Crohn’s disease (CD) and ulcerative colitis (UC) are gut inflammatory conditions of unknown etiology. Current hypothesis suggests that these conditions develop due to failure of body's immune system to tolerate antigen processed or generated within gut.
New paper in Science has pointed to one of the mechanisms for such failure. This study showed that CD's risk gene, ATG16L1, is involved in response to microbiota and promotes gut tolerance via IL-10 producing Foxp3+ Tregs cells.
Initially the authors showed that DCs deficient for ATG16L1 failed to induce IL-10 producing Foxp3+ regulatory T cells in response to WT PSA-OMV (Polysaccharide A derived from gut commensal Bacteroides fragilis and packaged within outer membrane vesicles). Conversely, WT DCs failed to induce IL-10 producing regulatory T cells in response to OMVs harvested from isogenic B. fragilis mutant lacking PSA (ΔPSA-OMV).
Similarly, NOD2-deficient DCs pulsed with WT PSA-OMV failed to support IL-10 production from Foxp3+ Tregs during in vitro co-cultures (NOD2 has been shown to physically interact with ATG16L1).
In vivo experiments confirmed that unlike WT mice, mice deficient for DC-specific ATG16L1 or NOD2 were not protected by WT PSA-OMV from chemical-induced colitis (though it is not clear whether chemically-induced mouse colitis models, i.e. 2,4-dinitrobenzenesulfonic acid (DNBS)-induced colitis or dextran sulfate sodium (DSS)-induced colitis, are representative of inflammations in Crohn's disease).
Finally, the authors showed that monocyte-derived dendritic cells (MoDC) from Crohn's patients harboring ATG16L1 T300A risk variant did not respond to WT PSA-OMV and failed to induce IL-10 production from Foxp3+ Tregs.
In summary, this study showed that failure to sense gut microbiota components by NOD2-ATG16L1 axis could predispose individuals to gut inflammation.