Non Celiac Gluten sensitivity (NCGS) was originally described in the 1980s and recently a “re-discovered” disorder characterized by intestinal and extra-intestinal symptoms related to the ingestion of gluten-containing food, in subjects that are not affected with either celiac disease (CD) or wheat allergy (WA). Although NCGS frequency is still unclear, epidemiological data have been generated that can help establishing the magnitude of the problem. Clinical studies further defined the identity of NCGS and its implications in human disease. An overlap between the irritable bowel syndrome (IBS) and NCGS has been detected, requiring even more stringent diagnostic criteria. Several studies suggested a relationship between NCGS and neuropsychiatric disorders, particularly autism and schizophrenia. The first case reports of NCGS in children have been described. Lack of biomarkers is still a major limitation of clinical studies, making it difficult to differentiate NCGS from other gluten related disorders. Recent studies raised the possibility that, beside gluten, wheat amylase-trypsin inhibitors and low-fermentable, poorly-absorbed, short-chain carbohydrates can contribute to symptoms (at least those related to IBS) experienced by NCGS patients. In this paper we report the major advances and current trends on NCGS.
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.
[3]
Sanders, D.S.; Aziz, I. Non celiac wheat sensitivity: Separating the wheat from the chaff. Am. J. Gastroenterol. 2012, 107, 1908–1912, doi:10.1038/ajg.2012.344.
[4]
Sapone, A.; Bai, J.C.; Ciacci, C.; Dolinsek, J.; Green, P.H.; Hadjivassiliou, M.; Kaukinen, K.; Rostami, K.; Sanders, D.S.; Schumann, M.; et al. Spectrum of gluten-related disorders: Consensus on new nomenclature and classification. BMC Med. 2012, 10, 13, doi:10.1186/1741-7015-10-13.
[5]
Ludvigsson, J.F.; Leffler, D.A.; Bai, J.C.; Biagi, F.; Fasano, A.; Green, P.H.; Hadjivassiliou, M.; Kaukinen, K.; Kelly, C.P.; Leonard, J.N.; et al. The Oslo definitions for coeliac disease and related terms. Gut 2013, 62, 43–52, doi:10.1136/gutjnl-2011-301346.
[6]
M？ki, M. Lack of consensus regarding definitions of coeliac disease. Nat. Rev. Gastroenterol. Hepatol. 2012, 9, 305–306, doi:10.1038/nrgastro.2012.91.
[7]
Koletzko, S.; Niggemann, B.; Arato, A.; Dias, J.A.; Heuschkel, R.; Husby, S.; Mearin, M.L.; Papadopoulou, A.; Ruemmele, F.M.; Staiano, A.; et al. European Society of Pediatric Gastroenterology, Hepatology, and Nutrition. Diagnostic approach and management of cow’s-milk protein allergy in infants and children: ESPGHAN GI Committee practical guidelines. J. Pediatr. Gastroenterol. Nutr. 2012, 55, 221–229, doi:10.1097/MPG.0b013e31825c9482.
[8]
Tanpowpong, P.; Ingham, T.R.; Lampshire, P.K.; Kirchberg, F.F.; Epton, M.J.; Crane, J.; Camargo, C.A., Jr.; New Zealand Asthma and Allergy Cohort Study Group. Coeliac disease and gluten avoidance in New Zealand children. Arch. Dis. Child. 2012, 97, 12–16, doi:10.1136/archdischild-2011-300248.
[9]
Tanpowpong, P.; Broder-Fingert, S.; Katz, A.J.; Camargo, C.A., Jr. Predictors of gluten avoidance and implementation of a gluten-free diet in children and adolescents without confirmed celiac disease. J. Pediatr. 2012, 161, 471–475, doi:10.1016/j.jpeds.2012.02.049.
[10]
Digiacomo, D.V.; Tennyson, C.A.; Green, P.H.; Demmer, R.T. Prevalence of gluten-free diet adherence among individuals without celiac disease in the USA: Results from the Continuous National Health and Nutrition Examination Survey 2009–2010. Scand. J. Gastroenterol. 2013, 48, 921–925.
[11]
Krosgaard, L.R.; Engsbro, A.L.; Bytzer, P. The epidemiology of irritable bowel syndrome in Denmark. A population-based survey in adults < 50 years of age. Scand. J. Gastroenterol. 2013, 48, 523–299, doi:10.3109/00365521.2013.775328.
[12]
Breckan, R.K.; Asfeldt, A.M.; Straume, B.; Florholmen, J.; Paulssen, E.J. Prevalence, comorbidity, and risk factors for functional bowel symptoms: A population-based survey in Northern Norway. Scand. J. Gastroenterol. 2012, 47, 1274–1282, doi:10.3109/00365521.2012.688215.
[13]
Biesiekierski, J.R.; Newnham, E.D.; Irving, P.M.; Barrett, J.S.; Haines, M.; Doecke, J.D.; Shepherd, S.J.; Muir, J.G.; Gibson, P.R. Gluten causes gastrointestinal symptoms in subjects without celiac disease: A double-blind randomized placebo-controlled trial. Am. J. Gastroenterol. 2011, 106, 508–514, doi:10.1038/ajg.2010.487.
[14]
Carroccio, A.; Mansueto, P.; Iacono, G.; Soresi, M.; D’Alcamo, A.; Cavataio, F.; Brusca, I.; Florena, A.M.; Ambrosiano, G.; Seidita, A.; et al. Non-celiac wheat sensitivity diagnosed by double-blind placebo-controlled challenge: Exploring a new clinical entity. Am. J. Gastroenterol. 2012, 107, 1898–1906, doi:10.1038/ajg.2012.236.
[15]
Volta, U.; Tovoli, F.; Cicola, R.; Parisi, C.; Fabbri, A.; Piscaglia, M.; Fiorini, E.; Caio, G. Serological tests in gluten sensitivity (non celiac gluten intolerance). J. Clin. Gastroenterol. 2012, 46, 680–685, doi:10.1097/MCG.0b013e3182372541.
[16]
Mastrototaro, L.; Castellaneta, S.; Gentile, A.; Fontana, C.; Tandoi, E.; Dellatte, S.; Romagnoli, V.; Catassi, C.; Francavilla, R. Gluten sensitivity in children: Clinical, serological, genetic and histological description of the first paediatric series. Dig. Liver Dis. 2012, 44, S254–S255.
[17]
Brottveit, M.; Vandvik, P.O.; Wojniusz, S.; L？vik, A.; Lundin, K.E.; Boye, B. Absence of somatization in non-coeliac gluten sensitivity. Scand. J. Gastroenterol. 2012, 47, 770–777.
[18]
Boettcher, E.; Crowe, S.E. Dietary proteins and functional gastrointestinal disorders. Am. J. Gastroenterol. 2013, 108, 728–736, doi:10.1038/ajg.2013.97.
[19]
Sainsbury, A.; Sanders, D.S.; Ford, A.C. Prevalence of irritable bowel syndrome-type symptoms in patients with celiac disease: A meta-analysis. Clin. Gastroenterol. Hepatol. 2013, 11, 359–365, doi:10.1016/j.cgh.2012.11.033.
[20]
Vazquez-Roque, M.I.; Camilleri, M.; Smirk, T.; Murray, J.A.; 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, doi:10.1053/j.gastro.2013.01.049.
[21]
Biesiekirski, J.R.; Peters, S.L.; Newnham, E.D.; Rosella, O.; Muir, J.G.; Gibson, P.R. 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, doi:10.1053/j.gastro.2013.04.051.
[22]
Batista, I.C.; Gandolfi, L.; Nobrega, Y.K.; Almeida, R.C.; Almeida, L.M.; Campos Junior, D.; Pratesi, R. Autism spectrum disorder and celiac disease: No evidence for a link. Arq. Neuropsiquiatr. 2012, 70, 28–33, doi:10.1590/S0004-282X2012000100007.
[23]
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, doi:10.1016/j.jada.2009.01.013.
[24]
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, doi:10.1097/MPG.0b013e3181dcc4a5.
[25]
Robertson, M.A.; Sigalet, D.L.; Holst, J.J.; Meddings, J.B.; Wood, J.; Sharkey, K.A. Intestinal permeability and glucagon-like peptide-2 in children with autism: A controlled pilot study. J. Autism Dev. Disord. 2008, 38, 1066–1071, doi:10.1007/s10803-007-0482-1.
[26]
Lau, N.M.; Green, P.H.; Taylor, A.K.; Hellberg, D.; Ajamian, M.; Tan, C.Z.; Kosofsky, B.E.; Higgins, J.J.; Rajadhyaksha, A.M.; Alaedini, A. Markers of celiac disease and gluten sensitivity in children with autism. PLoS One 2013, 8, e66155, doi:10.1371/journal.pone.0066155.
[27]
De Magistris, L.; Picardi, A.; Siniscalco, D.; Riccio, M.P.; Sapone, A.; Cariello, R. Antibodies against food antigens in patients with autistic spectrum disorders. BioMed. Res. Int. 2013, 2013, 729349.
[28]
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.
[29]
Whiteley, P.; Haracopos, D.; Knivsberg, A.M.; Reichelt, K.L.; 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, doi:10.1179/147683010X12611460763922.
[30]
Dohan, F.C. Cereals and schizophrenia data and hypothesis. Acta Psychiatr. Scand. 1966, 42, 125–152, doi:10.1111/j.1600-0447.1966.tb01920.x.
[31]
Vlissides, D.M.; Venulet, A.; Jenner, F.A. A double-blind glutenfree/gluten-load controlled trial in a secure ward population. Br. J. Psychiatry 1986, 148, 447–452, doi:10.1192/bjp.148.4.447.
[32]
Potkin, S.G.; Weinberger, D.; Kleinman, J.; Potkin, S.G.; 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, L.H.; Clopton, J.M.; Wright, C. Effects of gluten in schizophrenics. Arch. Gen. Psychiatry 1982, 39, 323–327, doi:10.1001/archpsyc.1982.04290030055010.
[34]
Cascella, N.G.; Kryszak, D.; Bhatti, B.; Gregory, P.; Kelly, D.L.; Mc Evoy, J.P.; Fasano, A.; Eaton, W.W. 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, doi:10.1093/schbul/sbp055.
[35]
Cascella, N.G.; Santora, D.; Gregory, P.; Kelly, D.L.; Fasano, A.; Eaton, W.W. Increased prevalence of transglutaminase 6 antibodies in sera from schizophrenia patients. Schizophr. Bull. 2013, 39, 867–871, doi:10.1093/schbul/sbs064.
[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, doi:10.1016/j.biopsych.2010.03.021.
[37]
Holmes, G. Non coeliac gluten sensitivity. Gastroenterol. Hepatol. Bed Bench 2013, 6, 115–119.
[38]
Brottveit, M.; Beitnes, A.C.; Tollefsen, S.; Bratlie, J.E.; Jahnsen, F.L.; Johansen, F.E.; Sollid, L.M.; Lundin, K.E. Mucosal cytokine response after short-term gluten challenge in celiac disease and non-celiac gluten sensitivity. Am. J. Gastroenterol. 2013, 108, 842–850, doi:10.1038/ajg.2013.91.
[39]
Bucci, C.; Zingone, F.; Russo, I.; Morra, I.; Tortora, R.; Pogna, N.; Scalia, G.; Iovino, P.; Ciacci, C. Gliadin does not induce mucosal inflammation or basophil activation in patients with non-celiac gluten sensitivity. Clin. Gastroenterol. Hepatol. 2013, 11, 1294–1299, doi:10.1016/j.cgh.2013.04.022.
[40]
Junker, Y.; Zeissig, S.; Kim, S.J.; Barisani, D.; Wieser, H.; Leffler, D.A.; Zevallos, V.; Libermann, T.A.; Dillon, S.; Freitag, T.L.; et al. Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4. J. Exp. Med. 2012, 209, 2395–2408, doi:10.1084/jem.20102660.
