NADPH oxidases and ROS signaling in the gastrointestinal tract Original paper
Researched by:
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Dr. Umar
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Dr. Umar
Read MoreClinical Pharmacist and Clinical Pharmacy Master’s candidate focused on antibiotic stewardship, AI-driven pharmacy practice, and research that strengthens safe and effective medication use. Experience spans digital health research with Bloomsbury Health (London), pharmacovigilance in patient support programs, and behavioral approaches to mental health care. Published work includes studies on antibiotic use and awareness, AI applications in medicine, postpartum depression management, and patient safety reporting. Developer of an AI-based clinical decision support system designed to enhance antimicrobial stewardship and optimize therapeutic outcomes.
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Dr. Umar
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Researched by:
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Dr. Umar
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Dr. Umar
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Microbiome Signatures identifies and validates condition-specific microbiome shifts and interventions to accelerate clinical translation. Our multidisciplinary team supports clinicians, researchers, and innovators in turning microbiome science into actionable medicine.
Dr. Umar
What was reviewed?
This review synthesized evidence on how NADPH-oxidases-gut-microbiome interactions shape reactive oxygen species (ROS) signaling at the gastrointestinal (GI) barrier, focusing on NADPH oxidase family members NOX1 and DUOX2 in intestinal epithelium and NOX2 in lamina propria phagocytes. Rather than treating ROS as a uniform “oxidative stress” hazard, the authors emphasized that specific ROS species—especially diffusible hydrogen peroxide (H₂O₂)—act as spatially and temporally controlled messengers that regulate microbial containment, epithelial restitution, mucus biology, and inflammatory tone.
Who was reviewed?
The article integrates data across human and animal contexts relevant to barrier–microbiota ecosystems. Human evidence includes inflammatory bowel disease (IBD) transcriptomic and protein-expression studies showing upregulation of DUOX2/DUOXA2 and NOX1 in Crohn’s disease, ulcerative colitis, pouchitis, and IBS, along with monogenic very-early-onset IBD (VEOIBD) cases carrying loss-of-function variants in NOX1, DUOX2, and NOX2-complex genes that reduce epithelial or phagocyte ROS generation. It also reviews mechanistic studies using epithelial cell lines and biopsy models, and multiple mouse models with targeted deletions in Nox1, Duox activation factors, or Nox2 complex components to connect ROS deficits with infection outcomes and microbiota shifts.
Most important findings
Across systems, a central microbiome-relevant insight is that low-level epithelial H₂O₂ is often protective, not injurious. NOX1/DUOX2-derived H₂O₂ can diffuse into bacteria and dampen virulence by disrupting phosphotyrosine signaling and regulating pathogenicity programs, reducing adherence and invasion by enteric pathogens. The review also highlights “defensive mutualism”: when epithelial NADPH oxidase activity is broadly impaired (e.g., via p22phox loss), the gut ecosystem can compensate by expanding H₂O₂-producing commensals such as Lactobacillus and Bifidobacterium, which reshapes niche structure and can suppress pathogen colonization and crypt pathology. Importantly for clinical interpretation, VEOIBD genetics argue against a simplistic “ROS excess” model—severe IBD-like phenotypes can arise from ROS deficiency at the barrier, implicating impaired microbial containment and altered community signaling as upstream drivers.
| Microbiome-related feature | Key association described |
|---|---|
| DUOX2/DUOXA2 induction | Often upregulated in active IBD; may reflect protective epithelial defense signaling |
| VEOIBD NADPH oxidase variants | NOX1/DUOX2/NOX2-complex loss-of-function linked to early severe intestinal inflammation |
| H₂O₂-producing commensals | Lactobacilli/bifidobacteria expand when host ROS is low, potentially restoring barrier ecology |
| Antivirulence signaling | Nanomolar–physiologic H₂O₂ disrupts bacterial tyrosine signaling and virulence programs |
Key implications
Clinically, the review reframes ROS biology as a dose-, species-, and source-dependent regulator of dysbiosis and mucosal healing: epithelial H₂O₂ signaling can suppress pathogen fitness, support restitution, and shape commensal community structure, whereas indiscriminate antioxidant strategies may fail because they erase beneficial redox messaging rather than correcting a specific pathogenic source. The VEOIBD genetics further suggest that identifying ROS-deficiency states (epithelial DUOX2/NOX1 or phagocyte NOX2 pathway defects) could guide precision approaches—such as targeted microbiota modulation or selective antimicrobials—aimed at restoring barrier-compatible microbial communities rather than simply reducing “oxidative stress.”
Citation
Aviello G, Knaus UG. NADPH oxidases and ROS signaling in the gastrointestinal tract. Mucosal Immunol. 2018;11(4):1011-1023. doi:10.1038/s41385-018-0021-8
Reactive oxygen species (ROS)
Reactive oxygen species (ROS) are oxygen-based molecules that act in immune defense and cellular signaling. In the gut, epithelial and immune-cell ROS shape microbial ecology and barrier function. Excess ROS contributes to oxidative stress, inflammation, and permeability changes relevant to microbiome medicine.