Determination of gluten immunogenic peptides for the management of the treatment adherence of celiac disease: A systematic review

Abstract

BACKGROUND Gluten is a complex mixture of proteins with immunogenic peptide sequences triggering the autoimmune activity in patients with celiac disease (CeD). Gluten immunogenic peptides (GIP) are resistant to gastrointestinal digestion and are then excreted via the stool and urine. Most common detection methods applied in the follow-up visits for CeD patients such as serology tests, dietetic interviews, questionnaires, and duodenal biopsy have been proved to be inefficient, invasive, or inaccurate for evaluating gluten-free diet (GFD) compliance. Determination of excreted GIP in stool and urine has been developed as a non-invasive, direct, and specific test for GFD monitoring. AIM To summarize published literature about the clinical utility of GIP determination in comparison to the tools employed for GFD monitoring. METHODS PubMed and Web of Science searches were performed using the keywords “gluten immunogenic peptides” or “gluten immunogenic peptide” and a combination of the previous terms with “feces”, “stools”, “urine”, “celiac disease”, “gluten-free diet”, and “adherence” to identify relevant clinical studies published in English and Spanish between 2012 to January 2021. Reference lists from the articles were reviewed to identify additional pertinent articles. Published articles and abstracts reporting the clinical use of GIP determination in stool and/or urine for the follow-up of patients with CeD in comparison with other tools in use were included. Case reports, commentaries, reviews, conference papers, letters, and publications that did not focus on the aims of this review were excluded. RESULTS Total of 15 publications were found that involved the use of GIP determination in stool and/or urine to monitor the adherence to the GFD in comparison to other tools. Studies included both children and adults diagnosed with CeD and healthy volunteers. Overall, these preliminary studies indicated that this novel technique was highly sensitive for the detection of GFD transgressions and therefore could facilitate the follow-up of patients with CeD. Tools identified in this work included the CeD-specific serology, dietetic questionnaires, symptomatology, and the duodenal biopsy. Review of the literature revealed that the rates of GFD adherence may vary between 30%-93% using either stool or urine GIP determination, 49%-96% by the serology, 59%-94% using the dietetic questionnaires, 56%-95% by the reported symptoms and 44%-76% with the duodenal biopsy. In addition, the association between the different methods and histological abnormalities (Marsh II-III) was found to be 33%-100% for GIP determination (stool and urine), 25%-39% for CeD-specific serology, 3%-50% for dietetic questionnaires, and 22%-28% for the symptomatology. CONCLUSION Excreted GIP detection is the precise approach for determining voluntary or involuntary gluten consumption in CeD patients pr...

Non-Responsive and Refractory Coeliac Disease: Experience from the NHS England National Centre

“…Furthermore, coeliac serology lacks sensitivity in the follow-up of CD [12,13], and mucosal healing can take years to achieve [4,5], meaning it is difficult to differentiate ongoing gluten exposure from slow healing, from RCD1 in some patients. Several recent studies have documented the utility of measuring urine and/or faecal GIPs as a marker of dietary gluten adherence in uncomplicated CD [14][15][16][29][30][31][32]. These studies have reported a window of detection for urine tests ranging from 4 h to 48 h after gluten ingestion [14,29], and a sensitivity of 95% following gluten doses of 2 g or more [33].…”

Controls and Result Interpretations in Studies of Urine Gluten Peptide Determinations

“…We have read with interest the article by Monachesi et al (1), in which the authors assess the diagnostic performance of urinary gluten immunogenic peptides (GIP) determination to detect gluten contamination of the gluten-free diet (GFD) in a group of healthy and qualified Italian volunteers adhering to GFD and undergoing repeated dietary challenges with increasing amounts of gluten. In contrast to over a dozen studies from multiple groups reporting the validity, utility, and reliability of the GIP tests in the monitoring of the GFD (2), this is the first study to date suggesting that the urine GIP test was not reliable because of a high frequency of reported false positive and negative determinations. Although it was not mentioned how they measured the GIP with the lateral flow immunoassays, they did not find the expected correlation between the ingested gluten (10, 50, 100, 500, and 1,000 mg) and the amount of excreted GIP, with significant negative results for the 1,000-mg ingestion.…”

E40 glutenase detoxification capabilities of residual gluten immunogenic peptides in in vitro gastrointestinal digesta of food matrices made of soft and durum wheat

“…While E40 is not intended to replace the GFD as a primary and sole management for CeD ( 54 ), it is envisaged to adjunct the GFD in order to protect against the detrimental effect of a few hundred milligrams to a few grams of gluten in patients with high gluten sensitivity. The reported fact that 40% of CeD patients with persistent villus atrophy have positive CeD serologies despite adhering to a GFD, is suggestive of commonly ongoing inadvertent gluten exposure or high sensitivity to the gluten content of a GFD, and the need to better control it ( 11 , 50 ). In this complex scenario, our results foster E40 to be shortly clinically tested in CeD patients, as a candidate for an OET and adjunct to a GFD aimed to manage gluten related disorders.…”

“…The use of a wide range of different in vitro digestive conditions utilized in published studies makes the meaningful comparison of results among different glutenases difficult, particularly in terms of destruction of T cell epitopes and prevention of GIPs generation (40,(44)(45)(46)(47)(48). Many of these GIPs are, so far, regarded as a standard for studying gluten exposure in CeD patients, either to confirm adherence to the GFD, or to detect an inadvertent gluten intake, thus fostering the maintenance of intestinal symptoms, and to some extent signs, in CeD patients (49)(50)(51). This study investigated the immune detoxifying capability on gluten peptides recognized by HLA-DQ2.5/2.2, the most represented haplotype in CeD.…”