Gut Microbiota-Driven NETosis Promotes Endometriosis : Gut | May 2026

Introduction

Endometriosis is a chronic inflammatory gynecological disease characterized by ectopic implantation of endometrial tissue and associated with pelvic pain, infertility and impaired quality of life. Although immune dysregulation and gut microbiota alterations have both been implicated in disease pathogenesis, the mechanistic link between intestinal dysbiosis and peritoneal lesion formation has remained poorly understood.

Problem Statement

The causal mechanisms through which gut microbiota influence peritoneal inflammation and lesion progression in endometriosis remain unclear, particularly regarding microbial translocation, neutrophil activation and the role of Neutrophil Extracellular Traps.

Summary

This translational study identifies a novel gut–peritoneum axis in endometriosis whereby translocated gut microbiota trigger NETosis and promote lesion development through activation of a distinct proinflammatory neutrophil population.

Using single-cell RNA sequencing of peritoneal immune cells, the investigators identified a membrane metalloendopeptidase-positive neutrophil subset enriched in endometriosis and primed for NET formation. These neutrophils released extracellular traps in response to bacterial lipopolysaccharide stimulation, directly enhancing endometrial cell proliferation, migration and lesion establishment.

Mechanistically, NETs acted not merely as inflammatory byproducts but as active structural and signaling platforms that facilitated ectopic endometrial implantation and persistence. Importantly, inhibition of NETosis or enzymatic degradation of NETs markedly suppressed endometriosis progression in murine models, highlighting NETosis as a functionally relevant disease driver rather than an epiphenomenon.

A major strength of the study was the integration of microbiome source-tracking analyses with functional experimental validation. Faecal microbiota transplantation from patients with endometriosis disrupted intestinal barrier integrity in mice and promoted microbial translocation into the peritoneal cavity.

Among translocating organisms, Pseudomonas aeruginosa emerged as a particularly important pathogenic driver. GFP-tagged bacterial experiments demonstrated migration of Pseudomonas into peritoneal lesions, where bacterial lipopolysaccharides triggered NETosis and amplified inflammatory lesion development.

These findings significantly expand the emerging concept of microbiota-driven extraintestinal inflammatory disease. Rather than acting indirectly through systemic metabolites alone, gut microorganisms may physically translocate across impaired intestinal barriers into distant compartments, directly driving local immune activation.

The work also positions NETosis as a central mechanistic bridge linking microbial dysbiosis, innate immunity and ectopic tissue remodeling in endometriosis. Similar NET-mediated pathways are increasingly recognized across inflammatory, autoimmune and cancer-related conditions, suggesting broader relevance of this inflammatory circuitry.

Clinically, the study opens several potentially important therapeutic avenues. Strategies targeting intestinal permeability, selective microbial modulation, Pseudomonas suppression or NETosis inhibition may eventually emerge as novel disease-modifying approaches in endometriosis management.

The findings are particularly interesting because they move beyond traditional hormone-centric models of endometriosis pathogenesis. While estrogen signaling remains fundamental, the disease increasingly appears to involve complex immune-microbiome interactions capable of sustaining chronic inflammatory lesion progression.

From a translational perspective, the study additionally reinforces the growing importance of cross-disciplinary convergence between gastroenterology, microbiome science, immunology and reproductive medicine. The gut–peritoneum axis described here resembles broader gut-organ inflammatory networks increasingly implicated across systemic diseases.

The identification of a disease-associated neutrophil subset also raises the possibility of future biomarker development using immune phenotyping or microbial signatures for disease stratification and therapeutic monitoring.

Overall, this study defines a novel gut microbiota–NETosis pathway in endometriosis, demonstrating that translocated gut-derived Pseudomonas activates proinflammatory neutrophils and drives lesion progression through pathogenic NET formation. The findings establish the gut–peritoneum immune axis as a potentially important therapeutic target in endometriosis.