Genotype-specific immune responses at the intestinal barrier predispose to colitis in chronic granulomatous disease in mice.

Abstract

Chronic granulomatous disease (CGD) is an inborn error of immunity caused by defects in any one of the 6 subunits (gp91phox, p47phox, p22phox, p67phox, p40phox or chaperone EROS) forming the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex 2 (NOX2) and resulting in defective phagocyte-derived reactive oxygen species (ROS) production. Almost 50% of patients with CGD have inflammatory bowel disease (IBD) associated with dysbiosis and age of IBD onset may vary according to CGD genotype. While we previously demonstrated that the intestinal microbiota determines colitis susceptibility in CGD mice, underlying mechanisms remain unknown. We hypothesized that NOX2 defects are associated with distinct intestinal microbiome signatures and immune responses, which impact colitis severity. Chemical colitis susceptibility was evaluated in 2 strains of CGD mice (gp91phox-/- and p47phox-/-) with distinct microbiota, from 2 different animal facilities, while also evaluating the impact of microbiota standardization and colitogenic microbiota transfer on mucosal immune responses at the intestinal barrier. While p47phox-/- and gp91phox-/-mice harbouring colitogenic microbiota had increased colitis severity, the intestinal epithelial cells from p47phox-/- mice produced more ROS which was associated with increased NOX isoform gene expression. In contrast, gp91phox-/- mice had decreased mucin production and a mucosal immune response profile suggestive of increased inflammasome activation at the intestinal barrier compared to control and p47phox-/- mice. Our findings suggest that the microbiota impacts colitis susceptibility in a CGD genotype-specific manner, thereby potentially explaining differences in the timing of IBD onset in patients with different CGD genotypes while identifying potential novel and personalized therapeutic targets.