{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T02:16:00Z","timestamp":1792030560899,"version":"4.4.0"},"reference-count":134,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T00:00:00Z","timestamp":1763510400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ricerca Corrente Funding of the Italian Ministry of Health"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Non-coeliac wheat sensitivity (NCWS) is characterised by gastrointestinal and extra-intestinal symptoms following gluten\/wheat ingestion in individuals without coeliac disease or wheat allergy but remains controversial due to symptom overlap with irritable bowel syndrome (IBS). This narrative review aims to provide a comprehensive, critical analysis of NCWS as a clinical and biological entity, examining the evidence for its distinction from related disorders. While self-reported rates are high (often &gt;10%) in the general population, rigorous double-blind, placebo-controlled challenge (DBPCC) studies confirm the diagnosis in only a minority of cases (typically &lt;30%). The clinical presentation is heterogeneous, combining IBS-like symptoms with systemic complaints such as \u201cbrain fog,\u201d headaches, and fatigue. The pathophysiology is distinct from coeliac disease, involving innate immune activation, altered intestinal barrier function, and gut dysbiosis. Non-gluten wheat components, particularly fructans and amylase-trypsin inhibitors, are implicated as potential triggers. Diagnosis is challenging, requiring the exclusion of other disorders and adherence to complex dietary challenge protocols such as the Salerno Experts\u2019 Criteria, which are impractical for routine clinical use. The search for validated biomarkers is a key research area and investigated candidates include serological markers such as IgG anti-gliadin antibodies, inflammatory markers such as faecal calprotectin, and proteins related to intestinal permeability such as zonulin, but results have been conflicting and require further validation. Management primarily involves elimination of wheat and gluten from the diet, although a low-FODMAP diet has also proven effective as an adjunctive treatment. In conclusion, NCWS is a clinical entity whose study and management are critically hampered by the absence of validated diagnostic criteria and biomarkers. Progress requires methodologically rigorous DBPCC trials to elucidate its mechanisms and develop reliable diagnostic tools.<\/jats:p>","DOI":"10.3390\/ijms262211174","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T11:17:27Z","timestamp":1763551047000},"page":"11174","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Non-Coeliac Wheat Sensitivity: Symptoms in Search of a Mechanism, or a Distinct Well-Defined Clinical Entity? A Narrative Review"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2057-8179","authenticated-orcid":false,"given":"Stiliano","family":"Maimaris","sequence":"first","affiliation":[{"name":"Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy"},{"name":"Istituti Clinici Scientifici Maugeri IRCCS, Gastroenterology Unit of Pavia Institute, Via Salvatore Maugeri 10, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Scarcella","sequence":"additional","affiliation":[{"name":"Istituti Clinici Scientifici Maugeri IRCCS, Gastroenterology Unit of Pavia Institute, Via Salvatore Maugeri 10, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giusi Aurora","family":"Memoli","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-8085-1098","authenticated-orcid":false,"given":"Carlotta","family":"Crisciotti","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8493-7698","authenticated-orcid":false,"given":"Annalisa","family":"Schiepatti","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy"},{"name":"Istituti Clinici Scientifici Maugeri IRCCS, Gastroenterology Unit of Pavia Institute, Via Salvatore Maugeri 10, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2227-4622","authenticated-orcid":false,"given":"Federico","family":"Biagi","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy"},{"name":"Istituti Clinici Scientifici Maugeri IRCCS, Gastroenterology Unit of Pavia Institute, Via Salvatore Maugeri 10, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,19]]},"reference":[{"key":"ref_1","first-page":"398","article-title":"Proceedings: Chronic diarrhoea and gluten sensitivity","volume":"17","author":"Cooper","year":"1976","journal-title":"Gut"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1358","DOI":"10.1016\/S0140-6736(78)92427-3","article-title":"Non-coeliac gluten sensitivity?","volume":"1","author":"Ellis","year":"1978","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1159\/000260087","article-title":"Differential mucosal IL-17 expression in two gliadin-induced disorders: Gluten sensitivity and the autoimmune enteropathy celiac disease","volume":"152","author":"Sapone","year":"2010","journal-title":"Int. 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