Defensive mutualism rescues NADPH oxidase inactivation in gut infection 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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Microbes
Microbes
Microbes are microscopic organisms living in and on the human body, shaping health through digestion, vitamin production, and immune protection. When microbial balance is disrupted, disease can occur. This guide explains key microbe types—bacteria, viruses, fungi, protozoa, and archaea—plus major pathogenic and beneficial examples.
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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 studied?
This mouse infection study tested how loss of intestinal epithelial reactive oxygen species (ROS) production reshapes the gut microbiome and alters susceptibility to enteric pathogens, focusing on the concept that H2O2-producing Lactobacillus suppresses Citrobacter virulence. The authors genetically inactivated the NADPH oxidase cofactor Cyba (p22phox) either throughout the body (eliminating NOX1–4 activity) or specifically in intestinal epithelial cells, then challenged mice with Citrobacter rodentium (a model for attaching-and-effacing pathogens such as EPEC/EHEC) and Listeria monocytogenes. They additionally used antibiotic-mediated microbiota depletion, Western diet–induced dysbiosis, mono-association with specific Lactobacillus strains, and cecal microbiota transplantation to dissect whether protection was host-intrinsic or microbiota-mediated.
Who was studied?
The experiments were performed in age- and sex-matched mice, including wild-type controls, Nox2-deficient mice (modeling phagocyte ROS deficiency), Cyba−/− (p22 KO) mice lacking NOX1–4 activity systemically, and epithelium-restricted Cyba-deficient (p22ΔIEC) mice. These models allowed separation of immune-cell ROS effects from epithelial ROS effects. Importantly, the work interrogated naturally acquired, transmissible microbiota states (via co-housing and fecal/cecal transfer) and showed that environmental pressure (antibiotics or Western diet) could erase the protective phenotype, highlighting host–microbiome–environment interactions rather than a single-gene explanation.
Most important findings
Contrary to expectations, epithelial Cyba deficiency protected mice from C. rodentium colitis and reduced pathogen colonization, with diminished inflammatory chemokines/cytokines despite profound epithelial ROS signaling defects (including failure to induce DUOX2 via a NOX1→p38/ATF2 axis). Microbiome profiling linked protection to enrichment of H2O2-producing commensals, most notably Lactobacillus, with species-level increases in L. reuteri and L. murinus, alongside elevations in other “probiotic” taxa such as Bifidobacterium and Butyricicoccus under chow feeding; Western diet reversed these shifts and abolished protection. Mechanistically, lactobacilli physically occupied the mucus niche and released H2O2, which did not kill C. rodentium but downregulated the LEE pathogenicity island: Lactobacillus-conditioned supernatant suppressed ler (the master LEE regulator), and in vivo C. rodentium recovered from p22ΔIEC mice showed reduced ler and escN expression, especially in adherent mucus-associated bacteria. Transferability was key: cecal microbiota transplantation from p22-deficient donors protected antibiotic-treated wild-type recipients, and mono-association with L. reuteri or L. murinus prevented systemic dissemination in ROS-compromised (Nox2 KO) hosts, while complete colonization resistance required a more complex community.
| Microbiome/host feature | Association with phenotype |
|---|---|
| Lactobacillus (↑, esp. L. reuteri, L. murinus) | Protection; niche occupation; H2O2 production |
| Bifidobacterium, Butyricicoccus (↑) | Co-enriched “probiotic” signature in protected mice |
| H2O2 exposure | Suppressed C. rodentium LEE genes (ler, escN) |
| Western diet or antibiotics | Loss of protective microbiome; increased susceptibility |
Key implications
Clinically, this study suggests a counterintuitive but actionable principle: when epithelial ROS signaling is impaired (a scenario relevant to NOX1/DUOX2 variants linked to very early onset IBD), microbiome compensation can restore colonization resistance by enriching commensals that generate low-level oxidants like H2O2, which function as antivirulence signals rather than direct antimicrobials. The most database-relevant “signature” is a Lactobacillus-dominant, H2O2-producing community associated with reduced expression of attaching-and-effacing virulence programs (LEE). However, the protection is fragile and environment-dependent-dietary fat/sugar and antibiotic depletion erased it—underscoring that microbiome-based interventions (targeted probiotics, community transplants, or strategies that locally boost H2O2 signaling) must be paired with supportive ecological conditions to be durable.
Citation
Pircalabioru G, Aviello G, Kubica M, et al. Defensive mutualism rescues NADPH oxidase inactivation in gut infection.Cell Host Microbe. 2016;19(5):651-663. doi:10.1016/j.chom.2016.04.007
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.