{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T23:36:20Z","timestamp":1790811380910,"version":"4.1.0"},"reference-count":105,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T00:00:00Z","timestamp":1777507200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>This review aims to comprehensively examine the role of the NF-\u03baB signalling pathway as a central mediator of intestinal inflammation, integrating evidence from microbiota dysbiosis, immune activation, neutrophil extracellular trap (NET) formation, and the gut\u2013brain axis, and to evaluate current and emerging NF-\u03baB-targeted therapeutic strategies for inflammatory intestinal disorders. The NF-\u03baB family comprises transcription factors that control key processes in immune responses and inflammation by regulating specific gene expression. NF-\u03baB signalling mediates intestinal inflammatory responses at different levels including cytokine secretion, inflammasome signalling, the recruiting of immune cells and antibody production. The NF-\u03baB 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-\u03baB, producing epithelial barrier dysfunction that can lead to a \u201cleaky gut\u201d 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\u2019s disease. In addition, NF-\u03baB 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-\u03baB signalling appears often in multiple chronic intestinal inflammatory conditions, such as Crohn\u2019s Disease (CD) and Ulcerative Colitis (UC), Celiac Disease (CeD) or microscopic colitis. In addition, NF-\u03baB 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-\u03baB 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-\u03baB pathway in intestinal inflammation, given its essential role in linking microbiota dysbiosis, infections and chronic inflammation. Finally, we propose the NF-\u03baB pathway as a main therapeutic target for inflammatory intestinal disorders and discuss current inhibitory therapies in use.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1816653","type":"journal-article","created":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T05:43:25Z","timestamp":1777527805000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["All roads lead to NF-\u03baB: the NF-\u03baB pathway as a major target for intestinal inflammatory disorders"],"prefix":"10.3389","volume":"17","author":[{"given":"Rasul","family":"Khasanov","sequence":"first","affiliation":[{"name":"Department of Pediatric Surgery, Medical Faculty of Mannheim, University of Heidelberg","place":["Mannheim, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Boettcher","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Medical Faculty of 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