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DOP085 Tight NADPH oxidase regulation is a prerequisite for gut health

Aviello G.*1,2, Conroy E.3, Bourke B.1, Knaus U.G.1,3

1National Children's Research Centre, Our Lady's Children's Hospital, Dublin, Ireland 2University of Aberdeen, The Rowett Institute, Aberdeen, United Kingdom 3University College Dublin, Conway Institute, Dublin, Ireland


Tight control of reactive oxygen species (ROS) production is vital in chronic inflammatory disorders. Overproduction of ROS can lead to oxidative stress, but likewise insufficient ROS compromises the host's antimicrobial defenses, exposing to an increased risk of developing life-threatening infections. ROS deficiency due to phagocytic NOX2 complex loss-of-function mutants is the cause of an inherited immunodeficiency disorder, termed chronic granulomatous disease (CGD). Up to 40% of CGD patients develop severe gastrointestinal complications, such as pancolitis and epithelioid granulomas. Recently, we identified and characterized functionally altered NOX1 and DUOX2 variants in very early onset IBD patients, which were associated with severe intestinal pathology. However, the role of ROS in the maintenance of intestinal homeostasis is still unclear as reduced and increased NADPH oxidase function have been associated with Crohn's disease and ulcerative colitis.


In order to systemically investigate the role of NADPH oxidase-derived ROS in the regulation of gut pathology, enteric inflammation was studied in a panel of Nox knockout strains. Oral challenge with colitogenic chemicals [(dextran sodium sulfate (DSS) and trinitrobenzene sulfonic acid (TNBS)] or Citrobacter rodentium were used to mimic commensal- or pathogen-driven intestinal pathology.


An impairment of ROS production due to discrete deletion (Nox1, Nox2, Nox4) or cumulative inactivation (p22phox) of NADPH oxidases in mice did not affect the severity of DSS-induced colitis. However, mice with limited ROS generation due to partial inactivation of NADPH oxidases showed increased susceptibility to develop severe intestinal inflammation, which compromised their recovery and led to premature death. This pro-inflammatory phenotype was observed in either the DSS or TNBS model of colitis. Mice showed altered mucus production, increased antimicrobial peptides, immune cell infiltration, iNOS overexpression and increased levels of Il6, Infg, Il1a, Il17c, and Cxcl1 mRNA. Wild type bone marrow transplantation reduced the DSS-induced inflammation, suggesting that the NADPH oxidase defect responsible of this phenotype resides in the hematopoietic cell compartment. In contrast, limited ROS generation did not impact infectious colitis induced by C. rodentium.


Single or cumulative Nox NADPH oxidase deficiency did not affect intestinal pathophysiology, while restricted ROS production in the myeloid cell compartment predisposed to severe chemical-induced intestinal inflammation following epithelial barrier damage. Overall these data suggest that tight NADPH oxidase regulation is a prerequisite to preserve gut homeostasis.