Beneficial Effects of a Low-Nickel Diet on Relapsing IBS-Like and Extraintestinal Symptoms of Celiac Patients during a Proper Gluten-Free Diet: Nickel Allergic Contact Mucositis in Suspected Non-Responsive Celiac Disease

Abstract

Background and Aim: Nickel (Ni)-rich foods can induce allergic contact mucositis (ACM) with irritable bowel syndrome (IBS)-like symptoms in predisposed subjects. Ni ACM has a high prevalence (>30%) in the general population and can be diagnosed by a Ni oral mucosa patch test (omPT). Many celiac disease (CD) patients on a gluten-free diet (GFD) often show a recrudescence of gastrointestinal and extraintestinal symptoms, although serological and histological remission has been achieved. Since a GFD often results in higher loads of ingested alimentary Ni (e.g., corn), we hypothesized that it would lead to a consequent intestinal sensitization to Ni in predisposed subjects. We wanted to (1) study Ni ACM prevalence in still symptomatic CD patients on a GFD and (2) study the effects of a low-Ni diet (LNiD) on their recurrent symptoms. Material and Methods: We recruited 102 consecutive CD patients (74 female, 28 male; age range 18–65 years, mean age 42.3 ± 7.4) on a GFD since at least 12 months, in current serological and histological remission (Marsh–Oberhuber type 0–I) who complained of relapsing gastrointestinal and/or extraintestinal symptoms. Inclusion criteria: presence of at least three gastrointestinal symptoms with a score ≥5 on the modified Gastrointestinal Symptom Rating Scale (GSRS) questionnaire. Exclusion criteria: IgE-mediated food allergy; history of past or current cancer; inflammatory bowel diseases; infectious diseases including Helicobacter pylori; lactose intolerance. All patients enrolled underwent Ni omPT and followed a LNiD for 3 months. A 24 symptoms questionnaire (GSRS modified according to the Salerno Experts’ Criteria, with 15 gastrointestinal and 9 extraintestinal symptoms) was administered at T0 (free diet), T1 (GFD, CD remission), T2 (recurrence of symptoms despite GFD), and T3 (GFD + LNiD) for comparisons. Comparisons were performed using Wilcoxon signed-rank test. RESULTS: Twenty patients (all female, age range 23–65 years, mean age 39.1 ± 2.9) out of 102 (19.6%) were finally included. All 20 patients enrolled (100%) showed positive Ni omPT, confirming an Ni ACM diagnosis. A correct GFD (T0 vs. T1) induced the improvement of 19 out of the total 24 (79.2%) symptoms, and 14 out of 24 (58.3%) were statistically significant (p-value < 0.0083 according to Bonferroni correction). Prolonged GFD (T1 vs. T2) revealed the worsening of 20 out of the total 24 (83.3%) symptoms, and 10 out of 24 (41.7%) were statistically significant. LNiD (T2 vs. T3) determined an improvement of 20 out of the total 24 (83.4%) symptoms, and in 10 out of 24 (41.7%) symptoms the improvement was statistically significant. Conclusions: Our data suggest that the recrudescence of gastrointestinal and extraintestinal symptoms observed in CD subjects during GFD may be due to the increase in alimentary Ni intake, once gluten contamination and persisting villous atrophy are excluded. Ni overload can induce Ni ACM, which can be diagnosed by a specific Ni omPT. Improvement of symptoms occurs after a proper LNiD. These encouraging data should be confirmed with larger studies.

New Insights into Intestinal Permeability in Irritable Bowel Syndrome-Like Disorders: Histological and Ultrastructural Findings of Duodenal Biopsies

“…Similar sub-atrophic microvilli have also been found in NCGS and Ni ACM patients, although there were no areas of total atrophy in these last two conditions: these microvillous alterations in NCGS and Ni ACM could represent an early manifestation of a non-IgE mediated intolerance/allergy which can cause gastrointestinal symptoms but not necessarily a malabsorption syndrome. Moreover, a proper GFD appeared to induce a significant elongation of microvilli in tCD, although they remained shorter than in controls: this could justify the persistent symptoms that CD patients often complain of, despite a proper GFD [37].…”

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“…The intensity of the reported symptoms was assessed using a numerical scale from 0 to 10 ( Supplementary Table S1 ). The GSRS questionnaire was considered positive if at least 3 symptoms of the 27 considered had a score ≥5 [ 4 ].…”

“…These conditions should be more properly indicated with the term adverse food reactions (AFRs), which are defined as the appearance of any anomalous clinical reaction following the ingestion, contact, or inhalation of foods or additives contained therein [ 3 ]. In this condition, the affected population presents with a wide variety of symptoms that are generally identified as an IBS-like syndrome, including bloating, diarrhea, and abdominal pain [ 4 ]. Additionally, various systemic manifestations, such as dermatological, joint, and respiratory disorders, may also occur in affected patients [ 5 ].…”

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“…Celiac disease patients on a gluten-free diet with positive Ni-omPT displayed a recurrence of gastrointestinal and extraintestinal symptoms, although serological and histological remission has been reached. Relief of symptoms appeared after a gluten-free-low-Ni diet [ 22 ]. Irritable bowel syndrome-like disorders are also present in endometriosis.…”