Accepted Manuscript. Duodenal and rectal eosinophilia are new biomarkers of non-celiac gluten sensitivity

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Accepted Manuscript Duodenal and rectal eosinophilia are new biomarkers of non-celiac gluten sensitivity M. Ellionore Järbrink-Sehgal, Nicholas J. Talley PII: S1542-3565(18)31316-8 DOI: https://doi.

1 Accepted Manuscript Duodenal and rectal eosinophilia are new biomarkers of non-celiac gluten sensitivity M. Ellionore Järbrink-Sehgal, Nicholas J. Talley PII: S (18) DOI: Reference: YJCGH To appear in: Clinical Gastroenterology and Hepatology Accepted Date: 24 November 2018 Please cite this article as: Järbrink-Sehgal ME, Talley NJ, Duodenal and rectal eosinophilia are new biomarkers of non-celiac gluten sensitivity, Clinical Gastroenterology and Hepatology (2018), doi: doi.org/ /j.cgh This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

2 Title: Duodenal and rectal eosinophilia are new biomarkers of non-celiac gluten sensitivity Editorial on manuscript CGH-D R3 Authors: M. Ellionore Järbrink-Sehgal and Nicholas J. Talley Correspondence: M. Ellionore Järbrink-Sehgal, Baylor College of Medicine, Michael E. DeBakey VA Medical Center, 2002 Holcombe Blvd, Houston, TX Author contributions: M. Ellionore Jarbrink-Sehgal, M.D.- Drafting of the manuscript Nicholas J. Talley, M.D., Ph.D.- Critical revision of manuscript. Disclosures: MEJS: none. NJT: grant/research support: Rome Foundation; Abbott Pharmaceuticals; Datapharm; Pfizer; Salix (Irritable bowel syndrome); Prometheus Laboratories Inc (Irritable bowel syndrome (IBS Diagnostic)); Commonwealth Diagnostics International (Biomarkers for FGIDs); Janssen (Constipation). Consultant/Advisory Boards: Adelphi Values (Functional dyspepsia (patient-reported outcome measures)); GI therapies (Chronic constipation (Rhythm IC)); Allergens PLC; Napo Pharmaceutical; Outpost Medicine; Samsung Bioepis; Yuhan (IBS); Synergy (IBS); Theravance (Gastroparesis); IM Health Sciences (dyspepsia). Patent Holder: Biomarkers of irritable bowel syndrome, Licensing Questionnaires (Mayo Clinic Talley Bowel Disease Questionnaire, Mayo Dysphagia Questionnaire); Nestec European Patent (Application No ); Singapore Provisional Patent (NTU Ref: TD/129/17 Microbiota Going gluten free is thought by many in the community to be the healthy option. Indeed, gluten free diet industry represents a $6 billion USD global business. (1) There continues to be

3 heightened coverage in the mainstream and social media about gluten and health. It is therefore not surprising that in population-based studies, 7% to 15% individuals report symptoms related to wheat ingestion in the absence of celiac disease. (2) Of those reporting symptoms related to gluten, about one in six have this suspicion confirmed by double-blind placebo-controlled (DBPC) wheat challenge, referred to as non-celiac gluten/wheat sensitivity (NCGS). NCGS is a clinical condition associated with as many as 24 intestinal and extra-intestinal symptoms, including bloating, early satiety, fatigue and headache. (3) By definition, there should be no evidence of celiac disease or wheat allergy (3) in order for an individual to be diagnosed as having NCGS. Established diagnostic biomarkers for NCGS are lacking. New insights on NCGS, including identification of a possible tissue biomarker (increased eosinophils in the duodenum and rectum), are published in this issue of Clinical Gastroenterology and Hepatology by Carraccio and colleagues. (4) Most of the literature regarding wheat sensitivity assumes NCGS to be a new and distinct disease (5), but many problems exist with this assertion. First, the definite exclusion of celiac disease can be difficult. In patients who presented with positive celiac genetics but negative celiac serology and lymphocytic enteritis, a randomized trial indicated 9 out of 10 had a clinical relapse during gluten challenge (compared with one third after placebo) and most had gamma/delta+ cells and transglutaminase deposits indicating these were likely celiac-lite cases, and not a separate disorder currently labelled as NCGS. (6) Second, the symptoms linked to NCGS can also overlap with the irritable bowel syndrome (IBS). (7) Third, a gluten-free diet can be inadvertently associated with lower intake of fermentable carbohydrates (FODMAPS); it may be these carbohydrates, rather than gluten or other wheat proteins, that induce symptoms attributed to NCGS. (8) Last, wheat also contains amylase-trypsin inhibitors (ATIs), which are

4 plant-derived proteins with parasitic enzyme inhibiting properties and the ability to trigger innate immune response in intestinal monocytes, macrophages, and dendritic cells. (9, 10) This immunogenic property has been confirmed in both in vitro and in vivo studies (9) possibly explaining another subset of individuals with symptoms after wheat ingestion. A methodological alternative challenging the current prevailing attitude towards NCGS being a distinct and new disease (3, 5) has been proposed. The starting point for investigating the role of wheat in gastrointestinal (GI) disease must begin with already well-defined conditions, including functional dyspepsia (FD) and IBS. Based on current Rome IV criteria, FD refers to troublesome upper GI symptoms thought to arise from the gastroduodenal region (11). Recent studies suggest a pathological rather than functional basis to FD symptoms; duodenal eosinophilia may play a key role in the pathogenesis of FD. (12) In the current issue of Clinical Gastroenterology and Hepatology, Carroccio et al. add new insights to the biology of NCGS. (4) They investigated the histological features of duodenal and rectal mucosa in NCGS patients and controls to identify possible distinctive markers among NCGS patients. Seventy-eight patients diagnosed with NCGS by DBPC wheat challenge were included; celiac disease was excluded by negative testing for serum anti-transglutaminase (antittg), anti-endomysium (EmA) IgA and IgG antibodies and absence of intestinal villous atrophy, and wheat allergy by negative IgE mediated immune-allergy test (skin prick tests and/or serum specific IgE detection). The strict diagnostic criteria used included: 1) resolution of symptoms on a standard oligoantigenic diet i.e. excluding wheat, cow s milk, egg, tomato, chocolate or other food(s) causing self-reported symptoms; and 2) symptom reappearance with the DBPC wheat challenge. Controls included 39 non-ncgs patients (self-reported NCGS with negative wheat challenge test results) and 16 celiac disease patients (confirmed by serology and histology).

5 Carroccio et al. found significantly higher numbers of intra-epithelial CD3+ T cells, lamina propria CD45+ immunocytes, and eosinophils in the duodenal mucosal biopsies of NCGS patients than those in non-ncgs controls. Further, in the duodenal lamina propria, NCGS patients with dyspepsia had a significantly higher number of eosinophils compared with NCGS patients without upper GI symptoms. Celiac disease controls had more duodenal immunocytes (CD45 +, CD3+ cells and eosinophils) than NCGS patients or controls. In the rectal mucosa, NCGS patients had more enlarged lymphoid follicles, intraepithelial CD3+ T cells, lamina propria CD45+ cells, and eosinophils compared to controls. In NCGS patients, the rectal mean eosinophil infiltration was >2.5-fold the upper normal limit and almost 2-fold in the duodenum, while an inverse pattern was seen in the non-ncgs controls. The sensitivity and specificity of the presence of rectal eosinophilia (> 9 eosinophils in the rectal lamina propria) was 94% and 70% respectively, and a positive and negative predictive value for true NCGS of 81% and 89%, respectively. The findings are of great interest and support a pathophysiological overlap between FD and NCGS. New epidemiological observations regarding the prevalence of self-reported wheat sensitivity and its association with FD have emerged. (2) In a survey of self- reported diagnoses and GI symptoms of 3542 participants selected from the Australian electoral roll (to which all adults are compulsorily registered), 15% of the group self-reported wheat sensitivity and 16% fulfilled modified Rome III criteria for FD. Further, FD was significantly associated with wheat sensitivity in the multivariate analysis (OR 1.5, 95% CI ). The association between duodenal eosinophilia and NCGS is consistent with these recent findings. Another study has identified a possible causal link between wheat ingestion and FD: Elli et al. (13) found that a small group of patients with FD (n=17) also met criteria for NCGS using a DBPC wheat

6 challenge; in this study postprandial fullness (p=0.01) and early satiety (p=0.03) were significantly associated with gluten ingestion. Thus, it is conceivable that one of the underlying drivers of duodenal eosinophilia in FD is wheat. (14) While other observational studies have linked the ingestion of food, including wheat, with symptoms in FD (15), high quality randomized controlled trials that examine the causal link between gluten or wheat ingestion and dyspeptic symptoms are lacking. It is unknown if the more proximal colon is also characterized by increased eosinophils in NCGS but direct contact of the mucosa with wheat proteins seems unlikely to explain increased rectal eosinophilia. Carroccio et al. have previously identified increased levels of fecal eosinophil cationic protein and tryptase in patients with IBS and food hypersensitivity, indicating both eosinophil and mast cell activation (16); it is conceivable that upstream immune activation may play a role in stimulating and recruiting mucosal eosinophils downstream in the rectum. The new data also raise the question about the role of microbiota in these conditions. Increased counts of duodenal eosinophils have been well described in FD, notably in those with early satiety and postprandial distress syndrome subtype (17), the latter has been linked with impaired duodenal barrier function and defective neuronal signaling. (12) Our group has demonstrated a unique duodenal microbiome profile in FD (18), but there is little in the literature regarding the effect of wheat ingestion on the profile of the small intestinal microbiome in patients with functional GI disorders. (19) Given that microbial hydrolysis influences the immunogenicity of gluten peptides (20), understanding how the microbiome in FD interacts with gluten may be critical to understanding the link between NCGS and FD. It is also plausible that the increased expression of toll like receptors on epithelial cells - demonstrated in NCGS (21) and important in the innate immune response to microbial pathogens -- is linked to dysbiosis.

7 NCGS and FD share symptoms which can improve when patients are on a gluten free diet. (7, 22) Based on the emerging evidence, we suggest that wheat proteins in genetically predisposed individuals may induce a Th2/Th17 response that recruit eosinophils. Degranulation of eosinophils can induce increased intestinal permeability (23), epithelial cell damage (24), and immune activation with increased expression of toll like receptors on epithelial cells and interferon gamma expression. (25) With increased duodenal permeability and presentation of microbial antigens to the immune system, the duodenal microbiome may play a key role in determining the symptomatic manifestations and outcome. This syndrome may present as classical FD or in some cases with systemic symptoms only, or be completely asymptomatic. In conclusion, NCGS is unlikely to be single or unique disease. In many cases, NCGS is likely a mislabeled functional GI disorder (IBS or FD) induced by wheat proteins or FODMAPS. Carraccio et al. have identified tissue eosinophilia as a potential biomarker, and it is particularly exciting that rectal eosinophils as well as duodenal eosinophils may be present in the same patients; although this observation needs further confirmation. We need longitudinal studies in NCGS to explore the diagnostic and prognostic value of eosinophilia in the duodenum and rectum. Research into the interaction of the duodenal microbiome with wheat ingestion may shed new light on the pathogenesis and complex relationship between wheat and functional symptoms, and more importantly identify the subgroup of patients who may benefit from a tailored diet. 1 Talley NJ, Walker MM. Celiac Disease and Nonceliac Gluten or Wheat Sensitivity: The Risks and Benefits of Diagnosis. JAMA Intern Med 2017;177: Potter MDE, Walker MM, Jones MP, et al. Wheat Intolerance and Chronic Gastrointestinal Symptoms in an Australian Population-based Study: Association Between Wheat Sensitivity, Celiac Disease and Functional Gastrointestinal Disorders. Am J Gastroenterol 2018;113: Catassi C, Elli L, Bonaz B, et al. Diagnosis of Non-Celiac Gluten Sensitivity (NCGS): The Salerno Experts' Criteria. Nutrients 2015;7:

8 4 Carroccio A, Giannone G, Mansueto P, et al. Duodenal and Rectal Mucosa Inflammation in Patients With Non-celiac Wheat Sensitivity. Clin Gastroenterol Hepatol Ellis A, Linaker BD. Non-coeliac gluten sensitivity? Lancet 1978;1: Rosinach M, Fernández-Bañares F, Carrasco A, et al. Double-Blind Randomized Clinical Trial: Gluten versus Placebo Rechallenge in Patients with Lymphocytic Enteritis and Suspected Celiac Disease. PLoS One 2016;11:e Catassi C, Alaedini A, Bojarski C, et al. The Overlapping Area of Non-Celiac Gluten Sensitivity (NCGS) and Wheat-Sensitive Irritable Bowel Syndrome (IBS): An Update. Nutrients 2017;9. 8 Skodje GI, Sarna VK, Minelle IH, et al. Fructan, Rather Than Gluten, Induces Symptoms in Patients With Self-Reported Non-Celiac Gluten Sensitivity. Gastroenterology 2018;154: e2. 9 Junker Y, Zeissig S, Kim SJ, et al. Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4. J Exp Med 2012;209: Schuppan D, Zevallos V. Wheat amylase trypsin inhibitors as nutritional activators of innate immunity. Dig Dis 2015;33: Stanghellini V, Chan FK, Hasler WL, et al. Gastroduodenal Disorders. Gastroenterology 2016;150: Walker MM, Potter M, Talley NJ. Eosinophilic gastroenteritis and other eosinophilic gut diseases distal to the oesophagus. Lancet Gastroenterol Hepatol 2018;3: Elli 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: Hunt JS WM, Keegan A, Liu C, et al. Sa1296 Duodenal Eosinophilia in Celiac Disease and Functional Dyspepsia - A Marker for Wheat Sensitivity? Gastroenterology. 2015;148(4):S Duncanson KR, Talley NJ, Walker MM, et al. Food and functional dyspepsia: a systematic review. J Hum Nutr Diet 2018;31: Carroccio A, Brusca I, Mansueto P, et al. Fecal assays detect hypersensitivity to cow's milk protein and gluten in adults with irritable syndrome. Clin Gastroenterol Hepatol Nov; 9(11): Walker MM, Talley NJ. The Role of Duodenal Inflammation in Functional Dyspepsia. J Clin Gastroenterol 2017;51: Zhong L, Shanahan ER, Raj A, et al. Dyspepsia and the microbiome: time to focus on the small intestine. Gut 2017;66: Potter M, Walker MM, Talley NJ. Non-coeliac gluten or wheat sensitivity: emerging disease or misdiagnosis? Med J Aust 2017;207: Gutiérrez S, Pérez-Andrés J, Martínez-Blanco H, et al. The human digestive tract has proteases capable of gluten hydrolysis. Mol Metab 2017;6: Sapone A, Lammers KM, Casolaro V, et al. Divergence of gut permeability and mucosal immune gene expression in two gluten-associated conditions: celiac disease and gluten sensitivity. BMC Med 2011;9: Potter MDE, Walker MM, Keely S, et al. What's in a name? 'Non-coeliac gluten or wheat sensitivity': controversies and mechanisms related to wheat and gluten causing gastrointestinal symptoms or disease. Gut Hollon J, Puppa EL, Greenwald B, et al. Effect of gliadin on permeability of intestinal biopsy explants from celiac disease patients and patients with non-celiac gluten sensitivity. Nutrients 2015;7: Uhde M, Ajamian M, Caio G, et al. Intestinal cell damage and systemic immune activation in individuals reporting sensitivity to wheat in the absence of coeliac disease. Gut 2016;65: Brottveit M, Beitnes AC, Tollefsen S, et al. Mucosal cytokine response after short-term gluten challenge in celiac disease and non-celiac gluten sensitivity. Am J Gastroenterol 2013;108:

Tuesday 10 th April 2018 Dr Rukhsana Hussain. Disclaimers apply:

Tuesday 10 th April 2018 Dr Rukhsana Hussain What is Non-Coeliac Gluten Sensitivity (NCGS)? Symptoms Pathophysiology Diagnosis Treatment Summary NCGS is a condition in which consumption of gluten leads