Impact of Neutrophils on the Tissue Microenvironment During Intestinal Inflammation

Faiz Minhajuddin,1 Sean P Colgan,1,2 Ian M Cartwright1,2 1Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; 2VA Eastern Colorado Health Care System, Aurora, CO, USACorrespondence: Ian M Cartwright, Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, 12700 E. 19th Ave. 10125, Aurora, CO, 80045, USA, Tel +1 303 724 7235, Email [email protected]: Neutrophils (polymorphonuclear leukocytes, PMN) are abundant innate immune cells that rapidly accumulate at mucosal surfaces during inflammation. While their antimicrobial functions are essential for host defense, sustained PMN activation profoundly alters the tissue microenvironment, driving epithelial barrier disruption, ECM remodeling, metabolic imbalance, and microbiome dysbiosis. In chronic inflammatory diseases such as inflammatory bowel disease (IBD), these processes contribute to persistent tissue injury and therapeutic resistance. In this review, we synthesize evidence from human mucosal biopsies, experimental models of intestinal inflammation, and emerging single-cell, spatial, and metabolic approaches to define how PMN shape the inflamed mucosal microenvironment. We highlight mechanisms governing PMN recruitment, retention, and survival; effector programs including reactive oxygen species production, protease release, and PMN extracellular trap formation; and bidirectional crosstalk with epithelial, stromal, and immune cell compartments. We further discuss how PMN-driven metabolic and microbiome alterations reinforce chronic inflammation and influence responses to biologic therapy. Collectively, these insights reframe PMN as context-dependent regulators of mucosal pathology and repair and identify PMN-centered pathways as promising targets for precision therapies aimed at restoring barrier function and promoting durable inflammatory resolution.Keywords: neutrophil, PMN, mucosal inflammation, innate immunity, barrier function, NETosis, microbiome, inflammatory disease