Non-celiac gluten sensitivity (NCGS) is a syndrome characterized by intestinal and extraintestinal symptoms related to the ingestion of gluten-containing food in subjects who are not affected by either celiac disease (CD) or wheat allergy (WA). The prevalence of NCGS is not clearly defined yet. Indirect evidence suggests that NCGS is slightly more common than CD, the latter affecting around 1% of the general population. NCGS has been mostly described in adults, particularly in females in the age group of 30-50 years; however, pediatric case series have also been reported. Since NCGS may be transient, gluten tolerance needs to be reassessed over time in patients with NCGS. NCGS is characterized by symptoms that usually occur soon after gluten ingestion, disappear with gluten withdrawal, and relapse following gluten challenge within hours/days. The ‘classical' presentation of NCGS is a combination of irritable bowel syndrome-like symptoms, including abdominal pain, bloating, bowel habit abnormalities (either diarrhea or constipation), and systemic manifestations such as ‘foggy mind', headache, fatigue, joint and muscle pain, leg or arm numbness, dermatitis (eczema or skin rash), depression, and anemia. In recent years, several studies explored the relationship between the ingestion of gluten-containing food and the appearance of neurological and psychiatric disorders/symptoms like ataxia, peripheral neuropathy, schizophrenia, autism, depression, anxiety, and hallucinations (so-called gluten psychosis). The diagnosis of NCGS should be considered in patients with persistent intestinal and/or extraintestinal complaints showing a normal result of the CD and WA serological markers on a gluten-containing diet, usually reporting worsening of symptoms after eating gluten-rich food. NCGS should not be an exclusion diagnosis only. Unfortunately, no biomarker is sensitive and specific enough for diagnostic purposes; therefore, the diagnosis of NCGS is currently based on establishing a clear-cut cause-effect relationship between the ingestion of gluten and the appearance of symptoms by a standardized double-blind, placebo-controlled gluten challenge.

1.
Sapone A, Bai JC, Ciacci C, Dolinsek J, Green PH, Hadjivassiliou M, Kaukinen K, Rostami K, Sanders DS, Schumann M, et al: Spectrum of gluten-related disorders: consensus on new nomenclature and classification. BMC Med 2012;10:13.
2.
Catassi C, Bai JC, Bonaz B, Bouma G, Calabrò A, Carroccio A, Castillejo G, Ciacci C, Cristofori F, Dolinsek J, et al: Non-celiac gluten sensitivity: the new frontier of gluten related disorders. Nutrients 2013;5:3839-3853.
3.
Schuppan D, Zevallos V: Wheat amylase trypsin inhibitors as nutritional activators of innate immunity. Dig Dis 2015;33:260-263.
4.
Ellis A, Linaker BD: Non coeliac gluten sensitivity? Lancet 1978;1:1358-1359.
5.
Cooper BT, Holmes GK, Ferguson R, Thompson RA, Allan RN, Cooke WT: Gluten-sensitive diarrhea without evidence of celiac disease. Gastroenterology 1981;81:192-194.
6.
Sapone A, Lammers K.M, Mazzarella G, Mikhailenko I, Cartenì M, Casolaro V, Fasano A: Differential mucosal IL-17 expression in two gliadin-induced disorders: gluten sensitivity and the autoimmune enteropathy celiac disease. Int Arch Allergy Immunol 2010;152:75-80.
7.
Aziz I, Lewis NR, Hadjivassiliou M, Winfield SN, Rugg N, Kelsall A, Newrick L, Sanders DS: A UK study assessing the population prevalence of self-reported gluten sensitivity and referral characteristics to secondary care. Eur J Gastroenterol Hepatol 2014;26:33-39.
8.
Volta U, Bardella MT, Calabrò A, Troncone R, Corazza GR; Study Group for Non-Celiac Gluten Sensitivity: An Italian prospective multicenter survey on patients suspected of having non-celiac gluten sensitivity. BMC Med 2014;12:85.
9.
Lionetti E, Gatti S, Pulvirenti A, Catassi C: Celiac disease from a global perspective. Best Pract Res Clin Gastroenterol 2015;29:365-379.
10.
Francavilla R, Cristofori F, Castellaneta S, Polloni C, Albano V, Dellatte S, Indrio F, Cavallo L, Catassi C: Clinical, serologic, and histologic features of gluten sensitivity in children. J Pediatr 2014;164:463-467.
11.
Feldman MF, Bird JA: Clinical, serologic, and histologic features of gluten sensitivity in children. Pediatrics 2014;134(suppl 3): S157-S158.
12.
Gibson PR, Varney J, Malakar S, Muir JG: Food components and irritable bowel syndrome. Gastroenterology 2015;148:1158-1174.
13.
Vazquez-Roque MI, Camilleri M, Smirk T, Murray JA, Marietta E, O'Neill J, Carlson P, Lamsam J: A controlled trial of gluten-free diet in patients with irritable bowel syndrome-diarrhea: effects on bowel frequency and intestinal function. Gastroenterology 2013;144:903-911.
14.
Di Sabatino A, Volta U, Salvatore C, Biancheri P, Caio G, De Giorgio R, Di Stefano M, Corazza GR: Small amounts of gluten in subjects with suspected nonceliac gluten sensitivity: a randomized, double-blind, placebo-controlled, cross-over trial. Clin Gastroenterol Hepatol 2015;13:1604-1612.e3.
15.
Biesiekierski JR, Newnham ED, Irving PM, Barrett JS, Haines M, Doecke JD, Shepherd SJ, Muir JG, Gibson PR: Gluten causes gastrointestinal symptoms in subjects without celiac disease: a double-blind randomized placebo-controlled trial. Am J Gastroenterol 2011;106:508-514.
16.
Biesiekirski JR, Peters SL, Newnham ED, Rosella O, Muir JG, Gibson PR: No effects of gluten in patients with self-reported non- celiac gluten sensitivity following dietary reduction of low-fermentable, poorly absorbed, short-chain carbohydrates. Gastroenterology 2013;145, 320-328.
17.
Carroccio A, Mansueto P, Iacono G, Soresi M, D'Alcamo A, Cavataio F, Brusca I, Florena AM, Ambrosiano G, Seidita A, Pirrone G, Rini GB: Non-celiac wheat sensitivity diagnosed by double-blind placebo-controlled challenge: exploring a new clinical entity. Am J Gastroenterol 2012;107:1898-1906.
18.
Batista IC, Gandolfi L, Nobrega YK, Almeida RC, Almeida LM, Campos Junior D, Pratesi R: Autism spectrum disorder and celiac disease: no evidence for a link. Arq Neuropsiquiatr 2012;70:28-33.
19.
Marcason W: What is the current status of research concerning use of a gluten-free, casein-free diet for children diagnosed with autism? J Am Diet Assoc 2009;109:572.
20.
De Magistris L, Familiari V, Pascotto A, Sapone A, Frolli A, Iardino P, Carteni M, de Rosa M, Francavilla R, Riegler G, et al: Alterations of the intestinal barrier in patients with autism spectrum disorders and in their first-degree relatives. J Pediatr Gastroenterol Nutr 2010;51:418-424.
21.
Robertson MA, Sigalet DL, Holst JJ. Meddings JB, Wood J, Sharkey KA: Intestinal permeability and glucagon-like peptide-2 in children with autism: a controlled pilot study. J Autism Dev Disord 2008;38:1066-1071.
22.
Navarro F, Pearson DA, Fatheree N, Mansour R, Hashmi SS, Rhoads JM: Are ‘leaky gut' and behavior associated with gluten and dairy containing diet in children with autism spectrum disorders? Nutr Neurosci 2015;18:177-185.
23.
Lau NM, Green PH, Taylor AK, Hellberg D, Ajamian M, Tan CZ, Kosofsky BE, Higgins JJ, Rajadhyaksha AM, Alaedini A: Markers of celiac disease and gluten sensitivity in children with autism. PLoS One 2013;8:e66155.
24.
De Magistris L, Picardi A, Siniscalco D, Riccio MP, Sapone A, Cariello R: Antibodies against food antigens in patients with autistic spectrum disorders. Biomed Res Int 2013;2013:729349.
25.
Millward C, Ferriter M, Calver S, Connell-Jones G: Gluten- and casein-free diets for autistic spectrum disorder. Cochrane Database Syst Rev 2008;2:CD003498.
26.
Marí-Bauset S, Zazpe I, Mari-Sanchis A, Llopis-González A, Morales-Suárez-Varela M: Evidence of the gluten-free and casein-free diet in autism spectrum disorders: a systematic review. J Child Neurol 2014;29:1718-1727.
27.
Whiteley P, Haracopos D, Knivsberg AM, Reichelt KL, Parlar S, Jacobsen J, Seim A, Pedersen L, Schondel M, Shattock P: The ScanBrit randomised, controlled, single-blind study of a gluten- and casein-free dietary intervention for children with autism spectrum disorders. Nutr Neurosci 2010;13:87-100.
28.
Pedersen L, Parlar S, Kvist K, Whiteley P, Shattock P: Data mining the ScanBrit study of a gluten- and casein-free dietary intervention for children with autism spectrum disorders: behavioural and psychometric measures of dietary response. Nutr Neurosci 2014;17:207-213.
29.
Pusponegoro HD, Ismael S, Firmansyah A, Sastroasmoro S, Vandenplas Y: Gluten and casein supplementation does not increase symptoms in children with autism spectrum disorder. Acta Paediatr 2015, Epub ahead of print.
30.
Dohan FC: Cereals and schizophrenia data and hypothesis. Acta Psychiatr Scand 1966;42:125-152.
31.
Vlissides DM, Venulet A, Jenner FA: A double-blind gluten-free/gluten-load controlled trial in a secure ward population. Br J Psychiatry 1986;148:447-452.
32.
Potkin SG, Weinberger D, Kleinman J, Potkin SG, Weinberger D, Kleinman J, Nasrallah H, Luchins D, Bigelow L, Linnoila M, et al: Wheat gluten challenge in schizophrenic patients. Am J Psychiatry 1981;138:1208-1211.
33.
Storms LH, Clopton JM, Wright C: Effects of gluten in schizophrenics. Arch Gen Psychiatry 1982;39:323-327.
34.
Cascella NG, Kryszak D, Bhatti B, Gregory P, Kelly DL, Mc Evoy JP, Fasano A, Eaton WW: Prevalence of celiac disease and gluten sensitivity in the United States clinical antipsychotic trials of intervention effectiveness study population. Schizophr Bull 2011;37:94-100.
35.
Cascella NG, Santora D, Gregory P, Kelly DL, Fasano A, Eaton WW: Increased prevalence of transglutaminase 6 antibodies in sera from schizophrenia patients. Schizophr Bull 2013;39:867-871.
36.
Dickerson F, Stallings C, Origoni A, Vaughan C, Khushalani S, Leister F, Yang S, Krivogorsky B, Alaedini A, Yolken R: Markers of gluten sensitivity and celiac disease in recent-onset psychosis and multi-episode schizophrenia. Biol Psychiatry 2010;68:100-104.
37.
Genuis SJ, Lobo RA: Gluten sensitivity presenting as a neuropsychiatric disorder. Gastroenterol Res Pract 2014;2014:293206..
38.
Lionetti E, Leonardi S, Franzonello C, Mancardi M, Ruggieri M, Catassi C: Gluten psychosis: confirmation of a new clinical entity. Nutrients 2015;7:5532-5539.
39.
Catassi C, Elli L, Bonaz B, et al: Diagnosis of non-celiac gluten sensitivity (NCGS): The Salerno Experts' Criteria. Nutrients 2015;7:4966-4977.
40.
Kulich KR, Madisch A, Pacini F, Piqué JM, Regula J, van Rensburg CJ, Ujszászy L, Carlsson J, Halling K, Wiklund IK: Reliability and validity of the Gastrointestinal Symptom Rating Scale (GSRS) and Quality of Life in Reflux and Dyspepsia (QOLRAD) questionnaire in dyspepsia: a six-country study. Health Qual Life Outcomes 2008;6:12.
41.
Van Overbeek FM, Uil-Dieterman IG, Mol IW, Köhler-Brands L, Heymans HS, Mulder CJ: The daily gluten intake in relatives of patients with coeliac disease compared with that of the general Dutch population. Eur J Gastroenterol Hepatol 1997;9:1097-1099.
42.
Caio G, Volta U, Tovoli F, De Giorgio R: Effect of gluten free diet on immune response to gliadin in patients with non-celiac gluten sensitivity. BMC Gastroenterol 2014;14:26.
You do not currently have access to this content.