CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands
Open accessAbstract
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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Mice deficient for Card9 have an altered microbiota that produces lower amounts of indole derivatives, similar to the microbiota of IBD patients.
“mice deficient for Card9, a gene that in humans is associated with IBD susceptibility, have an altered microbiota that produces lower amounts of indole derivatives, similar to the microbiota of IBD patients (Lamas et al., 2016).”
From Understanding the Holobiont: How Microbial Metabolites Affect Human Health and Shape the Immune System (2017) · cites this paper as Lamas et al., 2016
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- Authors
- Lamas, B., Richard, M. L., Leducq, V., Pham, H.-P., Michel, M.-L., Da Costa, G., Bridonneau, C., Jegou, S., Hoffmann, T. W., Natividad, J. M., Brot, L., Taleb, S., Couturier-Maillard, A., Nion-Larmurier, I., Merabtene, F., Seksik, P., Bourrier, A., Cosnes, J., Ryffel, B., Beaugerie, L., Launay, J.-M., Langella, P., Xavier, R. J., & Sokol, H.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- AgroParisTech (FR)
- Pitié-Salpêtrière Hospital (FR)
- Inserm (FR)
- Université d'Orléans (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- Broad Institute (US)
- Corresponding author
- Sokol, Harry
- ORCID
- Venue
- Nature Medicine
- Published
- 2016-05-09
- Volume
- 22
- Issue
- 6
- Pages
- 598-605
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC5087285
- OpenAlex
- W2346752870
- Cited by
- 1,482
- References
- 52
- Citations by year
- 2026: 144 · 2025: 157 · 2024: 187 · 2023: 174 · 2022: 180 · 2021: 153 · 2020: 150 · 2019: 106 · 2018: 122 · 2017: 77 · 2016: 30
- FWCI
- 57.70
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK043351)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- CARD9, colitis, gut microbiota, tryptophan metabolism, aryl hydrocarbon receptor ligands, IL-22, inflammatory bowel disease, Lactobacillus, microbial metabolites, intestinal inflammation, host-microbe interactions, germ-free mice, microbiota transfer
- MeSH terms
- Gastrointestinal Microbiome, Fecal Microbiota Transplantation, Interleukin-22, Adolescent, Adult, Animals, Chromatography, High Pressure Liquid, Colitis, Colon, Female, Humans, Interleukins, Lactobacillus, Male, Middle Aged, RNA, Ribosomal, 16S, Tryptophan, Inflammatory Bowel Diseases, Cytokines, Dextran Sulfate, Receptors, Aryl Hydrocarbon, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Profiling, Mice, CARD Signaling Adaptor Proteins, Young Adult
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