Patients carrying the X-linked CYBB/GP91PHOX mutation of NOX2 develop a more severe IBD at an earlier age than those carrying the autosomal NCF1/P47PHOX mutation. The genotype shapes the inflammatory response against colitogenic microbiota and determines the severity of colitis, by altering mucus production, activating the inflammasome, and reducing the anti-inflammatory Treg and dendritic cell pools. Inhibition of inflammasome activation and dietary changes to reverse dysbiosis could open new therapeutic perspective for IBD in CGD.