All roads lead to NF-κB: the NF-κB pathway as a major target for intestinal inflammatory disorders

This review aims to comprehensively examine the role of the NF-κB signalling pathway as a central mediator of intestinal inflammation, integrating evidence from microbiota dysbiosis, immune activation, neutrophil extracellular trap (NET) formation, and the gut-brain axis, and to evaluate current and emerging NF-κB-targeted therapeutic strategies for inflammatory intestinal disorders. The NF-κB family comprises transcription factors that control key processes in immune responses and inflammation by regulating specific gene expression. NF-κB signalling mediates intestinal inflammatory responses at different levels including cytokine secretion, inflammasome signalling, the recruiting of immune cells and antibody production. The NF-κB pathway acts as sensor of microbiota changes and is strongly activated by bacterial toxins such as LPS, MDP or TMAO. Thus, microbial dysbiosis activates pro-inflammatory NF-κB, producing epithelial barrier dysfunction that can lead to a "leaky gut" syndrome, allowing pro-inflammatory factors to leak into the systemic circulation. Consequently, the inflammation originating in the intestine spreads to other organs like the brain, where it might contribute to the development of neurodegenerative disorders, such as Parkinson's disease. In addition, NF-κB also promotes intestinal inflammation in response to Neutrophil Extracellular Traps (NETs) formation, promoting tissue damage and lesions of the intestinal epithelial lining. Therefore, a dysregulated NF-κB signalling appears often in multiple chronic intestinal inflammatory conditions, such as Crohn's Disease (CD) and Ulcerative Colitis (UC), Celiac Disease (CeD) or microscopic colitis. In addition, NF-κB is strongly activated in Irritable Bowel Syndrome (IBS) and in acute intestinal inflammation such as Necrotizing Enterocolitis (NEC). Confirming this evidence, inhibition of the NF-κB pathway by drugs, peptides or natural compounds has been demonstrated to ameliorate the symptoms in many of these inflammatory diseases. In this review, we explore the role of the NF-κB pathway in intestinal inflammation, given its essential role in linking microbiota dysbiosis, infections and chronic inflammation. Finally, we propose the NF-κB pathway as a main therapeutic target for inflammatory intestinal disorders and discuss current inhibitory therapies in use.