CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands.
Bruno LamasMathias L RichardValentin LeducqHang-Phuong PhamMarie-Laure MichelGregory Da CostaChantal BridonneauSarah JegouThomas W HoffmannJane M NatividadLoic BrotSoraya TalebAurélie Couturier-MaillardIsabelle Nion-LarmurierFatiha MerabtenePhilippe SeksikAnne BourrierJacques CosnesBernhard RyffelLaurent BeaugerieJean-Marie LaunayPhilippe LangellaRamnik J XavierHarry SokolPublished in: Nature medicine (2016)
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.
Keyphrases
- wild type
- ulcerative colitis
- high fat diet induced
- immune response
- genome wide
- oxidative stress
- ms ms
- escherichia coli
- metabolic syndrome
- gene expression
- single cell
- toll like receptor
- cell death
- transcription factor
- combination therapy
- induced apoptosis
- genome wide identification
- endoplasmic reticulum stress
- bioinformatics analysis