ROS in gastrointestinal inflammation: Rescue or sabotage Original paper

What was reviewed?

This narrative review, ROS in gastrointestinal inflammation, synthesizes evidence on how reactive oxygen species (ROS) act as both protective “signal-and-kill” molecules and potential drivers of tissue damage across the gastrointestinal (GI) tract. The authors focus on where ROS come from (notably NADPH oxidases—NOX1, NOX2, NOX4, and DUOX2—plus mitochondrial electron transport chain–derived ROS and nitric oxide synthase pathways) and how ROS levels shape mucosal immunity, epithelial barrier integrity, antimicrobial defense, and wound repair. A central theme is redox balance: insufficient ROS (e.g., due to loss-of-function oxidase variants) can impair microbial clearance and immune regulation, whereas excessive ROS (e.g., oxidase upregulation or mitochondrial dysfunction) can promote oxidative stress, epithelial injury, and chronic inflammation.

Who was reviewed

Rather than analyzing a single cohort, the review integrates findings from human inflammatory bowel disease (IBD) populations, including Crohn’s disease (CD), ulcerative colitis (UC), chronic granulomatous disease (CGD) patients with IBD-like colitis, and very early onset IBD (VEOIBD), alongside animal and mechanistic models (e.g., DSS/TNBS colitis models, IL-10–deficient mice, oxidase-deficient or antioxidant-enzyme–deficient transgenic strains, and infection models such as Helicobacter species). It also draws on epithelial-cell and immune-cell studies exploring pattern-recognition receptor signaling, cytokine-driven oxidase induction, and ROS-mediated control of restitution and repair in the presence of commensal microbiota and pathogens.

Most important findings

Across the GI tract, ROS are portrayed as context-dependent regulators of microbiome–host interactions. In the stomach, Helicobacter pylori promotes ROS via NOX1 in epithelial cells and NOX2 in neutrophils, while bacterial virulence factors (CagA/VacA) can increase mitochondrial ROS, linking infection to oxidative stress and mucosal injury. In the intestine, low ROS states are clinically relevant: inactivating variants in NOX2 complex genes (CGD) and functionally altered NOX1/DUOX2 variants in VEOIBD associate with severe colitis and reduced ROS production, implying ROS are required for appropriate antimicrobial and immune homeostatic responses. Conversely, high ROS states emerge in IBD through oxidase upregulation (notably DUOX2) and mitochondrial dysfunction. Importantly for microbiome-signature thinking, increased DUOX2 expression in UC was reported alongside higher Proteobacteria abundance, implying a feedback loop where dysbiosis induces epithelial ROS systems that further reshape the mucosal ecosystem. Microbiota-derived signals also drive repair: commensals (e.g., Lactobacillus rhamnosus) can stimulate NOX1-dependent ROS that promote epithelial proliferation and restitution through receptors such as FPR1, highlighting ROS as pro-healing signals when tightly controlled.

Key implications

Clinically, this review reframes ROS from a simplistic “harmful oxidants” model to a precision-redox model: the therapeutic goal is not blanket antioxidant suppression but restoring the right ROS tone in the right compartment. Patients with ROS-deficiency states (e.g., CGD-related colitis or oxidase-variant VEOIBD) may theoretically benefit from strategies that augment antimicrobial/redox signaling, while patients with mitochondrial ROS excess or oxidase overexpression may benefit from source-specific inhibition. For microbiome-informed practice, the linkage between epithelial DUOX2 responses and Proteobacteria-enriched dysbiosis supports incorporating redox-responsive host markers (e.g., DUOX2 pathways) alongside microbial signatures when stratifying IBD phenotypes and considering targeted interventions.

Citation

Aviello G, Knaus UG. ROS in gastrointestinal inflammation: Rescue or sabotage?British Journal of Pharmacology. 2017;174(12):1704-1718. doi:10.1111/bph.13428