Non-celiac Wheat Sensitivity Patients Research Articles

Anemia in non-celiac wheat sensitivity: Prevalence and associated clinical and laboratory features.

Patients suffering from non-celiac wheat sensitivity (NCWS) frequently report extra-intestinal symptoms, such as anemia. We investigated the prevalence and associated clinical features of anemia in NCWS patients. Data from 244 NCWS patients, diagnosed by double-blind placebo-controlled wheat challenge, were retrospectively reviewed and compared with 2 control groups (celiac disease (CD) and irritable bowel syndrome (IBS)). Furthermore, 31 NCWS anemic patients were prospectively re-evaluated after at least 12 months on the "strict" wheat-free diet (WFD). Anemia prevalence in NCWS patients was 34.8% (mean hemoglobin 10.4±1.4g/dl), significantly higher than in IBS (17.4%, P=0.03), but not in CD ones. The NCWS group, on the whole, had sideropenic-like features with low serum iron and altered iron deposits. Both anemia prevalence and sideropenic-like features were more evident in CD than in NCWS patients, whereas only a few IBS subjects showed such features. Significant differences were found in anemic vs non-anemic NCWS patients as regards to female sex, diagnostic delay, poly/hypermenorrhea, iron deficiency, and higher TSH values. A long-term WFD significantly reduced anemia and improved iron metabolism. Microcytic/hypochromic anemia and altered iron metabolism occur frequently in NCWS and can be treated with a long-term strict WFD. NCWS should be included in differential diagnosis of anemic patients with "functional gastrointestinal troubles".

Evaluation of gut microbiota of iranian patients with celiac disease, non-celiac wheat sensitivity, and irritable bowel syndrome: are there any similarities?

Background and aimsIndividuals with celiac disease (CD), non-celiac wheat sensitivity (NCWS), and irritable bowel syndrome (IBS), show overlapping clinical symptoms and experience gut dysbiosis. A limited number of studies so far compared the gut microbiota among these intestinal conditions. This study aimed to investigate the similarities in the gut microbiota among patients with CD, NCWS, and IBS in comparison to healthy controls (HC).Materials and methodsIn this prospective study, in total 72 adult subjects, including CD (n = 15), NCWS (n = 12), IBS (n = 30), and HC (n = 15) were recruited. Fecal samples were collected from each individual. A quantitative real-time PCR (qPCR) test using 16S ribosomal RNA was conducted on stool samples to assess the relative abundance of Firmicutes, Bacteroidetes, Bifidobacterium spp., and Lactobacillus spp.ResultsIn all groups, Firmicutes and Lactobacillus spp. had the highest and lowest relative abundance respectively. The phylum Firmicutes had a higher relative abundance in CD patients than other groups. On the other hand, the phylum Bacteroidetes had the highest relative abundance among healthy subjects but the lowest in patients with NCWS. The relative abundance of Bifidobacterium spp. was lower in subjects with CD (P = 0.035) and IBS (P = 0.001) compared to the HCs. Also, the alteration of Firmicutes to Bacteroidetes ratio (F/B ratio) was statistically significant in NCWS and CD patients compared to the HCs (P = 0.05).ConclusionThe principal coordinate analysis (PCoA), as a powerful multivariate analysis, suggested that the investigated gut microbial profile of patients with IBS and NCWS share more similarities to the HCs. In contrast, patients with CD had the most dissimilarity compared to the other groups in the context of the studied gut microbiota.

Potential tolerability of ancient grains in non-celiac wheat sensitivity patients: A preliminary evaluation.

Background and aimsA wheat-free diet (WFD) represents the elective treatment for Non-celiac Wheat Sensitivity (NCWS) patients. Preliminary reports have shown a possible better tolerability of ancient grains in these subjects. The aim of this observational study was to evaluate the frequency of consumption of ancient grains and its correlation with clinical manifestations in NCWS patients.Methods223 NCWS patients were recruited, and their consumption of ancient grains was monitored. Participants were first administered a modified version of the Pavia/Biagi questionnaire to investigate their adherence to “modern WFD.” The appearance/exacerbation of symptoms after ingestion of ancient grains was then assessed with WHO toxicity grading scale.Results50.2% of the recruited patients reported consuming ancient grains before NCWS diagnosis; the diagnostic delay in this group was significantly higher than in non-consumers [median (range) 72 (6–612) vs. 60 months (3–684), P = 0.03] and these patients reported lower frequency of constipation (P = 0.04). Of the 107 patients with optimal adherence to modern WFD, 14 reported eating ancient wheat after NCWS diagnosis. Among them, 5 reported milder symptoms than those caused by modern wheat intake and 3 had an excellent tolerability without symptoms. Timilia/Tumminia variety was the most frequently used ancient grain.ConclusionsNCWS patients who consume ancient grains may receive a late diagnosis due to the possible clinical benefit (tolerability) obtained with these grains. Even after diagnosis, 10% of the patients still consumed ancient grains and had mild or no symptoms. Further studies are required to define the pathophysiological mechanism behind their putative greater tolerability.

Effect of The Gluten-Free Diet on Quality of Life, Gastrointestinal Symptoms and Immune System in Patients with Fibromyalgia and Non-Celiac Wheat Sensitivity. Fibromyalgia and Non-Celiac Wheat Sensitivity

Fibromyalgia (FM) is a clinical syndrome characterized by chronic pain. FM patients complain hyperalgesia and allodynia and they are frequently affected by Non Celiac Wheat Sensitivity (NCWS), a condition where gastrointestinal and extraintestinal symptoms are triggered by gluten and/or wheat ingestion. The gluten-free diet (GFD) impact was evaluated on fibromyalgia-related and gastrointestinal symptoms, health-related quality of life and immune response of patients with both FM and NCWS in order to detect a possible pathogenetic role of wheat/gluten in the triggering of the inflammatory process. Peripheral blood from 8 FM patients, 10 FM and NCWS patients (FM+NCWS patients), 13 NCWS patients and 14 healthy subjects (HS) was taken before and after 8 weeks of GFD and used for cytofluorimetric analysis. In all FM+NCWS patients after GFD almost all the clinical parameters used to evaluate musculoskeletal and systemic symptoms related to FM were reduced as well as intestinal symptoms present before GFD. Moreover, pro-inflammatory cytokines production (IFN-γ, TNF- α, IL-17 and IL-22) by T helper (Th) cells of FM+NCWS patients was reduced after GFD. Our findings suggest that gluten/wheat could represent one of the triggering factors of the inflammatory condition playing an important role in the etiopathogenesis of both FM and NCWS.

Frequency and Clinical Aspects of Neurological and Psychiatric Symptoms in Patients with Non-Celiac Wheat Sensitivity.

Background: Non-Celiac Wheat Sensitivity (NCWS) is characterized by both intestinal and extra-intestinal symptoms. The study aims to investigate the frequency of neuropsychiatric manifestations in NCWS patients and identify their clinical and demographic characteristics. Methods: 278 clinical records of NCWS patients, diagnosed by a double-blind placebo-controlled wheat challenge between 2006 and 2020, were retrospectively revised. Fifty-two patients with Celiac Disease (CD) and 54 patients with Irritable Bowel Syndrome (IBS) served as controls. Results: 87% of the NCWS patients had an IBS-like clinical presentation. The NCWS group showed a longer duration of symptoms, a higher frequency of positive serum anti-nuclear antibodies than CD and IBS patients, and a higher frequency of DQ2/DQ8 haplotypes and duodenal mucosa lymphocytosis than IBS controls. In addition, 50% of NCWS patients showed neuropsychiatric manifestations, while lower percentages were observed in CD (25%) and IBS (28%) controls. Neuropsychiatric symptoms in NCWS were more frequently associated with the male sex, longer duration of symptoms, and IBS-diarrhea-like clinical presentation. Conclusions: Our data suggest that in patients with IBS-like symptoms and neuropsychiatric manifestations of unknown cause, it could be useful to investigate a correlation of these symptoms with wheat ingestion to identify NCWS patients with this ‘atypical’ manifestation.

A Riddle, Wrapped in a Mystery, Inside an Enigma: Another Key to Wheat Sensitivity?

Nonceliac gluten sensitivity, or the more preferred term, nonceliac wheat sensitivity (NCWS), is a heterogenous condition that is diagnosed purely on the basis of symptoms and without an understanding of disease mechanisms and triggers. Biomarkers to identify patients and implementation of dietary treatment in a personalized manner are needed. Mansueto et al. identified a population of NCWS patients with associated autoimmune markers and immune activation. The presence of these markers could be used, in combination with other serological tests, to help develop better diagnostic strategies for NCWS.

Purification and Functional Characterization of the Chloroform/Methanol-Soluble Protein 3 (CM3) From Triticum aestivum in Drosophila melanogaster.

Non-celiac wheat sensitivity (NCWS) has been proposed to be an independent disease entity that is characterized by intestinal (e.g., abdominal pain, flatulence) and extra-intestinal symptoms (e.g., headache, fatigue), which are propagated following the ingestion of wheat products. Increased activity of amylase trypsin inhibitors (ATIs) in modern wheat is suggested to be major trigger of NCWS, while underlying mechanisms still remain elusive. Here, we aimed to generate and functionally characterize the most abundant ATI in modern wheat, chloroform/methanol-soluble protein 3 (CM3), in vitro and in Drosophila melanogaster. We demonstrate that CM3 displays α-glucosidase but not α-amylase or trypsin inhibitory activity in vitro. Moreover, fruit flies fed a sucrose-containing diet together with CM3 displayed significant overgrowth of intestinal bacteria in a sucrose-dependent manner while the consumption of α-amylase and α-glucosidase inhibitors was sufficient to limit bacterial quantities in the intestine. Notably, both CM3 and acarbose-treated flies showed a reduced lifespan. However, this effect was absent in amylase inhibitor (AI) treated flies. Together, given α-glucosidase is a crucial requirement for disaccharide digestion, we suggest that inhibition of α-glucosidase by CM3 enhances disaccharide load in the distal gastrointestinal tract, thereby promoting intestinal bacteria overgrowth. However, it remains speculative if this here described former unknown function of CM3 might contribute to the development of gastrointestinal symptoms observed in NCWS patients which are very similar to symptoms of patients with small intestinal bacterial overgrowth.

Tritordeum breads are well tolerated with preference over gluten-free breads in non-celiac wheat-sensitive patients and its consumption induce changes in gut bacteria.

The ingestion of wheat and other cereals are related to several gut disorders. The specific components responsible for non-celiac wheat-sensitivity (NCWS) may include gluten and other compounds. Tritordeum is a new cereal derived from crossing durum wheat with a wild barley species, which differs from bread wheat in its gluten composition. In the present work, we examined the response of NCWS patients to tritordeum bread Gastrointestinal symptoms as well as tritordeum acceptability, gluten immunogenic peptides excretion, and the composition and structure of the intestinal microbiota were evaluated. Gastrointestinal symptoms of the subjects showed no significant change between the gluten-free bread and the tritordeum bread. Participating subjects rated tritordeum bread higher than the gluten-free bread. Analysis of the bacterial gut microbiota indicated that tritordeum consumption does not alter the global structure and composition of the intestinal microbiota, and only a few changes in some butyrate-producing bacteria were observed. All the results derived from acceptability, biochemical and microbiological tests suggest that tritordeum may be tolerated by a sub-set of NCWS sufferers who do not require strict exclusion of gluten from their diet. © 2020 Society of Chemical Industry.

TNF-α, IL-17, and IL-22 production in the rectal mucosa of nonceliac wheat sensitivity patients: role of adaptive immunity.

In recent years, a new gluten- or wheat-related disease has emerged, a condition labeled "nonceliac gluten sensitivity" (NCGS) or "nonceliac wheat sensitivity" (NCWS). NCWS pathogenesis is still uncertain and attributed to very different mechanisms. We aimed to study the different T-lymphocyte subsets in the rectal mucosa of NCWS patients to demonstrate the possible contribution of adaptative immune response. Twelve patients (11 women, 1 man, age range 23-61 yr, median 32 yr) with a definitive diagnosis of NCWS were recruited at random for the present study. They underwent rectal endoscopy with multiple mucosal biopsies at the end of a double-blind placebo-controlled (DBPC) wheat challenge when they reported the reappearance of the symptoms. As controls we included 11 "healthy patients", sex- and age-matched with the patients who underwent colonoscopy evaluation for rectal bleeding due to hemorrhoids. Cells freshly obtained from rectal tissue were stained to detect anti-CD45, anti-CD3, anti-CD4, and anti-CD8. Furthermore, intracellular staining was performed with anti-tumor necrosis factor (TNF)-α, anti-interleukin (IL)-17, and anti-IL-22. Production of TNF-α by CD45+, CD3+, CD4+, and CD8+ cells, as well as of IL-17 by CD4+ cells, was higher in the rectal tissue of NCWS patients than in controls. On the contrary, IL-22 production by CD8+ cells was lower in NCWS patients than in the controls. In NCWS patients diagnosed by DBPC wheat challenge, there is a complex immunological activation, with a significant role for the adaptive response.NEW & NOTEWORTHY Nonceliac wheat sensitivity (NCWS) is a syndrome characterized by symptoms triggered by gluten intake. The pathogenesis is still uncertain. Studies have shown a role for innate immunity. We demonstrated that production of TNF-α by CD45+, CD3+, CD4+, and CD8+ cells and of IL-17 by CD4+ cells is higher in the rectal tissue of NCWS patients than in controls. We clearly demonstrated that in patients with NCWS there is a significant role for the adaptive response.

An Exploratory Gene Expression Study of the Intestinal Mucosa of Patients with Non-Celiac Wheat Sensitivity.

Non-celiac wheat sensitivity (NCWS) is a recently recognized syndrome triggered by a gluten-containing diet. The pathophysiological mechanisms engaged in NCWS are poorly understood and, in the absence of laboratory markers, the diagnosis relies only on a double-blind protocol of symptoms evaluation during a gluten challenge. We aimed to shed light on the molecular mechanisms governing this disorder and identify biomarkers helpful to the diagnosis. By a genome-wide transcriptomic analysis, we investigated gene expression profiles of the intestinal mucosa of 12 NCWS patients, as well as 7 controls. We identified 300 RNA transcripts whose expression differed between NCWS patients and controls. Only 37% of these transcripts were protein-coding RNA, whereas the remaining were non-coding RNA. Principal component analysis (PCA) and receiver operating characteristic curves showed that these microarray data are potentially useful to set apart NCWS from controls. Literature and network analyses indicated a possible implication/dysregulation of innate immune response, hedgehog pathway, and circadian rhythm in NCWS. This exploratory study indicates that NCWS can be genetically defined and gene expression profiling might be a suitable tool to support the diagnosis. The dysregulated genes suggest that NCWS may result from a deranged immune response. Furthermore, non-coding RNA might play an important role in the pathogenesis of NCWS.

An explorative study identifies miRNA signatures for the diagnosis of non-celiac wheat sensitivity.

Non-celiac wheat sensitivity (NCWS), also referred to as non-celiac gluten sensitivity, is a recently described disorder triggered by wheat/gluten ingestion. NCWS elicits a wide range of symptoms including diarrhoea, intestinal discomfort, and fatigue in analogy with other wheat/gluten-related disorders and celiac disease in particular. From the pathological standpoint, NCWS patients only have a slight increase of intraepithelial lymphocytes, while antibodies to tissue transglutaminase (tTG) and villous atrophy, otherwise diagnostic features of celiac disease, are absent. To date, the diagnosis of NCWS relies on symptoms and exclusion of confounding diseases, since biomarkers are not yet available. Here, the expression levels of selected miRNAs were examined in duodenal biopsies and peripheral blood leukocytes collected from newly diagnosed patients with NCWS and, as controls, from patients with celiac disease and gluten-independent gastrointestinal problems. We identified a few miRNAs whose expression is higher in the intestinal mucosa of patients affected by NCWS in comparison to control patients affect by gluten-independent dyspeptic symptoms (Helicobacter pylori-negative) and celiac disease. The present study provided the first evidence that NCWS patients have a characteristic miRNA expression patterns, such peculiarity could be exploited as a biomarker to the diagnosis of this disease.

Abdominal Ultrasound Does Not Reveal Significant Alterations in Patients With Nonceliac Wheat Sensitivity.

The goal of this study was (A) to evaluate abdominal ultrasound signs in nonceliac wheat sensitivity (NCWS) patients for features useful in diagnosis and (B) to compare these aspects with those of celiac patients to assess whether ultrasound can be useful in the differential diagnosis between NCWS and celiac disease (CD). NCWS diagnosis is difficult as no biomarkers of this condition have as yet been identified. In CD ultrasound aspects have been identified that have a good diagnostic accuracy. We prospectively recruited 45 NCWS patients (11 males, 34 females; mean age 35.7 y). Three control groups were included: (A) 99 age-matched CD patients; (B) 18 patients with seronegative CD; (C) 50 patients with irritable bowel syndrome (IBS) who did not improve on a wheat-free diet. NCWS diagnosis was confirmed on the basis of an elimination diet and double-blind placebo-controlled (DBPC) challenge. Ultrasound sign investigation included: dilatation of the small bowel loops, thickening of the small bowel wall, hyperperistalsis, enlarged mesenteric lymph nodes, ascites, hyposplenism, altered diameter of the portal vein. NCWS patients showed a low frequency of pathologic ultrasound findings. Dilated or thickened loops appeared more often in CD patients than in NCWS patients (88.8% vs. 20%; P<0.0001). These US signs were significantly more frequent in seronegative CD than in NCWS patients (both P<0.0001), whereas no difference was found between NCWS patients and IBS controls. In NCWS patients' ultrasound does not show a characteristic pattern which could be helpful for diagnosis. However, US can be useful to differentiate between NCWS and CD patients and especially those with seronegative CD. (ClinicalTrials.gov NCT03017274).

Long term effects of gluten-free diet in non-celiac wheat sensitivity

Information about the clinical outcome of patients with non-celiac wheat sensitivity (NCWS) treated with gluten-free diet (GFD) derive from studies assessing the symptom response in the first few weeks of treatment. We aimed to evaluate the clinical response to the GFD and the quality of life (QoL) of NCWS patients in the long term. Forty-four NCWS (diagnosed according to the Salerno criteria) participated in the study. Participants rated their symptoms according to a 0-10 scale patients and filled in a QoL questionnaire (CDQ) before the beginning of the GFD and during a follow-up evaluation performed after at least one year. To assess the reliability of the questionnaire we also included a control group of 43 matched patients with celiac disease (CD). Upon diagnosis, NCWS patients had a high prevalence of intestinal and extraintestinal symptoms. Also, most symptoms were described as severe and the QoL questionnaire showed high scores. On follow-up, both prevalence and severity of the most common symptoms were significantly reduced. However, persistent intestinal and extraintestinal symptoms of mild severity were found in 65.9 and 72.7% of NCWS patients. In comparison, in the CD group, the prevalence was lower (32.6 and 23.2% respectively) and consistent with previous studies. The analyses of the determinant of QoL showed that, upon diagnosis, NCWS patients had higher scores in the CDQ "gastrointestinal symptoms" (p<0.001), "emotional aspects" (p<0.001) and "social problems" (p<0.001) subclasses compared to CD patients. After the GFD, NCWS and CD patients shared similar scores in all of the subclasses. A significant proportion of NCWS patients still complains of intestinal and extraintestinal symptoms, even if significantly attenuated by the GFD, even years after the diagnosis. A comprehensive nutritional evaluation of these patients is required to further improve their symptoms and their QoL.

ContactDermatitisDuetoNickelAllergyinPatients SufferingfromNon-CeliacWheatSensitivity.

Background: Non-celiac wheat sensitivity (NCWS) is a new clinical entity in the world of gluten-related diseases. Nickel, the most frequent cause of contact allergy, can be found in wheat and results in systemic nickel allergy syndrome and mimics irritable bowel syndrome (IBS). Objective: To evaluate the frequency of contact dermatitis due to nickel allergy in NCWS patients diagnosed by a double-blind placebo-controlled (DBPC) challenge, and to identify the characteristics of NCWS patients with nickel allergy. Methods: We performed a prospective study of 60 patients (54 females, 6 males; mean age 34.1 ± 8.1 years) diagnosed with NCWS from December 2014 to November 2016; 80 age- and sex-matched subjects with functional gastrointestinal symptoms served as controls. Patients reporting contact dermatitis related to nickel-containing objects underwent nickel patch test (Clinicaltrials.gov registration number: NCT02750735). Results: Six out of sixty patients (10%) with NCWS suffered from contact dermatitis and nickel allergy and this frequency was statistically higher (p = 0.04) than observed in the control group (5%). The main clinical characteristic of NCWS patients with nickel allergy was a higher frequency of cutaneous symptoms after wheat ingestion compared to NCWS patients who did not suffer from nickel allergy (p < 0.0001). Conclusions: Contact dermatitis and nickel allergy are more frequent in NCWS patients than in subjects with functional gastrointestinal disorders; furthermore, these patients had a very high frequency of cutaneous manifestations after wheat ingestion. Nickel allergy should be evaluated in NCWS patients who have cutaneous manifestations after wheat ingestion.

Predominance of Type 1 Innate Lymphoid Cells in the Rectal Mucosa of Patients With Non-Celiac Wheat Sensitivity: Reversal After a Wheat-Free Diet.

OBJECTIVES:Non-celiac wheat sensitivity (NCWS) is defined as a reaction to ingested wheat after exclusion of celiac disease and wheat allergy. As its pathogenesis is incompletely understood, we evaluated the inflammatory response in the rectal mucosa of patients with well-defined NCWS.METHODS:The prospective study included 22 patients with irritable bowel syndrome (IBS)-like clinical presentation, diagnosed with NCWS by double-blind placebo-controlled challenge. Eight IBS patients not improving on wheat-free diet were used as controls. Two weeks after oral challenge was performed with 80 grams of wheat daily, cells were isolated from rectal biopsies and thoroughly characterized by fluorescence-activated cell sorting analysis for intracellular cytokines and surface markers.RESULTS:Rectal biopsies from wheat-challenged NCWS patients showed that a significant mucosal CD45+ infiltrate consisted of CD3+ and CD3− lymphocytes, with the latter spontaneously producing more interferon (IFN)-γ than IBS controls. About 30% of IFN-γ-producing CD45+ cells were T-bet+, CD56−, NKP44−, and CD117−, defining them as a type-1 innate lymphoid cells (ILC1). IFN-γ-producing ILC1 cells significantly decreased in 10 patients analyzed 2 weeks after they resumed a wheat-free diet.CONCLUSIONS:These data indicate that, in patients with active NCWS, IFN-γ-producing ILC1 cells infiltrate rectal mucosa and support a role for this innate lymphoid cell population in the pathogenesis of NCWS.

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Non-Celiac Wheat Sensitivity as an Allergic Condition: Personal Experience and Narrative Review

Non-celiac wheat sensitivity (NCWS) is a newly described clinical entity characterized by symptoms, which can involve the gastrointestinal tract, the nervous system, the skin, and other organs. There is little data on the pathogenesis of NCWS and it is probable that different pathogenic mechanisms are involved in the different clinical manifestations of the disease. The only common denominator of NCWS "syndrome" is wheat consumption: the symptoms disappear on exclusion of wheat from the diet, and reappear on wheat consumption. The objective of this study was to review our prior data regarding NCWS and to review relevant medical literature regarding NCWS, with particular attention to the hypothesis that NCWS patients could suffer from non-immunoglobulin E (IgE)-mediated wheat allergy. We reviewed our data on 276 patients diagnosed with NCWS by means of double-blind placebo-controlled (DBPC) wheat challenge. The data indicating a possible wheat allergy diagnosis were examined and other data in the literature were reviewed; we review the role of serum immunoglobulin G antibodies and the basophil activation assay in food allergy, and the histology findings in the food allergy diagnosis. The comparison between patients suffering from NCWS and presenting with irritable bowel syndrome (IBS) and controls with IBS not due to NCWS showed that NCWS was characterized by: a personal history of food allergy in the pediatric age (0.01), coexistent atopic diseases (0.0001), positive serum anti-gliadin (0.0001) and anti-betalactoglobulin (0.001) antibodies, positive cytofluorimetric assay revealing in vitro basophil activation by food antigens (0.0001), and a presence of eosinophils in the intestinal mucosa biopsies (0.0001). Patients with NCWS and multiple food sensitivity show several clinical, laboratory, and histological characteristics that suggest they might be suffering from non-IgE-mediated food allergy. However, other pathogenic mechanisms need to be considered.