The Glycolysis-NETosis Feedback Loop: A Metabolic-Immune Axis in Inflammatory Bowel Disease

Inflammatory bowel disease (IBD), encompassing Crohn's disease and ulcerative colitis, is a chronic relapsing inflammatory condition of the gastrointestinal tract with rising global incidence. Neutrophils, as first-line responders to intestinal inflammation, release neutrophil extracellular traps (NETs) that trap pathogens but also perpetuate tissue damage. Emerging evidence reveals that NETosis is intimately linked to metabolic reprogramming, with glycolysis serving as a central regulator. This review comprehensively examines the bidirectional crosstalk between glycolysis and NET formation in IBD. We discuss how glycolytic flux provides ATP, NAD + , and metabolic intermediates that support the energetic and biosynthetic demands of NETosis, including the roles of key glycolytic enzymes such as hexokinase 2, PFKFB3, and PKM2. Conversely, NET components and the inflammatory microenvironment are hypothesized to enhance glycolytic reprogramming in neutrophils and adjacent intestinal cells through HIF-1alpha activation and NF-kappaB signaling, potentially establishing positive feedback loops. The clinical implications of this metabolic-immune axis are considered, including potential biomarkers, ongoing clinical trials targeting glycolysis and NETosis, and emerging therapeutic strategies. We propose that the glycolysis-NETosis feedback loop represents a critical pathogenic axis in IBD and an actionable target for therapeutic intervention, offering new avenues for patient stratification and precision medicine approaches.