaux de Paris, UPMC, Paris, France.
12
INSERM, UMR S938, Centre de Recherche Saint-Antoine, Plateforme Morphologie du Petit Animal, Paris, France.
13
Institute of Infectious Disease and Molecular Medicine (IDM), University of Cape Town, Cape Town, Republic of South Africa.
14
INSERM, UMR S942, Department of Biochemistry, Lariboisière Hospital, Paris, France.
15
Centre for Biological Resources BB-0033-00064, Lariboisière Hospital, Paris, France.
16
Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, Massachusetts, USA.
17
Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
18
Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
19
Center for Microbiome Informatics and Therapeutics, MIT, Cambridge, Massachusetts, USA.

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.

PMID:
27158904
PMCID:
PMC5087285
DOI:
10.1038/nm.4102
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare no competing financial interests.

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