Nonceliac Gluten Sensitivity: What Is the Culprit?
2018; Elsevier BV; Volume: 154; Issue: 3 Linguagem: Inglês
10.1053/j.gastro.2018.01.013
ISSN1528-0012
Autores Tópico(s)Whipple's Disease and Interleukins
ResumoSee "Fructan, rather than gluten, induces symptoms in patients with self-reported non-celiac gluten sensitivity," by Skodje GI, Sarna VK, Minelle IH, et al, on page 529. See "Fructan, rather than gluten, induces symptoms in patients with self-reported non-celiac gluten sensitivity," by Skodje GI, Sarna VK, Minelle IH, et al, on page 529. In 1978, the term nonceliac gluten sensitivity (NCGS) was coined in a case report describing the resolution of persistent gastrointestinal symptoms in a patient (in which celiac disease had been excluded) with the adoption of a gluten-free diet.1Ellis A. Linaker B.D. Non-coeliac gluten sensitivity?.Lancet. 1978; 1: 1358-1359Abstract PubMed Scopus (89) Google Scholar Currently, NCGS has been defined as a clinical entity induced by the ingestion of gluten leading to intestinal and/or extraintestinal symptoms that resolve once the gluten-containing foodstuff is eliminated from the diet and when celiac disease and wheat allergy have been ruled out.2Fasano A. Sapone A. Zevallos V. et al.Nonceliac gluten sensitivity.Gastroenterology. 2015; 148: 1195-1204Abstract Full Text Full Text PDF PubMed Scopus (249) Google Scholar The main gluten-containing cereals are wheat, barley, and rye. Whereas the adaptive immune system is involved in celiac disease, NCGS was shown to be mediated by an innate immune response to gluten-containing food.3Sapone A. Lammers K.M. Mazzarella G. et al.Differential mucosal IL-17 expression in two gliadin-induced disorders: gluten sensitivity and the autoimmune enteropathy celiac disease.Int Arch Allergy Immunol. 2010; 152: 75-80Crossref PubMed Scopus (209) Google Scholar Nevertheless, it remains highly controversial whether the symptoms of NCGS are effectively due to consumption of gluten proteins. The current study of Skodje et al4Skodje G.I. Sarna V.K. Minelle I.H. et al.Fructan, rather than gluten, induces symptoms in patients with self-reported non-celiac gluten sensitivity.Gastroenterology. 2018; 154: 529-539Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar found no evidence for induction of symptoms by consumption of gluten in participants with self-reported NCGS and rather attributed symptoms to the fructans present in wheat. These data confirm the results of a previous study that failed to demonstrate specific or dose-dependent effects of gluten in a placebo-controlled cross-over rechallenge study in NCGS patients on a low FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) diet.5Biesiekierski J.R. Peters S.L. Newnham E.D. et al.No effects of gluten in patients with self-reported non-celiac gluten sensitivity after dietary reduction of fermentable, poorly absorbed, short-chain carbohydrates.Gastroenterology. 2013; 145: 320-328Abstract Full Text Full Text PDF PubMed Scopus (623) Google Scholar Similarly, other studies identified only 5% and 14%, respectively, of the participants as responders to gluten in double-blind placebo controlled trials, suggesting that factors others than gluten are implicated in NCGS.6Di Sabatino A. Volta U. Salvatore C. et al.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: 1604-1612Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar, 7Elli L. Tomba C. Branchi F. et al.Evidence for the presence of non-celiac gluten sensitivity in patients with functional gastrointestinal symptoms: results from a multicenter randomized double-blind placebo-controlled gluten challenge.Nutrients. 2016; 8: 84Crossref PubMed Scopus (139) Google Scholar Therefore, some authors suggested that the term nonceliac wheat sensitivity is more appropriate than nonceliac gluten sensitivity.8Carroccio A. Rini G. Mansueto P. Non-celiac wheat sensitivity is a more appropriate label than non-celiac gluten sensitivity.Gastroenterology. 2014; 146: 320-321Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar However, because the effects are not limited to wheat but also apply for barley and rye, this nomenclature is confusing and debatable. In addition to gluten, other components of wheat, rye and barley have been identified as potential culprits for the induction of symptoms, including FODMAPs and α-amylase-trypsin inhibitors (ATIs; Figure 1). In this issue of Gastroenterology, Skodje et al4Skodje G.I. Sarna V.K. Minelle I.H. et al.Fructan, rather than gluten, induces symptoms in patients with self-reported non-celiac gluten sensitivity.Gastroenterology. 2018; 154: 529-539Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar carefully investigated the contribution of gluten and FODMAPs in the induction of symptoms. The participants (n = 59) in this randomized, placebo-controlled, cross-over study were all on a gluten-free diet and consumed daily 1 muesli bar containing either 5.7 g gluten (but not fructans) or 2.1 g fructans (but no gluten) or placebo (neither gluten nor fructans). Each intervention period lasted 7 days and washout periods were at least 7 days. Gastrointestinal symptoms as well as quality of life, anxiety and depression, and fatigue were recorded before and after each intervention period using validated questionnaires. After correction for multiple testing, gastrointestinal symptoms were borderline significantly higher after intervention with fructans compared with gluten (P = .049). The authors concluded that fructans are more likely to induce the NCGS symptoms than gluten, despite the very small differences between the 3 interventions. Fructans are nondigestible but fermentable carbohydrates that belong to the class of FODMAPs. In contrast to inulin-type fructans, the fructans in cereal grains are branched and contain fructosyl units with both β(2-1) and β(2-6) linkages.9Verspreet J. Dornez E. Van den Ende W. et al.Cereal grain fructans: Structure, variability and potential health effects.Trends Food Sci Technol. 2015; 43: 32-42Crossref Scopus (75) Google Scholar The average degree of polymerization amounts to 4 for wheat flower and barley, whereas oat and rye kernels contain higher degree of polymerization fructans. Among the cereal grains, fructan concentrations are highest in rye (3.6%-6.6% of dry matter). Concentrations in wheat vary between 0.7% and 2.9%, whereas barley contains only trace amounts of fructans.10Åman P. Hesselman K. Tilly A.-C. The variation in chemical composition of Swedish barleys.J Cereal Sci. 1985; 3: 73-77Crossref Scopus (58) Google Scholar The daily intake of fructans in a Western diet has been estimated between 1 and 10 g, depending on geographic and demographic parameters.11van Loo J. Coussement P. de Leenheer L. et al.On the presence of inulin and oligofructose as natural ingredients in the western diet.Crit Rev Food Sci Nutr. 1995; 35: 525-552Crossref PubMed Scopus (679) Google Scholar Fructans are considerably degraded during some types of cereal processing such as bread baking because of the yeast enzyme yeast invertase.9Verspreet J. Dornez E. Van den Ende W. et al.Cereal grain fructans: Structure, variability and potential health effects.Trends Food Sci Technol. 2015; 43: 32-42Crossref Scopus (75) Google Scholar FODMAPs trigger gastrointestinal symptoms in subjects who are hypersensitive to luminal distention12Major G. Pritchard S. Murray K. et al.Colon hypersensitivity to distension, rather than excessive gas production, produces carbohydrate-related symptoms in individuals with irritable bowel syndrome.Gastroenterology. 2017; 152: 124-133Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar owing to osmotic effects, attracting water to the intestinal lumen,13Barrett J.S. Gearry R.B. Muir J.G. et al.Dietary poorly absorbed, short-chain carbohydrates increase delivery of water and fermentable substrates to the proximal colon.Aliment Pharmacol Ther. 2010; 31: 874-882PubMed Google Scholar and bacterial fermentation, resulting in (excessive) gas production.14Shepherd S.J. Lomer M.C. Gibson P.R. Short-chain carbohydrates and functional gastrointestinal disorders.Am J Gastroenterol. 2013; 108: 707-717Crossref PubMed Scopus (202) Google Scholar As such, the immune system is not involved in symptom generation, and the symptoms should be classified as food intolerance rather than food sensitivity. 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.15Aziz I. Hadjivassiliou M. Sanders D.S. The spectrum of noncoeliac gluten sensitivity.Nat Rev Gastroenterol Hepatol. 2015; 12: 516-526Crossref PubMed Scopus (57) Google Scholar Therefore, it is unlikely that they are the sole cause of NCGS. ATIs are plant-based proteins that make up not more than 4% of the wheat proteins.16Altenbach S.B. Vensel W.H. Dupont F.M. The spectrum of low molecular weight alpha-amylase/protease inhibitor genes expressed in the US bread wheat cultivar Butte 86.BMC Res Notes. 2011; 4: 242Crossref PubMed Scopus (74) Google Scholar They protect the plant against pests and parasites by inhibiting their digestive enzymes. Breeding of wheat varieties that are high yielding and highly pest resistant has led to increasing amounts of ATIs in modern hexaploid wheat cultivars.17Zevallos V.F. Raker V. Tenzer S. et al.Nutritional wheat amylase-trypsin inhibitors promote intestinal inflammation via activation of myeloid cells.Gastroenterology. 2017; 152: 1100-1113.e12Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar Daily consumption is estimated at about 0.5 to 1.5 g of ATIs per day.18Schuppan D. Pickert G. Ashfaq-Khan M. et al.Non-celiac wheat sensitivity: differential diagnosis, triggers and implications.Best Pract Res Clin Gastroenterol. 2015; 29: 469-476Crossref PubMed Scopus (89) Google Scholar Because of their intrachain disulfide bonds, they resist proteolytic degradation in the human intestine. Those ATIs are potent activators of innate immune cells, including dendritic cells, monocytes, and macrophages via stimulation of Toll-like receptor 4.19Junker Y. Zeissig S. Kim S.J. et al.Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of Toll-like receptor 4.J Exp Med. 2012; 209: 2395-2408Crossref PubMed Scopus (489) Google Scholar Toll-like receptor 4 activation induces the release of several proinflammatory cytokines and chemokines initiating in this way an inflammatory response. A recent study in mice demonstrated that ATIs exert an adjuvant effect on preexisting inflammation induced by DSS.17Zevallos V.F. Raker V. Tenzer S. et al.Nutritional wheat amylase-trypsin inhibitors promote intestinal inflammation via activation of myeloid cells.Gastroenterology. 2017; 152: 1100-1113.e12Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar Subsequent potentiation of adaptive immune reactions by migration of dendritic cells to mesenteric lymph nodes and contact with already primed T cells might also worsen inflammation at extraintestinal sites. This mechanism might explain the exacerbation of inflammation upon ingestion of ATI-containing grains in patients with preexisting diseases, whereas the majority of healthy adults will not develop symptoms. At present, studies directly comparing modern wheat with high ATI content with ancient cultivars like Einkorn and Emmer that contain low levels of ATIs in NCGS are lacking. To better support the role of ATIs as triggers of NCGS, additional human trials are required using such varieties or ATI-free diets. To improve the clinical management of patients with NCGS, the causative factor(s) needs to be identified and studies, like that of Skodje et al,4Skodje G.I. Sarna V.K. Minelle I.H. et al.Fructan, rather than gluten, induces symptoms in patients with self-reported non-celiac gluten sensitivity.Gastroenterology. 2018; 154: 529-539Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar that carefully disentangle the contribution of the different suspected components in cereal grains are highly warranted. They might stimulate the food industry to develop adapted food products eliminating the need for gluten-free diets for NCGS patients. Adoption of a gluten-free diet might reduce the consumption of cereal fiber or whole grains, affecting cardiovascular risk,20Lebwohl B. Cao Y. Zong G. et al.Long term gluten consumption in adults without celiac disease and risk of coronary heart disease: prospective cohort study.BMJ. 2017; 357: j1892Crossref PubMed Scopus (125) Google Scholar and should therefore not be encouraged in subjects without celiac disease. Fructan, Rather Than Gluten, Induces Symptoms in Patients With Self-Reported Non-Celiac Gluten SensitivityGastroenterologyVol. 154Issue 3PreviewNon-celiac gluten sensitivity is characterized by symptom improvement after gluten withdrawal in absence of celiac disease. The mechanisms of non-celiac gluten sensitivity are unclear, and there are no biomarkers for this disorder. Foods with gluten often contain fructans, a type of fermentable oligo-, di-, monosaccharides and polyols. We aimed to investigate the effect of gluten and fructans separately in individuals with self-reported gluten sensitivity. Full-Text PDF Covering the CoverGastroenterologyVol. 154Issue 3PreviewIn a randomized, double-blind, placebo-controlled crossover trial among patients with nonceliac gluten hypersensitivity, fructan, but not gluten, was associated with higher irritable bowel syndrome scores. Full-Text PDF
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