NCWS or IBS/FD in Relatives of CD Patients

Over 50% of non-celiac wheat sensitivity (NCWS) patients are HLA DQ2/DQ8 positive and often have a Celiac Disease (CD) family history. Studies have identified a subgroup of NCWS patients whose clinical and immunological features are closer to CD than to irritable bowel syndrome/functional dyspepsia (IBS/FD) ('inflammatory subgroup'). The investigators hypothesized that among CD patient's relatives, there might be a high number of NCWS subjects, who hypothetically belong to the 'inflammatory subgroup'. Therefore, the aim of this multi-step project is to identify the prevalence of both self-reported NCWS and IBS/FD not related to wheat ingestion among CD patient's relatives (parents, grandparents, siblings and sons).

Study Overview

• Status: Recruiting
• Conditions: Functional Dyspepsia; Celiac Disease; Non Celiac Wheat Sensitivity; IBS (Irritable Bowel Syndrome)
• Intervention / Treatment: Other: Wheat-Free Diet

Detailed Description

Hypothesis, Rationale and Aims Over 50% of non-celiac wheat sensitivity (NCWS) patients are HLA DQ2/DQ8 positive and often have a Celiac Disease (CD) family history. Studies have identified a subgroup of NCWS patients whose clinical and immunological features are closer to CD than to irritable bowel syndrome/functional dyspepsia (IBS/FD) ('inflammatory subgroup'). The investigators hypothesized that among CD patient's relatives, there might be a high number of NCWS subjects, who hypothetically belong to the 'inflammatory subgroup'.

To the best of investigators' knowledge, very few studies have tried to identify NCWS, or even IBS/FD not related to wheat ingestion prevalence among CD patient's relatives, nor have studied their clinical, immunological, intestinal permeability (IP) and gut microbiota (GM) features, or the changes induced by a wheat-free diet (WFD). More specifically, in 1996, Troncone et al. showed high lymphocyte counts (i.e. total intraepithelial lymphocyte number and/or numbers of lamina propria and intraepithelial CD3+ and γδ+ cells) after rectal gluten instillation in siblings of CD children, revealing a gluten sensitization not restricted to HLA. Esteve M et al. analyzed the duodenal histological pattern and clinical features of 110 HLA-DQ2 positive CD patient's first-degree relatives, proving that 22.2% of them had some evidence of 'gluten-sensitive enteropathy'; subjects with Marsh I and Marsh II-III lesions were significantly more often symptomatic (56.3% and 53.8%, respectively) than patients with normal mucosa (Marsh 0 21.1%, p=0.002). Another Spanish study group analyzed the prevalence of gastrointestinal symptoms and the influence of gluten intake in 139 CD patient's first-degree relatives, finding that 57.6% had gastrointestinal symptoms [bloating (16.5%), constipation (15.1%), diarrhea (14.4%), and abdominal pain (5.8%)] and 32.7% (n. 37/113) had a Marsh I degree at duodenal histology examination. At baseline, 45.7% of the participants reported symptoms (evaluated with CD-specific symptom index), which reduced to 24.5% (i.e. reduction ≥20%) during a 4-week gluten-free diet, going-back to 38.1% during a gluten-overload diet (i.e. 15g of gluten supplement to their normal diet containing gluten). Moreover, Araya M et al. reported that among 166 CD patient's first-degree relatives, the most spontaneously declared being asymptomatic, but detailed questioning revealed that 60.7% experienced symptoms, which had not been investigated.

Therefore, the aim of this multi-step project is to identify the prevalence of both self-reported NCWS and IBS/FD not related to wheat ingestion among CD patient's relatives (parents, grandparents, siblings and sons).

Inclusion criteria

• CD patient's relatives
• >18 years old
• reporting IBS/FD-like and extraintestinal (EI) symptoms

Exclusion criteria

• self-exclusion of wheat from the diet and refuse to reintroduce it for diagnostic purposes;
• drug and/or alcohol (>30 g/day for men and >20 g/day for women) abuse;
• treatment with steroids and/or non-steroidal anti-inflammatory drugs in the 2 weeks before duodenal biopsy;
• pregnancy or breastfeeding;
• Helicobacter pylori and other bacterial and/or parasitic infections;
• diagnosis of chronic inflammatory bowel disease or other organic pathologies affecting the digestive system [e.g., IgE-mediated Wheat Allergy (WA), microscopic colitis, diverticulitis, segmental colitis associated with diverticulosis, etc.], neurological diseases, major psychiatric disorders, infectious diseases, immunological deficiencies, and impairments limiting physical activity;
• patients undergoing radiotherapy and chemotherapy.

Diagnostic criteria of NCWS and IBS/FD not related to wheat ingestion

1. NCWS

   • subjects with wheat-dependent symptoms, both gastrointestinal and extraintestinal;
   • negativity of anti-deamidated gliadin peptide (DGP) immunoglobulin (Ig)A and IgG antibodies, anti-tissue transglutaminase (tTG) IgA and IgG antibodies, and anti-endomysial antibodies (EMA);
   • absence of duodenal villous atrophy in all patients carrying the human leukocyte antigen (HLA) DQ2 and/or DQ8 haplotypes (therefore regardless of the negativity of CD-specific serum antibodies), evaluated when the patients had consumed a minimum of 100g of pasta and/or bread a day, for at least 45 days;
   • absence of WA: negative skin prick test and/or specific serum immunoglobulin E (IgE) assay for wheat, gluten and gliadin;
   • resolution of symptoms on a strict WFD.
2. IBS/FD not related to wheat intake - subjects diagnosed with IBS/FD, according to the Rome IV classification, who did not specifically report gastrointestinal or EI symptoms/signs following ingestion of wheat and who did not respond to a WFD.

Research plan, Experimental design and Methodologies The study consists of 2 work packages (WP) that will be carried out in collaboration between the partners and according to a prospective study design.

WP1: Identification of CD patient's first-degree relatives with IBS/FD-like and extraintestinal (EI) symptoms

CD patient's relatives (>18 years old, non-pregnant, non-breastfeeding) will fill out the following online questionnaires (T0):

• Demographic/anthropometric features [Sex, Age, Ethnicity, Height, Weight, Body Mass Index (BMI)]
• Self-perceived food intolerance (including NCWS)
• Gastrointestinal Symptom Rating Scale (GSRS)
• Bristol Stool Scale
• IBS-Symptom Severity Scale (IBS-SSS)
• Extraintestinal Symptom Rating Scale (ESRS)
• IBS-Quality of Life (IBS-QoL). All patients complaining of IBS/FD-like and EI symptoms will undergo HLA DQ2/DQ8 and CD serological screening (DGP IgA and IgG antibodies, tTG class IgA and IgG antibodies, EMA). Symptomatic patients with CD suspicion (HLA DQ2/DQ8 positivity, regardless of serology results) will undergo duodenal biopsy (examined according to Marsh-Oberhuber classification). Other organic diseases will be excluded according to the clinician's choice, according to the National Health Systems (NHS) screening programs for symptomatic CD relatives. At the end of all required examinations, we will identify a subgroup of patients suffering from IBS/FD-like and EI symptoms not related to other organic diseases (T1).

WP2: Identification of CD patient's relatives with potential NCWS vs IBS/FD not related to wheat intake with 6-week long strict WFD Patients, identified at T1, will undergo a 6-week long strict WFD (preliminary dietician consul will be granted to all subjects), at the end of which (T2) they will fill-out an online form including a WFD adherence questionnaire (i.e. modified 'Biagi' score) and the questionnaires reported in WP1 (except the self-perceived food intolerance one). Patients reporting a reduction ≥30% in at least one questionnaire after WFD will be identified as self-reported NCWS, all the others will be identified as IBS/FD not related to wheat intake.

Power Calculation The sample size is difficult to determine as very low data are known about NCWS/IBS/FD prevalence among CD patient's relatives. According to previous studies, up to 50-60% CD patient's relatives complain symptoms. In addition, some studies, assessing NCWS immunological pattern, obtained statistical significance with almost 35 patients.

According to the multicenter design of this study, the investigators planned to screen CD patient relatives as much as possible (at least 600 subjects), with esteemed identification of 200-300 subjects with IBS/FD-like and/or EI symptoms (WP1). It is not possible to establish a priori how many patients will be identified as affected by self-reported NCWS and, therefore, it is not possible to indicate how many will access the subsequent phases of the study (WP2).

Potential pitfalls and caveats, and alternative approaches WP1, which consists of a simple screening survey and subsequent clinical assessment of CD patients' relatives, should be carried out without pitfalls, mostly following the NHS recommendations for CD early screening.

Usually, patients who self-report NCWS easily agree to start a period of WFD. A 6-week long WFD challenge represents a sufficient period to evaluate the evolution of symptoms in these patients, without risking determining nutritional deficiencies that could alter the patient's state of health.

Expected results, and Impact This multicenter study will define exactly, for the first time, the prevalence of self-reported NCWS and IBS/FD not related to wheat intake among CD patient's relatives. In addition, a screening carried out on these subjects will allow both to early identify subjects with CD, and to direct subjects affected by NCWS or IBS/FD not related to wheat intake towards a more rapid diagnosis, consequently reducing direct and indirect costs for NHS, and an adequate therapeutic approach, consistently improving their QoL.

• Clinical benefits: thanks to this project, which starts with a general screening of CD patient's first-degree relatives, physicians will both early diagnose new CD patients and identify and treat those subjects who, although not celiac, suffer from NCWS or IBS/FD not related to wheat intake. Moreover, the early identification of new CD subjects will be useful to prevent possible long-term consequences, such as malnutrition, osteoporosis, and neoplastic diseases development.
• Research benefits: this study will add a piece to the knowledge about CD, NCWS, and IBS/FD not related to wheat ingestion, and defining, for the first time, the prevalence of the last 2 conditions in CD patient's familiar.
• Social benefits: the early diagnosis of CD, NCWS and IBS/FD not related to wheat intake will improve health status (considering physical, psychological and social issues) of recruited subjects.
• Economic benefits: the early diagnosis of CD, NCWS and IBS/FD not related to wheat intake would determine a reduction in the number of medical visits and examinations, as well as of lost workdays, with substantial economic savings for the NHS and improvement of patient's QoL. In addition, in new CD subjects, the early diagnosis will also reduce the costs related to the development of CD long-term complications.

• Study Type: Interventional
• Enrollment (Estimated): 600
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Pasquale Mansueto, MD; Phone Number: +393477279879; Email: pasquale.mansueto@unipa.it
• Study Contact Backup: Name: Aurelio Seidita, MD; Email: aurelio.seidita@unipa.it

Study Locations

• Italy
  • PA
    • Palermo, PA, Italy, 90127
      • Recruiting
      • Celiac Disease and Food Intolerance Clinic, Geriatrics Unit, "P. Giaccone" University Hospital, Palermo
      • Contact: Pasquale Mansueto; Phone Number: 3477279879; Email: pamansueto@gmail.com
    • Palermo, PA, Italy, 90146
      • Recruiting
      • Internal Medicine Unit, P.O. "V. Cervello," Ospedali Riuniti "Villa Sofia-Cervello," Palermo
      • Contact: Pasquale Mansueto; Phone Number: 3477279879; Email: pamansueto@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion criteria

• CD patient's relatives
• >18 years old
• reporting IBS/FD-like and extraintestinal (EI) symptoms

Exclusion criteria

• self-exclusion of wheat from the diet and refuse to reintroduce it for diagnostic purposes;
• drug and/or alcohol (>30 g/day for men and >20 g/day for women) abuse;
• treatment with steroids and/or non-steroidal anti-inflammatory drugs in the 2 weeks before duodenal biopsy;
• pregnancy or breastfeeding;
• diagnosis of chronic inflammatory bowel disease or other organic pathologies affecting the digestive system [e.g., IgE-mediated Wheat Allergy (WA), microscopic colitis, diverticulitis, segmental colitis associated with diverticulosis, etc.], neurological diseases, major psychiatric disorders, infectious diseases, immunological deficiencies, and impairments limiting physical activity.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Active Comparator: Six-week long strict Wheat-Free Diet; CD patient's first-degree relatives with IBS/FD-like and extraintestinal (EI) symptoms

Other: Wheat-Free Diet; Patients, identified at T1, will undergo a 6-week long strict WFD (preliminary dietician consul will be granted to all subjects), at the end of which (T2) they will fill-out an online form including a WFD adherence questionnaire (i.e. modified 'Biagi' score) and the questionnaires reported in WP1. Patients reporting a reduction ≥30% in at least one questionnaire after WFD will be identified as self-reported NCWS, all the others will be identified as IBS/FD not related to wheat intake.; Other Names: WFD

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Identification of patients with self-reported NCWS or IBS/FD not related to wheat intake among relatives of CD patients: Gastrointestinal Symptom Rating Scale (GSRS)	CD patient's relatives included in the study will refill out the following online questionnaire at the end of the 6-week long strict WFD (T2): - Gastrointestinal Symptom Rating Scale (GSRS) (range from 15 to 105) Patients reporting a reduction ≥30% in the questionnaire after WFD will be identified as patients with self-reported NCWS. Patients not reporting a reduction ≥30% in at least one questionnaire after WFD will be identified as patients with IBS/FD not related to wheat intake.	From baseline to 6-week

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Identification of patients with self-reported NCWS or IBS/FD not related to wheat intake among relatives of CD patients: Bristol Stool Scale	CD patient's relatives included in the study will refill out the following online questionnaire at the end of the 6-week long strict WFD (T2): - Bristol Stool Scale (from type 1, separate hard lumps, like nuts, to type 7, watery, no solid pieces, entirely liquid) Patients reporting a reduction ≥30% in the questionnaire after WFD will be identified as patients with self-reported NCWS. Patients not reporting a reduction ≥30% in at least one questionnaire after WFD will be identified as patients with IBS/FD not related to wheat intake.	From baseline to 6-week
Identification of patients with self-reported NCWS or IBS/FD not related to wheat intake among relatives of CD patients: IBS-Symptom Severity Scale (IBS-SSS)	CD patient's relatives included in the study will refill out the following online questionnaire at the end of the 6-week long strict WFD (T2): - IBS-Symptom Severity Scale (IBS-SSS) (range from less than 75 to 300 or greater) Patients reporting a reduction ≥30% in the questionnaire after WFD will be identified as patients with self-reported NCWS. Patients not reporting a reduction ≥30% in at least one questionnaire after WFD will be identified as patients with IBS/FD not related to wheat intake.	From baseline to 6-week
Identification of patients with self-reported NCWS or IBS/FD not related to wheat intake among relatives of CD patients: Extraintestinal Symptom Rating Scale (ESRS)	CD patient's relatives included in the study will refill out the following online questionnaire at the end of the 6-week long strict WFD (T2): - Extraintestinal Symptom Rating Scale (ESRS) (range 0 to 24 for women, and 0 to 22 for men) Patients reporting a reduction ≥30% in the questionnaire after WFD will be identified as patients with self-reported NCWS. Patients not reporting a reduction ≥30% in at least one questionnaire after WFD will be identified as patients with IBS/FD not related to wheat intake.	From baseline to 6-week
Identification of patients with self-reported NCWS or IBS/FD not related to wheat intake among relatives of CD patients: IBS-Quality of Life (IBS-QoL)	CD patient's relatives included in the study will refill out the following online questionnaire at the end of the 6-week long strict WFD (T2): - IBS-Quality of Life (IBS-QoL) (range from 0 to 100). Patients reporting a reduction ≥30% in the questionnaire after WFD will be identified as patients with self-reported NCWS. Patients not reporting a reduction ≥30% in at least one questionnaire after WFD will be identified as patients with IBS/FD not related to wheat intake.	From baseline to 6-week

Collaborators and Investigators

• Sponsor: University of Palermo
• Investigators: Study Director: Antonio Carroccio, MD, University of Palermo

Publications and helpful links

General Publications

• Carroccio A, Rini G, Mansueto P. Non-celiac wheat sensitivity is a more appropriate label than non-celiac gluten sensitivity. Gastroenterology. 2014 Jan;146(1):320-1. doi: 10.1053/j.gastro.2013.08.061. Epub 2013 Nov 22. No abstract available.
• Carroccio A, Mansueto P, Iacono G, Soresi M, D'Alcamo A, Cavataio F, Brusca I, Florena AM, Ambrosiano G, Seidita A, Pirrone G, Rini GB. Non-celiac wheat sensitivity diagnosed by double-blind placebo-controlled challenge: exploring a new clinical entity. Am J Gastroenterol. 2012 Dec;107(12):1898-906; quiz 1907. doi: 10.1038/ajg.2012.236. Epub 2012 Jul 24.
• Drossman DA, Hasler WL. Rome IV-Functional GI Disorders: Disorders of Gut-Brain Interaction. Gastroenterology. 2016 May;150(6):1257-61. doi: 10.1053/j.gastro.2016.03.035. No abstract available.
• Di Liberto D, Mansueto P, D'Alcamo A, Lo Pizzo M, Lo Presti E, Geraci G, Fayer F, Guggino G, Iacono G, Dieli F, Carroccio A. Predominance of Type 1 Innate Lymphoid Cells in the Rectal Mucosa of Patients With Non-Celiac Wheat Sensitivity: Reversal After a Wheat-Free Diet. Clin Transl Gastroenterol. 2016 Jul 7;7(7):e178. doi: 10.1038/ctg.2016.35.
• Biagi F, Bianchi PI, Marchese A, Trotta L, Vattiato C, Balduzzi D, Brusco G, Andrealli A, Cisaro F, Astegiano M, Pellegrino S, Magazzu G, Klersy C, Corazza GR. A score that verifies adherence to a gluten-free diet: a cross-sectional, multicentre validation in real clinical life. Br J Nutr. 2012 Nov 28;108(10):1884-8. doi: 10.1017/S0007114511007367. Epub 2012 Feb 10.
• Vaquero L, Rodriguez-Martin L, Alvarez-Cuenllas B, Hernando M, Iglesias-Blazquez C, Menendez-Arias C, Vivas S. Coeliac disease and gastrointestinal symptom screening in adult first-degree relatives. J Gastroenterol Hepatol. 2017 Dec;32(12):1931-1937. doi: 10.1111/jgh.13801.
• Troncone R, Greco L, Mayer M, Mazzarella G, Maiuri L, Congia M, Frau F, De Virgiliis S, Auricchio S. In siblings of celiac children, rectal gluten challenge reveals gluten sensitization not restricted to celiac HLA. Gastroenterology. 1996 Aug;111(2):318-24. doi: 10.1053/gast.1996.v111.pm8690196.
• Seidita A, Giuliano A, Soresi M, Chiavetta M, Nardi E, Mogavero G, Giannone G, Carroccio A, Mansueto P. Fecal calprotectin levels in patients with non-celiac wheat sensitivity: a proof of concept. Intern Emerg Med. 2024 Aug;19(5):1255-1266. doi: 10.1007/s11739-024-03595-7. Epub 2024 Apr 12.
• Sapone A, Lammers KM, Casolaro V, Cammarota M, Giuliano MT, De Rosa M, Stefanile R, Mazzarella G, Tolone C, Russo MI, Esposito P, Ferraraccio F, Carteni M, Riegler G, de Magistris L, Fasano A. Divergence of gut permeability and mucosal immune gene expression in two gluten-associated conditions: celiac disease and gluten sensitivity. BMC Med. 2011 Mar 9;9:23. doi: 10.1186/1741-7015-9-23.
• Mansueto P, Di Liberto D, Fayer F, Soresi M, Geraci G, Giannone AG, Seidita A, D'Alcamo A, La Blasca F, Lo Pizzo M, Florena AM, Dieli F, Carroccio A. TNF-alpha, IL-17, and IL-22 production in the rectal mucosa of nonceliac wheat sensitivity patients: role of adaptive immunity. Am J Physiol Gastrointest Liver Physiol. 2020 Sep 1;319(3):G281-G288. doi: 10.1152/ajpgi.00104.2020. Epub 2020 Jul 13.
• Esteve M, Rosinach M, Fernandez-Banares F, Farre C, Salas A, Alsina M, Vilar P, Abad-Lacruz A, Forne M, Marine M, Santaolalla R, Espinos JC, Viver JM. Spectrum of gluten-sensitive enteropathy in first-degree relatives of patients with coeliac disease: clinical relevance of lymphocytic enteritis. Gut. 2006 Dec;55(12):1739-45. doi: 10.1136/gut.2006.095299. Epub 2006 May 18.
• Brottveit M, Beitnes AC, Tollefsen S, Bratlie JE, Jahnsen FL, Johansen FE, Sollid LM, Lundin KE. Mucosal cytokine response after short-term gluten challenge in celiac disease and non-celiac gluten sensitivity. Am J Gastroenterol. 2013 May;108(5):842-50. doi: 10.1038/ajg.2013.91. Epub 2013 Apr 16.
• Araya M, Oyarzun A, Lucero Y, Espinosa N, Perez-Bravo F. DQ2, DQ7 and DQ8 Distribution and Clinical Manifestations in Celiac Cases and Their First-Degree Relatives. Nutrients. 2015 Jun 18;7(6):4955-65. doi: 10.3390/nu7064955.

Helpful Links

• PubMed

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2026
• Primary Completion (Estimated): April 30, 2027
• Study Completion (Estimated): April 30, 2028

Study Registration Dates

• First Submitted: April 25, 2026
• First Submitted That Met QC Criteria: May 7, 2026
• First Posted (Actual): May 13, 2026

Study Record Updates

• Last Update Posted (Actual): May 13, 2026
• Last Update Submitted That Met QC Criteria: May 7, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: functional dyspepsia; celiac disease; Relatives; irritable bowel syndrome; non celiac wheat sensitivity
• Additional Relevant MeSH Terms: Metabolic Diseases; Intestinal Diseases; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Malabsorption Syndromes; Colonic Diseases, Functional; Nutritional and Metabolic Diseases; Irritable Bowel Syndrome; Celiac Disease
• Other Study ID Numbers: ACPM35

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No