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 mediates colitis recovery via interleukin 22 pathway activation and Card9-/- mice have enhanced susceptibility to colitis. To reveal the mechanisms responsible of this defect in Card9-/-mice, we compared colon transcriptomics in WT and Card9-/- mice before and during DSS-induced colitis. Mice transcriptomes clusterized according to the genotype supporting a pattern clearly different in WT and Card9-/- mice. The number of up-regulated genes at day 7 was largely higher in Card9-/- compared to WT mice. Pathway analyses of the induced transcripts showed a dominance of immune-related pathway with a stronger signal in Card9-/- mice. Interestingly, NOD-like receptor signaling pathway, in which CARD9 is involved, was an exception with weaker activation in Card9-/- than in WT mice. During the recovery period at day 12, pathways involved in cell proliferation and replication were significantly activated in WT compared to Card9-/- mice confirming the healing defect in Card9-/- mice. Results published in Nature Medicine, doi:10.1038/nm.4102 For the induction of colitis, mice were given drinking water supplemented with 2% (w/v) Dextran sulphate sodium (DSS) for 7 days, then allowed to recover by drinking water alone for 5 additional days. 3 mice of each groups (WT and Card9-/-) were sacrified before DSS administration. 5 WT mice and 5 Card9-/- mice were sacrified 7 days after DSS administration and 5 mice of each group were sacrified at day 12.