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

It is crucial to decipher the host-microbiota interactions as they are involved in intestinal homeostasis and diseases. Caspase Recruitment Domain 9 (Card9) is an inflammatory bowel disease (IBD) susceptibility gene coding for an adapter protein for innate immunity toward many microorganisms. Card9 has been shown to mediate colitis recovery via interleukin 22 (IL22) pathway activation and CARD9 knockout (Card9-/-) mice have enhanced susceptibility to colitis and increased load of intestinal fungi. Dysbiosis is often seen as an actor of intestinal inflammation via the increase level of pro-inflammatory microorganisms such as Proteobacteria. However, the lack of microorganisms with regulatory effects might also enhance inflammation. In the current study we used C57BL/6 wild-type (WT), Card9-/- and germ-free (GF) mice to study the role of the intestinal microbiota in the impaired recovery of Card9-/- mice after colitis. We found that CARD9 deletion had a dramatic effect on both bacterial and fungal gut microbiota. Moreover, the transfer of Card9-/- microbiota into WT GF recipient was sufficient to recapitulate the defective IL22 activation as well as the increased sensitivity to colitis observed in Card9-/- mice. Results published in Nature Medicine; doi:10.1038/nm.4102