CARD9, the microbiota and tryptophan in intestinal homeostasis

▸ Lamas B, Richard ML, Leducq V, et al. CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands. Nat Med 2016;22:598–605. doi:10.1038/nm.4102

Genetics, environment and diet influence the composition of the gut microbiota. A change in any of these factors results in a dysbiosis, and this contributes to the pathogenesis of IBD. CARD9 is a susceptibility gene for IBD that is involved in immune responses against microorganisms. Card9 knockout mice (Card9−/−) are more susceptible to colitis and have an increased load of gut-resident fungi, and CARD9 promotes recovery from colitis through interleukin (IL)-22 pathway activation. Recent data have suggested that tryptophan catabolites generated by microbiota metabolism play a role in mucosal immune responses. In the present study, Lamas and colleagues investigated the interaction between CARD9, the microbiota and tryptophan in intestinal homeostasis. Deleting Card9 in mice resulted in altered fungal and bacterial microbiota in the gut along with defective healing of the mucosa associated with an IL-22 deficiency. When the microbiota of Card9−/− mice was transferred to wild-type germ-free mice exposed to dextran sulfate sodium (DSS), the mice became more susceptible to colitis and had reduced IL-22 production. The gut microbiota of Card9−/− mice affected the recipient mouse by altering the IL-22 signalling pathway through impaired tryptophan metabolism, ultimately leading to defective aryl hydrocarbon receptor (AHR) activation. Interestingly, these mechanisms were reversible. When Card9−/− mice were given three Lactobacillus strains able to metabolise tryptophan or treated with an AHR agonist, intestinal inflammation was reduced and IL-22 levels were normalised. The researchers tested whether these findings in mice were applicable to human IBD. Faecal samples from healthy subjects and patients with IBD were assessed for ability to activate AHR. Faecal samples from healthy subjects had greater activation of AHR than those from patients with …