Neutrophil extracellular traps as a potential therapeutic target in inflammatory bowel disease: a systematic review and meta-analysis.

BACKGROUND

Elevated Neutrophil extracellular traps (NETs) associated biomarkers have been documented in inflammatory bowel disease (IBD) patients and preclinical models, but the therapeutic potential of targeting NETs remains unclear. This systematic review summarizes NETs-associated biomarkers in IBD patients and evaluates NETs-targeted interventions in preclinical models.

METHODS

Following PRISMA guidelines, we searched databases up to November 2025. Clinical and preclinical studies assessing NETs expression and targeted modulation in IBD were included. Standardized mean difference (SMD) and 95% confidence interval (CI) were calculated using random-effects models.

RESULTS

Forty-eight studies (12 clinical, 31 pre-clinical, 5 mixed) were identified. In clinical studies, NETs-associated biomarkers were elevated in the colonic mucosa and blood compared with healthy controls, and higher NETs burden was associated with more severe disease severity and poorer prognosis in IBD patients. In preclinical studies, direct NETs inhibition and degradation reduced disease activity index (SMD = -1.00 and -1.71, P< 0.05) and histological scores (SMD = -1.70 and -2.95, P< 0.01), and reversed colon shortening (P< 0.05). NETs modulation restored epithelial barrier by increasing occludin expression (SMD = 1.35 and 2.59, P< 0.01) and reducing intestinal permeability (P<0.05). Interventions suppressed pro-inflammatory cytokines (IL-1β, IL-6, TNF-α, and IFN-γ; P< 0.05) and increased anti-inflammatory cytokines (TGF-β, IL-10; P< 0.05). Subgroup analyses suggested administration route, modeling methods, and sample types may contribute to heterogeneity, although testing for subgroup differences was limited by the small number of studies. Sensitivity analyses indicated that pooled estimates for most outcomes were relatively stable, although several outcomes were not robust in sensitivity analyses after excluding individual studies. These findings should therefore be interpreted with caution.

CONCLUSION

NETs accumulation is a hallmark pathological feature of IBD. In preclinical IBD models, targeted NETs modulation ameliorates colitis by restoring the intestinal barrier integrity and suppressing inflammatory cascades. Further high-quality preclinical and translational studies are needed to define standardized detection methods, optimal dosing, and delivery strategies for clinical translation.

SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO, identifier CRD420261365119.