Neutrophil Plasticity and De Novo DUOX2 Expression in Inflammatory Bowel Disease Pathogenesis: A Review of Single-Cell Transcriptomic Advances and Therapeutic Strategies

Inflammatory bowel disease (IBD) arises from the interplay of genetic susceptibility, microbial dysbiosis, and dysregulated innate immunity, leading to chronic intestinal inflammation. Recent advances in single-cell and spatial multi-omics technologies have redefined neutrophils as highly heterogeneous and transcriptionally plastic cells rather than short-lived effectors. In the inflamed gut, cytokine gradients, hypoxia, and microbial metabolites such as short-chain fatty acids dynamically reprogram neutrophil states toward either protective or pathogenic phenotypes. Emerging evidence identifies de novo induction of the NADPH oxidase enzyme DUOX2 in intestinal neutrophils as a key driver of redox signaling, amplifying epithelial and immune activation through NF-κB and p38 MAPK pathways. This redox diversification enhances antimicrobial defense but also perpetuates dysbiosis, barrier dysfunction, and NET-associated thrombo-inflammation. Experimental models demonstrate that myeloid DUOX2 ablation mitigates colitis, supporting therapeutic strategies that target this axis—such as JAK/STAT inhibition, CXCR2 blockade, p38/MK2 modulation, or butyrate-based interventions—to recalibrate neutrophil function while preserving host protection. Integrating single-cell atlases, redox proteomics, and functional imaging will be essential to translate neutrophil plasticity into biomarker-guided, precision therapies for durable mucosal healing in IBD.