Editing Gluten (section)

==Disorders==
{{Main article|Gluten-related disorders|Gluten-sensitive enteropathy-associated conditions|Gluten-sensitive idiopathic neuropathies}}

"Gluten-related disorders" is the umbrella term for all diseases triggered by gluten, which include [[celiac disease]] (CD), [[non-celiac gluten sensitivity]] (NCGS), [[wheat allergy]], <ref name=Costantino22>{{cite journal |vauthors=Costantino A, Aversano GM, Lasagni G, Smania V, Doneda L, Vecchi M, Roncoroni L, Pastorello EA, Elli L |title=Diagnostic management of patients reporting symptoms after wheat ingestion |journal=Front Nutr |volume=9 |issue= |pages=1007007 |date=2022 |pmid=36276818 |pmc=9582535 |doi=10.3389/fnut.2022.1007007 |doi-access=free}}</ref> [[gluten ataxia]] and [[dermatitis herpetiformis]] (DH).<ref name=LudvigssonLeffler2013>{{cite journal |vauthors=Ludvigsson JF, Leffler DA, Bai JC, Biagi F, Fasano A, Green PH, Hadjivassiliou M, Kaukinen K, Kelly CP, Leonard JN, Lundin KE, Murray JA, Sanders DS, Walker MM, Zingone F, Ciacci C |title=The Oslo definitions for coeliac disease and related terms |journal=Gut |volume=62 |issue=1 |pages=43–52 | date=January 2013 |pmid=22345659 |pmc=3440559 |doi=10.1136/gutjnl-2011-301346|type=Review  |doi-access=free}}</ref>

===Pathophysiological research===

The gluten [[peptide]]s are responsible for triggering gluten-related disorders.<ref name=LammersHerrera2018 /> In people who have celiac disease, the peptides trigger an immune response that causes injury of the intestines, ranging from [[inflammation]] to partial or total destruction of the [[intestinal villus|intestinal villi]].<ref name=DicksonStreutker2006>{{cite journal| vauthors=Dickson BC, Streutker CJ, Chetty R| title=Coeliac disease: an update for pathologists | journal=J Clin Pathol | year= 2006 | volume= 59 | issue= 10 | pages= 1008–16 | pmid=17021129 | doi=10.1136/jcp.2005.035345 | pmc=1861744 | type=Review }}</ref><ref name=StovenMurray2013 /> To study mechanisms of this damage, laboratory experiments are done ''in vitro'' and ''in vivo''.<ref name=KupferJabri2012>{{cite journal| vauthors=Kupfer SS, Jabri B| title=Pathophysiology of celiac disease | journal=Gastrointest Endosc Clin N Am | year= 2012 | volume= 22 | issue= 4 | pages= 639–60 | pmid=23083984 | doi=10.1016/j.giec.2012.07.003 | pmc=3872820 |type=Review }}</ref><ref name=StovenMurray2013>{{cite journal| vauthors=Stoven S, Murray JA, Marietta EV| title=Latest in vitro and in vivo models of celiac disease | journal=Expert Opin Drug Discov | year= 2013 | volume= 8 | issue= 4 | pages= 445–57 | pmid=23293929 | doi=10.1517/17460441.2013.761203 | pmc=3605231 |type=Review }}</ref> Among the gluten peptides, [[gliadin]] has been studied extensively.<ref name=LammersHerrera2018 />

====''In vitro'' and ''in vivo'' studies====
In the context of celiac disease, [[Gliadin|gliadin peptides]] are classified in [[basic research|basic]] and [[clinical research]] as  [[Immunogenicity|immunogenic]], depending on their [[mechanism of action]]:<ref name=LammersHerrera2018>{{cite journal| vauthors=Lammers KM, Herrera MG, Dodero VI| title=Translational Chemistry Meets Gluten-Related Disorders | journal=ChemistryOpen | year= 2018 | volume= 7 | issue= 3 | pages= 217–232 | pmid=29531885 | doi=10.1002/open.201700197 | pmc=5838388 | type=Review }}</ref><ref name=SilanoVincentini2009>{{cite journal| vauthors=Silano M, Vincentini O, De Vincenzi M| title=Toxic, immunostimulatory and antagonist gluten peptides in celiac disease | journal=Curr Med Chem | year= 2009 | volume= 16 | issue= 12 | pages= 1489–98 | pmid=19355902 | type=Review | doi=10.2174/092986709787909613 }}</ref>

* The peptides are those capable of directly affecting cells and intestinal preparations ''in vitro'', producing cellular damage ''in vivo'' and eliciting the innate immune response.<ref name=LammersHerrera2018 /><ref name=SilanoVincentini2009 /> ''In vitro'', the peptides promote cell [[apoptosis]] (a form of [[programmed cell death]]) and inhibit the synthesis of [[nucleic acid]]s (DNA and RNA) and proteins, reducing the viability of cells.<ref name=ElliRoncoroni2015 /> Experiments ''in vivo'' with normal mice showed that they cause an increase in cell death and the production of [[interferon type I]] (an inflammatory mediator).<ref name=LammersHerrera2018 />  ''In vitro'', gluten alters cellular [[morphology (biology)|morphology]] and [[motility]], [[cytoskeleton]] organization, [[redox|oxidative balance]], and [[tight junction]]s.<ref name=Fasano2011>{{cite journal | author = Fasano A | date = Jan 2011 | title = Zonulin and its regulation of intestinal barrier function: the biological door to inflammation, autoimmunity, and cancer | journal = Physiol. Rev. | volume = 91 | issue = 1| pages = 151–75 | doi = 10.1152/physrev.00003.2008 | pmid = 21248165 | type = Review| citeseerx = 10.1.1.653.3967 | quote= There are at least 50 toxic epitopes in gluten peptides exerting cytotoxic, immunomodulatory, and gut-permeating activities. }}</ref><ref name=ElliRoncoroni2015>{{cite journal| vauthors=Elli L, Roncoroni L, Bardella MT| title=Non-celiac gluten sensitivity: Time for sifting the grain | journal=World J Gastroenterol | year= 2015 | volume= 21 | issue= 27 | pages= 8221–6 | pmid=26217073 | doi=10.3748/wjg.v21.i27.8221 | pmc=4507091 | type=Review | doi-access=free }}</ref><ref name=LeonardSapone2017 />
* The immunogenic peptides are those able to activate [[T cell]]s ''in vitro''.<ref name=LammersHerrera2018 />

At least 50 [[epitope]]s of gluten may produce cytotoxic, immunomodulatory, and [[intestinal permeability|gut-permeating]] activities.<ref name=Fasano2011 />

The effect of oat peptides (avenins) in celiac people depends on the oat [[cultivar]] consumed because of prolamin genes, protein amino acid sequences, and the immunotoxicity of prolamins which vary among oat varieties.<ref name=PenaginiDilillo>{{cite journal | vauthors = Penagini F, Dilillo D, Meneghin F, Mameli C, Fabiano V, Zuccotti GV| title = Gluten-free diet in children: an approach to a nutritionally adequate and balanced diet | journal = Nutrients | volume = 5| issue = 11| pages = 4553–65| date = Nov 18, 2013| pmid = 24253052|pmc= 3847748| doi = 10.3390/nu5114553| type=Review| doi-access = free }}</ref><ref name=DeSouzaDeschenes2016>{{cite journal| vauthors=de Souza MC, Deschênes ME, Laurencelle S, Godet P, Roy CC, Djilali-Saiah I| title=Pure Oats as Part of the Canadian Gluten-Free Diet in Celiac Disease: The Need to Revisit the Issue | journal=Can J Gastroenterol Hepatol | year= 2016 | volume= 2016 | pages= 1–8 | pmid=27446824 | doi=10.1155/2016/1576360 | pmc=4904650 | type= Review | doi-access=free }}</ref><ref name=CominoMoreno2015>{{cite journal | vauthors = Comino I, Moreno Mde L, Sousa C | title = Role of oats in celiac disease | journal = World J Gastroenterol | volume = 21 | issue = 41 | pages = 11825–31 | date = Nov 7, 2015 | pmid = 26557006 |pmc= 4631980 | doi = 10.3748/wjg.v21.i41.11825 |quote= It is necessary to consider that oats include many varieties, containing various amino acid sequences and showing different immunoreactivities associated with toxic prolamins. As a result, several studies have shown that the immunogenicity of oats varies depending on the cultivar consumed. Thus, it is essential to thoroughly study the variety of oats used in a food ingredient before including it in a gluten-free diet. | doi-access = free }}</ref> In addition, oat products may be cross-contaminated with the other gluten-containing [[cereal]]s.<ref name="DeSouzaDeschenes2016"/>

===Incidence===
{{As of|2017}}, gluten-related disorders were increasing in frequency in different geographic areas.<ref name=LeonardSapone2017>{{cite journal| vauthors=Leonard MM, Sapone A, Catassi C, Fasano A| title=Celiac Disease and Nonceliac Gluten Sensitivity: A Review | journal=JAMA | year= 2017 | volume= 318 | issue= 7 | pages= 647–656 | pmid=28810029 | doi=10.1001/jama.2017.9730 | s2cid=205094729 | url=https://directory.doabooks.org/handle/20.500.12854/129651 | type=Review | quote=Previous studies have shown that gliadin can cause an immediate and transient increase in gut permeability. This permeating effect is secondary to the binding of specific undigestible gliadin fragments to the CXCR3 chemokine receptor with subsequent release of zonulin, a modulator of intercellular tight junctions. This process takes place in all individuals who ingest gluten. For the majority, these events do not lead to abnormal consequences. However, these same events can lead to an inflammatory process in genetically predisposed individuals when the immunologic surveillance system mistakenly recognizes gluten as a pathogen. }}</ref><ref name=TovoliMasi>{{cite journal | vauthors = Tovoli F, Masi C, Guidetti E, Negrini G, Paterini P, Bolondi L| title = Clinical and diagnostic aspects of gluten related disorders| journal = World J Clin Cases| volume = 3| issue = 3| pages = 275–84| date = Mar 16, 2015| pmid = 25789300|pmc= 4360499| doi = 10.12998/wjcc.v3.i3.275|type=Review| doi-access = free}}</ref><ref name=LionettiGatti2015>{{cite journal|vauthors=Lionetti E, Gatti S, Pulvirenti A, Catassi C|title=Celiac disease from a global perspective |journal=Best Pract Res Clin Gastroenterol |volume=29 |issue=3 |pages=365–79 |date=Jun 2015|pmid=26060103|doi=10.1016/j.bpg.2015.05.004|type=Review}}</ref><ref name=SaponeBai2012>{{cite journal |vauthors=Sapone A, Bai JC, Ciacci C, Dolinsek J, Green PH, Hadjivassiliou M, Kaukinen K, Rostami K, Sanders DS, Schumann M, Ullrich R, Villalta D, Volta U, Catassi C, Fasano A |title=Spectrum of gluten-related disorders: consensus on new nomenclature and classification |journal=BMC Medicine |volume=10 |pages=13 |year=2012 |pmid=22313950 |pmc=3292448 |doi=10.1186/1741-7015-10-13 |type=Review |doi-access=free }} {{open access}}</ref> Some suggested explanations for this increase include the following: the growing westernization of diets,<ref name=TovoliMasi /> the increasing use of wheat-based foods included in the [[Mediterranean diet]],<ref name=VoltaCaioQuestionsQuotation>{{cite journal|vauthors=Volta U, Caio G, Tovoli F, De Giorgio R|title=Non-celiac gluten sensitivity: questions still to be answered despite increasing awareness|journal=Cellular and Molecular Immunology|volume=10|issue=5|year=2013|pages=383–392 |doi=10.1038/cmi.2013.28|pmid=23934026|type=Review|pmc=4003198}}</ref><ref name=GuandaliniPolanco>{{cite journal|vauthors=Guandalini S, Polanco I|title=Nonceliac gluten sensitivity or wheat intolerance syndrome?|journal=J Pediatr|volume=166|issue=4|pages=805–11|date=Apr 2015|pmid=25662287|doi=10.1016/j.jpeds.2014.12.039|type=Review|quote=The increase in world-wide consumption of a Mediterranean diet, which includes a wide range of wheat-based foods, has possibly contributed to an alarming rise in the incidence of wheat (gluten?)-related disorders.1, 2 }}</ref> the progressive replacement of rice by wheat in many countries in Asia, the Middle East, and North Africa,<ref name=TovoliMasi /> the higher content of gluten in bread and bakery products due to the reduction of dough fermentation time,<ref name="VoltaCaioQuestions">{{cite journal |vauthors=Volta U, Caio G, Tovoli F, De Giorgio R |date=September 2013 |title=Non-celiac gluten sensitivity: questions still to be answered despite increasing awareness |journal=Cellular & Molecular Immunology |type=Review |volume=10 |issue=5 |pages=383–92 |doi=10.1038/cmi.2013.28 |pmc=4003198 |pmid=23934026 |quote=mechanization of farming and the growing industrial use of pesticides have favored the development of new types of wheat with a higher amount of toxic gluten peptides that cause the development of gluten-related disorders}}</ref><ref name="GobbettiGiuseppe2007">{{cite journal|vauthors=Gobbetti M, Giuseppe Rizzello C, Di Cagno R, De Angelis M |title=Sourdough lactobacilli and celiac disease |journal=Food Microbiol |volume=24 |issue=2 |pages=187–96 |date=Apr 2007 |pmid=17008163 |doi= 10.1016/j.fm.2006.07.014|type=Review}}</ref> and the development in recent years of new types of wheat with a higher amount of [[cytotoxicity|cytotoxic]] gluten [[peptide]]s,<ref name="VoltaCaioQuestions" /><ref name="Belderok">{{cite journal |author=Belderok B |date=2000 |title=Developments in bread-making processes |journal=Plant Foods Hum Nutr |type=Review |volume=55 |issue=1 |pages=1–86 |doi=10.1023/A:1008199314267 |pmid=10823487 |s2cid=46259398}}</ref>  However, a 2020 study that grew and analyzed 60 wheat cultivars from between 1891 and 2010 found no changes in albumin/globulin and gluten contents over time. "Overall, the harvest year had a more significant effect on protein composition than the cultivar. At the protein level, we found no evidence to support an increased [[immunostimulant|immunostimulatory]] potential of modern winter wheat."<ref name="Scherf">{{cite journal |last1=Pronin |first1=Darina |last2=Borner |first2=Andreas |last3=Weber |first3=Hans |last4=Scherf |first4=Ann |title=Wheat (''Triticum aestivum'' L.) Breeding from 1891 to 2010 Contributed to Increasing Yield and Glutenin Contents but Decreasing Protein and Gliadin Contents |journal=[[Journal of Agricultural and Food Chemistry]]|date=10 July 2020 |volume=68 |issue=46 |pages=13247–13256 |doi=10.1021/acs.jafc.0c02815|pmid=32648759 |bibcode=2020JAFC...6813247P |s2cid=220469138 }}</ref>

===Celiac disease===
{{Main article|Coeliac disease}}
[[File:Inflammed mucous layer of the intestinal villi depicting Celiac disease.jpg|thumb|Medical animation still showing flattened intestinal villi.]]
[[Celiac disease]] (CD) is a chronic, multiple-organ [[autoimmune disorder]] primarily affecting the [[small intestine]] caused by the ingestion of wheat, barley, rye, oats, and derivatives, that appears in [[genetic predisposition|genetically predisposed]] people of all ages.<ref name=":0">{{Cite journal|last1=Caio|first1=Giacomo|last2=Volta|first2=Umberto|last3=Sapone|first3=Anna|last4=Leffler|first4=Daniel A.|last5=De Giorgio|first5=Roberto|last6=Catassi|first6=Carlo|last7=Fasano|first7=Alessio|date=2019-07-23|title=Celiac disease: a comprehensive current review|journal=BMC Medicine|volume=17|issue=1|pages=142|doi=10.1186/s12916-019-1380-z |pmid=31331324|pmc=6647104 |doi-access=free }}</ref> CD is not only a gastrointestinal disease, because it may involve several organs and cause an extensive variety of non-gastrointestinal symptoms, and most importantly, it may be apparently asymptomatic.<ref name=Biesiekierski2017 /><ref name=WGO2016>{{cite web|url=http://www.worldgastroenterology.org/guidelines/global-guidelines/celiac-disease/celiac-disease-english|title=Celiac disease|date=July 2016|publisher=[[World Gastroenterology Organisation]] Global Guidelines|access-date=23 April 2017}}</ref> Many asymptomatic people become accustomed to living with a chronic bad health status as if it were normal, but they are able to recognize that they actually had symptoms related to celiac disease after starting a gluten-free diet and improvement occurs.<ref name=WGO2016 /><ref name=LudvigssonCard /><ref name=LionettiGatti2015 /> Added difficulties for diagnosis are the fact that serological markers ([[Anti-transglutaminase antibodies#Anti-tissue transglutaminase|anti-tissue transglutaminase]] [TG2]) are not always present<ref name=NEJM2012>{{cite journal|last1=Fasano|first1=A|last2=Catassi|first2=C|title=Clinical practice. Celiac disease.|journal=The New England Journal of Medicine|date=December 2012|volume=367|issue=25|pages=2419–26|pmid=23252527|doi=10.1056/NEJMcp1113994}}</ref> and many people may have minor mucosal lesions, without atrophy of the [[intestinal villi]].<ref name=BoldRostami>{{cite journal | vauthors = Bold J, Rostami K| title = Gluten tolerance; potential challenges in treatment strategies | journal = Gastroenterol Hepatol Bed Bench | volume = 4| issue = 2| pages = 53–7| date = 2011 | pmid = 24834157|pmc= 4017406}}</ref>

CD affects approximately 1–2% of the general population,<ref name=LundinWijmenga2015>{{cite journal|vauthors=Lundin KE, Wijmenga C|title=Coeliac disease and autoimmune disease-genetic overlap and screening|journal=Nat Rev Gastroenterol Hepatol|volume=12|issue=9|pages=507–15|date =Sep 2015|pmid=26303674|doi=10.1038/nrgastro.2015.136|s2cid=24533103}}</ref> but most cases remain unrecognized, undiagnosed and untreated, and at risk for serious long-term health complications.<ref name=LundinWijmenga2015 /><ref name=LionettiGatti2015 /><ref name=Fasano2005Pediatric>{{cite journal | author = Fasano A| title = Clinical presentation of celiac disease in the pediatric population | journal = Gastroenterology | volume = 128| issue = 4 Suppl 1| pages = S68–73| date = Apr 2005| pmid = 15825129 | doi = 10.1053/j.gastro.2005.02.015}}</ref><ref name=ElliBranchi>{{cite journal | vauthors = Elli L, Branchi F, Tomba C, Villalta D, Norsa L, Ferretti F, Roncoroni L, Bardella MT| title = Diagnosis of gluten related disorders: Celiac disease, wheat allergy and non-celiac gluten sensitivity | journal = World J Gastroenterol | volume = 21 | issue = 23 | pages = 7110–9 | date = Jun 2015 | pmid = 26109797 |pmc= 4476872 | doi =  10.3748/wjg.v21.i23.7110 | doi-access = free }}</ref> People may suffer severe disease symptoms and be subjected to extensive investigations for many years, before a proper diagnosis is achieved.<ref name=LudvigssonCard>{{cite journal | vauthors = Ludvigsson JF, Card T, Ciclitira PJ, Swift GL, Nasr I, Sanders DS, Ciacci C| title = Support for patients with celiac disease: A literature review | journal = United European Gastroenterol J | volume = 3 | issue = 2 | pages = 146–59 | date = Apr 2015 | pmid = 25922674 | pmc = 4406900 |doi = 10.1177/2050640614562599}}</ref> Untreated CD may cause [[malabsorption]], reduced quality of life, [[iron deficiency]], [[osteoporosis]], an increased risk of intestinal [[lymphoma]]s, and greater mortality.<ref name=LebwoholLudvigsson>{{cite journal | vauthors =Lebwohl B, Ludvigsson JF, Green PH | title = Celiac disease and non-celiac gluten sensitivity | journal = BMJ | volume = 351 | pages = h4347| date = Oct 2015 | pmid = 26438584|pmc= 4596973 | doi = 10.1136/bmj.h4347|type= Review }}</ref> CD is associated with some other autoimmune diseases, such as [[diabetes mellitus type 1]], [[thyroiditis]],<ref name=LundinWijmenga>{{cite journal | vauthors = Lundin KE, Wijmenga C| title = Coeliac disease and autoimmune disease-genetic overlap and screening| journal = Nat Rev Gastroenterol Hepatol| volume = 12| issue = 9| pages = 507–15| date = Sep 2015 | pmid = 26303674 | doi = 10.1038/nrgastro.2015.136| s2cid = 24533103}}</ref> [[ataxia|gluten ataxia]], [[psoriasis]], [[vitiligo]], [[autoimmune hepatitis]], [[dermatitis herpetiformis]], [[primary sclerosing cholangitis]], and more.<ref name=":0" /><ref name=LundinWijmenga />

CD with "classic symptoms", which include gastrointestinal manifestations such as chronic diarrhea and abdominal distention, malabsorption, loss of appetite, and impaired growth, is currently the least common presentation form of the disease and affects predominantly small children generally younger than two years of age.<ref name=":0" /><ref name=LudvigssonCard /><ref name=Fasano2005Pediatric />

CD with "non-classic symptoms" is the most common clinical type<ref name=LudvigssonCard /> and occurs in older children (over two years old),<ref name=LudvigssonCard /> adolescents, and adults.<ref name=LudvigssonCard /> It is characterized by milder or even absent gastrointestinal symptoms and a wide spectrum of non-intestinal manifestations that can involve any organ of the body, and very frequently may be completely asymptomatic<ref name=Fasano2005Pediatric /> both in children (at least in 43% of the cases<ref name=VriezingaSchweizer>{{cite journal |vauthors=Vriezinga SL, Schweizer JJ, Koning F, Mearin ML |title=Coeliac disease and gluten-related disorders in childhood |journal=Nature Reviews. Gastroenterology & Hepatology |volume= 12 |issue= 9 |pages= 527–36 |date= Sep 2015 |pmid=26100369 |doi=10.1038/nrgastro.2015.98 |s2cid=2023530 |type=Review}}</ref>) and adults.<ref name=Fasano2005Pediatric />

Asymptomatic CD (ACD) is present in the majority of affected patients and is characterized by the absence of classical gluten-intolerance signs, such as diarrhea, bloating, and abdominal pain. Nevertheless, these individuals very often develop diseases that can be related with gluten intake. Gluten can be degraded into several morphine-like substances, named [[gluten exorphin]]s. These compounds have proven opioid effects and could mask the deleterious effects of gluten protein on gastrointestinal lining and function.<ref>{{cite journal |last1=Pruimboom |first1=Leo |last2=de Punder |first2=Karin |title=The opioid effects of gluten exorphins: asymptomatic celiac disease |journal=Journal of Health, Population, and Nutrition |date=24 November 2015 |volume=33 |page=24 |doi=10.1186/s41043-015-0032-y |pmid=26825414 |pmc=5025969 | type=Review |doi-access=free }}</ref>

===Non-celiac gluten sensitivity===
{{Main article|Non-celiac gluten sensitivity}}

Non-celiac gluten sensitivity (NCGS) is described as a condition of multiple symptoms that improves when switching to a [[gluten-free diet]], after celiac disease and wheat allergy are excluded.<ref name=NijeboerBontkes>{{cite journal|last1=Mooney|first1=P|last2=Aziz|first2=I|last3=Sanders|first3=D|title=Non-celiac gluten sensitivity: clinical relevance and recommendations for future research|journal=Neurogastroenterology & Motility|date=2013|volume=25|issue=11|pages=864–871|doi=10.1111/nmo.12216|pmid=23937528|s2cid=9277897}}</ref><ref>{{cite journal|last1=Nijeboer|
first1=P|last2=Bontkes|first2=H|last3=Mulder|first3=C|last4=Bouma|first4=G|title=Non-celiac gluten sensitivity. Is it in the gluten or the grain?|journal=Journal of Gastrointestinal and Liver Disorders|date=2013|volume=22|issue=4|pages=435–40|pmid=24369326}}</ref> Recognized since 2010,<ref name=CatassiBai /><ref name=FasanoSapone2015>{{cite journal |last1=Fasano |first1=Alessio |last2=Sapone |first2=Anna |last3=Zevallos |first3=Victor |last4=Schuppan |first4=Detlef |title=Nonceliac Gluten Sensitivity |journal=Gastroenterology |date=May 2015 |volume=148 |issue=6 |pages=1195–1204 |doi=10.1053/j.gastro.2014.12.049 |pmid=25583468 |doi-access=free }}</ref> it is included among [[gluten-related disorders]].<ref name=CatassiBai /> Its [[pathogenesis]] is not yet well understood, but the activation of the innate immune system, the direct negative effects of gluten and probably other wheat components, are implicated.<ref name=FasanoSapone2015 /><ref name=ElliRoncoroni2015/>

NCGS is the most common syndrome of [[gluten intolerance]],<ref name=CatassiBai /><ref name=CzajaBulsa>{{cite journal | author = Czaja-Bulsa G | title = Non coeliac gluten sensitivity - A new disease with gluten intolerance | journal = Clin Nutr | volume = 34| issue = 2| pages = 189–94| date = Apr 2015| pmid = 25245857 | doi = 10.1016/j.clnu.2014.08.012| doi-access = free}}</ref> with a prevalence estimated to be 6-10%.<ref name=MolinaInfanteSantolaria>{{cite journal | vauthors = Molina-Infante J, Santolaria S, Montoro M, Esteve M, Fernández-Bañares F| title = [Non-celiac gluten sensitivity: a critical review of current evidence] [Article in Spanish] | journal = Gastroenterol Hepatol | volume = 37| issue = 6 | pages = 362–71 | date = 2014 | pmid = 24667093 | doi = 10.1016/j.gastrohep.2014.01.005}}</ref> NCGS is becoming a more common diagnosis, but its true prevalence is difficult to determine because many people self-diagnose and start a gluten-free diet, without having previously tested for celiac disease or having the dietary prescription from a physician.<ref name="Igbinedion2017">{{cite journal|vauthors=Igbinedion SO, Ansari J, Vasikaran A, Gavins FN, Jordan P, Boktor M, Alexander JS |title=Non-celiac gluten sensitivity: All wheat attack is not celiac |journal=World Journal of Gastroenterology |volume=23 |issue=20 |pages=7201–10 |date=Oct 2017 |pmid=29142467 |pmc=5677194 |doi=10.3748/wjg.v23.i40.7201 | type=Review |doi-access=free }}</ref> People with NCGS and gastrointestinal symptoms remain habitually in a "no man's land", without being recognized by the specialists and lacking the adequate medical care and treatment.<ref name=VerduArmstrong2009>{{cite journal| vauthors=Verdu EF, Armstrong D, Murray JA| title=Between celiac disease and irritable bowel syndrome: the "no man's land" of gluten sensitivity | journal=Am J Gastroenterol | year= 2009 | volume= 104 | issue= 6 | pages= 1587–94 | pmid=19455131 | doi=10.1038/ajg.2009.188 | pmc=3480312 | type= Review }}</ref> Most of these people have a long history of health complaints and unsuccessful consultations with numerous physicians, trying to get a diagnosis of celiac disease, but they are only labeled as [[irritable bowel syndrome]].<ref name=VerduArmstrong2009 /><ref name="mansueto-etal-2014" /> A consistent although undefined number of people eliminate gluten because they identify it as responsible for their symptoms and these improve with the [[gluten-free diet]], so they self-diagnose as NCGS.<ref name=VerduArmstrong2009 /><ref name="mansueto-etal-2014">{{cite journal|last1=Mansueto|first1=Pasquale|last2=Seidita|first2=Aurelio|last3=D'Alcamo|first3=Alberto|last4=Carroccio|first4=Antonio|title=Non-Celiac Gluten Sensitivity: Literature Review|journal=Journal of the American College of Nutrition|volume=33|issue=1|year=2014|pages=39–54 |doi=10.1080/07315724.2014.869996|pmid=24533607|type=Review|hdl=10447/90208 |hdl-access=free |s2cid=22521576 }}</ref>

People with NCGS may develop gastrointestinal symptoms, which resemble those of [[irritable bowel syndrome]] or [[wheat allergy]],<ref name=CatassiBai>{{cite journal | vauthors = Catassi C, Bai JC, Bonaz B, Bouma G, Calabrò A, Carroccio A, Castillejo G, Ciacci C, Cristofori F, Dolinsek J, Francavilla R, Elli L, Green P, Holtmeier W, Koehler P, Koletzko S, Meinhold C, Sanders D, Schumann M, Schuppan D, Ullrich R, Vécsei A, Volta U, Zevallos V, Sapone A, Fasano A| title = Non-Celiac Gluten sensitivity: the new frontier of gluten related disorders | journal = Nutrients | volume = 5| issue = 10| pages = 3839–53| date = Sep 2013 | pmid =24077239 |pmc= 3820047| doi = 10.3390/nu5103839| doi-access = free }}</ref><ref name=ElliRoncoroni2015 /> or a wide variety of non-gastrointestinal symptoms, such as [[headache]], chronic [[fatigue (medical)|fatigue]], [[fibromyalgia]], [[atopy|atopic diseases]], [[allergy|allergies]], [[neurological disorder|neurological diseases]], or [[mental disorder|psychiatric disorders]], among others.<ref name=LebwoholLudvigsson /><ref name=FasanoSapone2015 /><ref name=VoltaCaio2015>{{cite journal | vauthors = Volta U, Caio G, De Giorgio R, Henriksen C, Skodje G, Lundin KE| title = Non-celiac gluten sensitivity: a work-in-progress entity in the spectrum of wheat-related disorders | journal = Best Pract Res Clin Gastroenterol | volume = 29| issue = 3| pages = 477–91| date = Jun 2015| pmid = 26060112 | doi = 10.1016/j.bpg.2015.04.006}}</ref> The results of a 2017 study suggest that NCGS may be a chronic disorder, as is the case with celiac disease.<ref name=VoltaDeGiorgio2019 />

Besides gluten, additional components present in wheat, rye, barley, oats, and their derivatives, including other proteins called amylase-trypsin inhibitors (ATIs) and short-chain [[carbohydrates]] known as [[FODMAP]]s, may cause NCGS symptoms.<ref name=FasanoSapone2015 /> As of 2019, reviews conclude that although FODMAPs present in wheat and related grains may play a role in non-celiac gluten sensitivity, they only explain certain gastrointestinal symptoms, such as [[bloating]], but not the [[non-celiac gluten sensitivity#Extraintestinal|extra-digestive symptoms]] that people with non-celiac gluten sensitivity may develop, such as [[neurological disorder]]s, [[fibromyalgia]], psychological disturbances, and [[dermatitis]].<ref name=Verbeke2018>{{cite journal |last1=Verbeke |first1=K |title=Nonceliac Gluten Sensitivity: What Is the Culprit? |journal=Gastroenterology |date=February 2018 |volume=154 |issue=3 |pages=471–473 |doi=10.1053/j.gastro.2018.01.013 |pmid=29337156| quote=Although intolerance to fructans and other FODMAPs may contribute to NCGS, they may only explain gastrointestinal symptoms and not the extraintestinal symptoms observed in NCGS patients, such as neurologic dysfunction, psychological disturbances, fibromyalgia, and skin rash.15 Therefore, it is unlikely that they are the sole cause of NCGS.|doi-access=free }}</ref><ref name=VoltaDeGiorgio2019>{{cite journal| vauthors=Volta U, De Giorgio R, Caio G, Uhde M, Manfredini R, Alaedini A| title=Nonceliac Wheat Sensitivity: An Immune-Mediated Condition with Systemic Manifestations | journal=Gastroenterol Clin North Am | date= March 2019 | volume= 48 | issue= 1 | pages= 165–182 | pmid=30711208 | doi=10.1016/j.gtc.2018.09.012 | pmc=6364564 | type=Review |quote=Furthermore, a role for the FODMAP (eg, fructans) component of wheat as the sole trigger for symptoms is somewhat doubtful, because many patients with NCWS report resolution of symptoms after the withdrawal of wheat and related cereals, while continuing to ingest vegetables and fruits with high FODMAP content in their diets.59 On the whole, it is conceivable that more than one culprit may be involved in symptoms of NCWS (as they are currently defined), including gluten, other wheat proteins, and FODMAPs.60–62 }}</ref><ref name="FasanoSapone2015" /> ATIs may cause toll-like receptor 4 ([[TLR4]])-mediated intestinal [[inflammation]] in humans.<ref name="BaroneTroncone2014">{{cite journal|last1=Barone|first1=Maria|last2=Troncone|first2=Riccardo|last3=Auricchio|first3=Salvatore|title=Gliadin Peptides as Triggers of the Proliferative and Stress/Innate Immune Response of the Celiac Small Intestinal Mucosa|journal=International Journal of Molecular Sciences|volume=15|issue=11|year=2014|pages=20518–20537 |doi=10.3390/ijms151120518|pmid=25387079|type=Review|pmc=4264181|doi-access=free }}</ref><ref name="junker-etal-2012">{{cite journal|last1=Junker|first1=Y.|last2=Zeissig|first2=S.|last3=Kim|first3=S.-J.|last4=Barisani|first4=D.|last5=Wieser|first5=H.|last6=Leffler|first6=D. A.|last7=Zevallos|first7=V.|last8=Libermann|first8=T. A.|last9=Dillon|first9=S.|last10=Freitag|first10=T. L.|last11=Kelly|first11=C. P.|last12=Schuppan|first12=D.|author-link12=Detlef Schuppan|title=Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4|journal=Journal of Experimental Medicine|volume=209|issue=13|year=2012|pages=2395–2408 |doi=10.1084/jem.20102660|pmid=23209313|pmc=3526354}}</ref>

===Wheat allergy===
{{Main article|Wheat allergy}}

People can also experience adverse effects of wheat as result of a [[wheat allergy]]. <ref name=Costantino22/> 
As with most allergies, a wheat allergy causes the immune system to respond abnormally to a component of wheat that it treats as a threatening foreign body. This immune response is often time-limited and does not cause lasting harm to body tissues.<ref>{{cite web|url=http://www.cureceliacdisease.org/archives/faq/what-is-the-difference-between-gluten-intolerance-gluten-sensitivity-and-wheat-allergy|publisher=The University of Chicago Celiac Disease Center|title=What's the difference between celiac disease, gluten intolerance, non-celiac gluten sensitivity and wheat allergy?|date=2015|access-date=4 January 2015}}</ref> Wheat allergy and celiac disease are different disorders. <ref name=Costantino22/><ref name=ElliBranchi/><ref>{{cite web |url=http://www.food.gov.uk/multimedia/pdfs/allergyfactsheettwo.pdf |title=Food intolerance and coeliac disease |publisher=Food Standards Agency |date=September 2006 |access-date=8 September 2009 |archive-date=15 October 2012 |archive-url=https://web.archive.org/web/20121015113504/http://www.food.gov.uk/multimedia/pdfs/allergyfactsheettwo.pdf |url-status=dead }}</ref> Gastrointestinal symptoms of wheat allergy are similar to those of celiac disease and non-celiac gluten sensitivity, but there is a different interval between exposure to wheat and onset of symptoms. An allergic reaction to wheat has a fast onset (from minutes to hours) after the consumption of food containing wheat and could include [[anaphylaxis]].<ref name=NEJM2012 />

===Gluten ataxia===
[[File:Gluten ataxia eng.ogg|thumb|A male with gluten ataxia: previous situation and evolution after three months of gluten-free diet]]

[[Ataxia#Gluten ataxia|Gluten ataxia]] is an autoimmune disease triggered by the ingestion of gluten.<ref name="sapone-etal-2010-b">{{cite journal | vauthors = Sapone A, Bai JC, Ciacci C, Dolinsek J, Green PH, Hadjivassiliou M, Kaukinen K, Rostami K, Sanders DS, Schumann M, Ullrich R, Villalta D, Volta U, Catassi C, Fasano A | title = Spectrum of gluten-related disorders: consensus on new nomenclature and classification | journal = BMC Medicine | volume = 10 | pages = 13 | year = 2012 | pmid = 22313950 | pmc = 3292448 | doi = 10.1186/1741-7015-10-13 | type = Review | doi-access = free }}</ref> With gluten ataxia, damage takes place in the [[cerebellum]], the balance center of the brain that controls coordination and complex movements like walking, speaking and swallowing, with loss of [[Purkinje cell]]s. People with gluten ataxia usually present [[gait abnormality]] or incoordination and tremor of the upper limbs. Gaze-evoked [[nystagmus]] and other ocular signs of cerebellar dysfunction are common. [[Myoclonus]], palatal tremor, and [[opsoclonus myoclonus syndrome|opsoclonus-myoclonus]] may also appear.<ref name="HadjivassiliouSanders2015" />

Early diagnosis and treatment with a [[gluten-free diet]] can improve ataxia and prevent its progression. The effectiveness of the treatment depends on the elapsed time from the onset of the ataxia until diagnosis, because the death of [[Purkinje cells|neurons in the cerebellum]] as a result of gluten exposure is irreversible.<ref name="HadjivassiliouSanders2015" /><ref name="MitomaAdhikari2016">{{cite journal| vauthors=Mitoma H, Adhikari K, Aeschlimann D, Chattopadhyay P, Hadjivassiliou M, Hampe CS, et al | title=Consensus Paper: Neuroimmune Mechanisms of Cerebellar Ataxias | journal=Cerebellum | year= 2016 | volume= 15 | issue= 2 | pages= 213–32 | pmid=25823827 | doi=10.1007/s12311-015-0664-x | pmc=4591117 | type=Review }}</ref>

Gluten ataxia accounts for 40% of ataxias of unknown origin and 15% of all ataxias.<ref name="HadjivassiliouSanders2015">{{cite journal| vauthors=Hadjivassiliou M, Sanders DD, Aeschlimann DP| title=Gluten-related disorders: gluten ataxia | journal=Dig Dis | year= 2015 | volume= 33 | issue= 2 | pages= 264–8 | pmid=25925933 | doi=10.1159/000369509 | s2cid=207673823 | type=Review }}</ref><ref name="pmid12566288">{{cite journal | vauthors = Hadjivassiliou M, Grünewald R, Sharrack B, Sanders D, Lobo A, Williamson C, Woodroofe N, Wood N, Davies-Jones A | title = Gluten ataxia in perspective: epidemiology, genetic susceptibility and clinical characteristics | journal = Brain | volume = 126 | issue = Pt 3 | pages = 685–91 | date = March 2003 | pmid = 12566288 | doi = 10.1093/brain/awg050 | doi-access = free }}</ref> Less than 10% of people with gluten ataxia present any gastrointestinal symptom, yet about 40% have intestinal damage.<ref name="HadjivassiliouSanders2015" />

===Other neurological disorders===
In addition to gluten ataxia, gluten sensitivity can cause a wide spectrum of neurological disorders, which develop with or without the presence of digestive symptoms or intestinal damage.<ref name=ZisHadjivassiliou2019>{{cite journal| vauthors=Zis P, Hadjivassiliou M| title=Treatment of Neurological Manifestations of Gluten Sensitivity and Coeliac Disease | journal=Curr Treat Options Neurol | date= 26 February 2019 | volume= 21 | issue= 3 | pages= 10 | pmid=30806821 | doi=10.1007/s11940-019-0552-7 | type=Review | doi-access=free }}</ref> These include [[peripheral neuropathy]], [[epilepsy]], [[headache]], [[encephalopathy]], vascular [[dementia]], and various
[[movement disorder]]s ([[restless legs syndrome]], [[chorea]], [[parkinsonism]], [[Tourette syndrome]], [[tremor|palatal tremor]], [[myoclonus]], [[dystonia]], [[opsoclonus myoclonus syndrome]], [[paroxysmal attack|paroxysms]], [[dyskinesia]], myorhythmia, [[myokymia]]).<ref name=ZisHadjivassiliou2019 /><ref name=VinagreAragonGrunewald2018>{{cite journal| vauthors=Vinagre-Aragón A, Zis P, Grunewald RA, Hadjivassiliou M| title=Movement Disorders Related to Gluten Sensitivity: A Systematic Review | journal=Nutrients | year= 2018 | volume= 10 | issue= 8 | pages=  1034| pmid=30096784 | doi=10.3390/nu10081034 | pmc=6115931 | type=Review | doi-access=free }}</ref>

The diagnosis of underlying gluten sensitivity is complicated and delayed when there are no digestive symptoms. People who do experience gastrointestinal problems are more likely to receive a correct diagnosis and treatment. A [[gluten-free diet|strict gluten-free diet]] is the first-line treatment, which should be started as soon as possible. It is effective in most of these disorders. When dementia has progressed to an advanced degree, the diet has no beneficial effect. Cortical myoclonus appears to be treatment-resistant on both gluten-free diet and immunosuppression.<ref name=ZisHadjivassiliou2019 />