Colitis susceptibility in p47phox-/- mice is mediated by the microbiome

Abstract

Background: Chronic granulomatous disease (CGD) is caused by defects in nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) complex subunits (gp91phox (a.k.a. Nox2), p47phox, p67phox, p22phox, p40phox) leading to reduced phagocyte-derived reactive oxygen species production. Almost half of patients with CGD develop inflammatory bowel disease, and the involvement of the intestinal microbiome in relation to this predisposing immunodeficiency has not been explored. Results: Although CGD mice do not spontaneously develop colitis, we demonstrate that p47phox-/- mice have increased susceptibility to dextran sodium sulfate colitis in association with a distinct colonic transcript and microbiome signature. Neither restoring NOX2 reactive oxygen species production nor normalizing the microbiome using cohoused adult p47phox-/- with B6Tac (wild type) mice reversed this phenotype. However, breeding p47phox+/- mice and standardizing the microflora between littermate p47phox-/- and B6Tac mice from birth significantly reduced dextran sodium sulfate colitis susceptibility in p47phox-/- mice. We found similarly decreased colitis susceptibility in littermate p47phox-/- and B6Tac mice treated with Citrobacter rodentium. Conclusions: Our findings suggest that the microbiome signature established at birth may play a bigger role than phagocyte-derived reactive oxygen species in mediating colitis susceptibility in CGD mice. These data further support bacteria-related disease in CGD colitis.