NCWS or IBS/FD in Relatives of CD Patients

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