The Gluten-Free Diet for Celiac Disease and Beyond

The gluten-free diet (GFD) has gained popularity beyond its main medical indication as the treatment for gluten-induced immune-mediated disorders such as celiac disease (CD), dermatitis herpetiformis, gluten ataxia, wheat allergy, and non-celiac gluten sensitivity. However, the diet carries some disadvantages such as elevated costs, nutritional deficiencies, and social and psychological barriers. The present work aims to review indications, proven benefits, and adverse events of a gluten-free diet. Close follow-up with patients following the diet is recommended. More data is needed to assess the effectiveness of the diet in managing mental and cognitive disorders and to establish a connection between the brain and gluten.     

Estimated Levels of Gluten Incidentally Present in a Canadian Gluten-Free Diet

Avoiding exposure to gluten is currently the only effective treatment for celiac disease. However, the evidence suggests that for most affected individuals, exposure to less than 10 mg/day is unlikely to cause histological changes to the intestinal mucosa. The daily diet of people with celiac disease does not rely solely on gluten-free pre-packaged foods, but also on naturally gluten-free grains (e.g., rice, buckwheat, ...) and foods with grain-derived ingredients (i.e., flour and starches) used for cooking and baking at home. The objective of this study was to estimate the level of incidental gluten potentially present in gluten-free diets from a Canadian perspective. We have conducted gluten exposure estimations from grain-containing foods and foods with grain-derived ingredients, taking into consideration the various rates of food consumption by different sex and age groups. These estimates have concluded that if gluten was present at levels not exceeding 20 ppm, exposure to gluten would remain below 10 mg per day for all age groups studied. However, in reality the level of gluten found in naturally gluten-free ingredients is not static and there may be some concerns related to the flours made from naturally gluten-free cereal grains. It was found that those containing a higher level of fiber and that are frequently used to prepare daily foods by individuals with celiac disease could be a concern. For this category of products, only the flours and starches labelled “gluten-free” should be used for home-made preparations.     

Nutritional Imbalances in Adult Celiac Patients Following a Gluten-Free Diet

Celiac disease (CD) is a chronic autoimmune disorder of the small intestine, whose only effective treatment is a gluten-free diet (GFD). It is characterized by the atrophy of the intestinal villi that leads to altered nutrient absorption. This study describes the nutritional imbalances which may be found in adults with CD following a GFD. During the first year of treatment, deficiencies will overcome as the intestinal mucosa recovers. Thus, biochemical data will show this progression, together with the decrease in symptoms. In contrast, in the long term, when a strict GFD is followed and mucosal recovery is achieved, analyzing nutrient intake makes more sense. Macronutrient consumption is characterized by its low complex carbohydrate and fiber intakes, and high fat (especially SFA) and sugar intakes. This profile has been related to the consumption of GFP and their nutritional composition, in addition to unbalanced dietary habits. The most notable deficiencies in micronutrients are usually those of iron, calcium and magnesium and vitamin D, E and some of group B. It is necessary to follow up patients with CD and to promote nutritional education among them, since it could help not only to achieve a gluten free but also a balanced diet.     

Microbiota and Metabolomic Patterns in the Breast Milk of Subjects with Celiac Disease on a Gluten-Free Diet

The intestinal microbiome may trigger celiac disease (CD) in individuals with a genetic disposition when exposed to dietary gluten. Research demonstrates that nutrition during infancy is crucial to the intestinal microbiome engraftment. Very few studies to date have focused on the breast milk composition of subjects with a history of CD on a gluten-free diet. Here, we utilize a multi-omics approach with shotgun metagenomics to analyze the breast milk microbiome integrated with metabolome profiling of 36 subjects, 20 with CD on a gluten-free diet and 16 healthy controls. These analyses identified significant differences in bacterial and viral species/strains and functional pathways but no difference in metabolite abundance. Specifically, three bacterial strains with increased abundance were identified in subjects with CD on a gluten-free diet of which one (Rothia mucilaginosa) has been previously linked to autoimmune conditions. We also identified five pathways with increased abundance in subjects with CD on a gluten-free diet. We additionally found four bacterial and two viral species/strains with increased abundance in healthy controls. Overall, the differences observed in bacterial and viral species/strains and in functional pathways observed in our analysis may influence microbiome engraftment in neonates, which may impact their future clinical outcomes.     

Pandemic Effects and Gluten-Free Diet: An Adherence and Mental Health Problem

The COVID-19 pandemic has been present for many months, influencing diets such as the gluten-free diet (GFD), which implies daily challenges even in non-pandemic conditions. Persons following the GFD were invited to answer online ad hoc and validated questionnaires characterizing self-perceptions of the pandemic, current clinical condition, dietary characteristics, adherence to GFD, anxiety, and depression. Of 331 participants, 87% experienced shortage and higher cost of food and 14.8% lost their jobs. Symptoms increased in 29% and 36.6% failed to obtain medical help. Although 52.3% increased food preparation at home and purchased alternative foodstuffs, 53.8% had consumed gluten-containing foods. The Health Eating Index was intermediate/“needs improvement” (mean 65.6 ± 13.3 points); in 49.9% (perception) and 44.4% (questionnaire), adherence was “bad”. Anxiety and depression scores were above the cutoff in 28% and 40.4%, respectively. Adherence and mental health were strongly related. The likelihood of poor adherence was 2.3 times higher (p < 0.004) in participants declaring that pandemic altered GFD. Those suffering depressive symptoms were 1.3 times more likely to have poor adherence (p < 0.000). Depression and faulty GFD (mandatory for treatment) appear, affecting a high proportion of participants, suggesting that support measures aimed at these aspects would help improve the health condition of people that maintain GFD. Comparisons of data currently appearing in the literature available should be cautious because not only cultural aspects but conditions and timing of data collection are most variable.     

The Gluten-Free Diet: Testing Alternative Cereals Tolerated by Celiac Patients

A strict gluten-free diet (GFD) is the only currently available therapeutic treatment for patients with celiac disease, an autoimmune disorder of the small intestine associated with a permanent intolerance to gluten proteins. The complete elimination of gluten proteins contained in cereals from the diet is the key to celiac disease management. However, this generates numerous social and economic repercussions due to the ubiquity of gluten in foods. The research presented in this review focuses on the current status of alternative cereals and pseudocereals and their derivatives obtained by natural selection, breeding programs and transgenic or enzymatic technology, potential tolerated by celiac people. Finally, we describe several strategies for detoxification of dietary gluten. These included enzymatic cleavage of gliadin fragment by Prolyl endopeptidases (PEPs) from different organisms, degradation of toxic peptides by germinating cereal enzymes and transamidation of cereal flours. This information can be used to search for and develop cereals with the baking and nutritional qualities of toxic cereals, but which do not exacerbate this condition.     

Hepatic Steatosis in Patients with Celiac Disease: The Role of Packaged Gluten-Free Foods

Background: An increased risk of nonalcoholic fatty liver disease (NAFLD) in patients with celiac disease (CD) adhering to a gluten-free diet (GFD) was recently reported. The nutritional composition of packaged gluten-free foods (PGFF) has been proposed as a possible cause. This hypothesis has not been investigated further, since a systematic structural nutritional interview for all patients would be problematic in clinical practice. Methods: We administered a simple questionnaire based on a Recency, Frequency, and Monetary value (RFM) analysis (a cornerstone of direct marketing segmentation) to consecutive CD patients on a GFD for >6 months and verified its association with NAFLD. Subgroup analyses were performed to understand whether specific patterns of PGFF consumption were significantly associated with NAFLD. Results: Amongst 147 patients (female 82%, median age 42 years), 45 (30.6%) had NAFLD. Total RFM score (adjusted odds ratio = 1.223, 95% CI: 1.059–1.413, p = 0.006), body mass index, and total cholesterol and triglycerides were independently related to NAFLD, and “Bread and bakery” (p = 0.002), “salty convenience” (p = 0.005), and “sweet convenience” (p = 0.049) products were significantly related with NAFLD. Also, questions about the number of purchased PGFF in the last month (monetary value) and different categories of PGFF consumed in the last week (recency) were particularly able to identify NAFLD patients. Conclusions: The specific GFD dietary habits of CD patients were correlated with the degree of risk of NAFLD. Information was obtained through a questionnaire which could be used in clinical practice to favor a patient-tailored approach and in future studies to verify the reproducibility of our results in different geographical areas.     

Gluten-Free Diet in Children: An Approach to a Nutritionally Adequate and Balanced Diet

Gluten-free diet (GFD) is the cornerstone treatment for celiac disease (CD). GFD implies a strict and lifelong elimination from the diet of gluten, the storage protein found in wheat, barley, rye and hybrids of these grains, such as kamut and triticale. The absence of gluten in natural and processed foods, despite being the key aspect of GFD, may lead to nutritional consequences, such as deficits and imbalances. The nutritional adequacy of GFD is particularly important in children, this the age being of maximal energy and nutrient requirements for growth, development and activity. In recent years, attention has focused on the nutritional quality of gluten-free products (GFPs) available in the market. It is well recognized that GFPs are considered of lower quality and poorer nutritional value compared to the gluten-containing counterparts. The present review focuses on the nutritional adequacy of GFD at the pediatric age, with the aim being to increase awareness of the potential complications associated with this diet, to identify strategies in order to avoid them and to promote a healthier diet and lifestyle in children with CD.     

Application of Dairy Proteins as Technological and Nutritional Improvers of Calcium-Supplemented Gluten-Free Bread

Effect of dairy proteins on gluten-free dough behavior, and nutritional and technological properties of gluten-free bread was evaluated. Experimental doughs, containing dairy powders, showed low consistency. Obtained gluten-free breads were rich in proteins, and, regarding the energy value delivered by proteins, they could be considered as a source of proteins or high in proteins. Applied dairy proteins affected the technological properties of experimental breads causing a significant (p < 0.05) increase of the specific volume, crust darkening, and crumb lightness, depending on the dairy supplementation level, rather than the protein type. Dairy proteins incorporated at a 12% level, significantly (p < 0.05) decreased the hardness; nevertheless, the highest amount of proteins tested led to the opposite effect. These results indicate that milk proteins tested could be successfully added to gluten-free bread with beneficial effects on technological and nutritional properties.     

Food Safety and Cross-Contamination of Gluten-Free Products: A Narrative Review

A gluten-free diet (GFD) is currently the only effective treatment for celiac disease (CD); an individual’s daily intake of gluten should not exceed 10 mg. However, it is difficult to maintain a strict oral diet for life and at least one-third of patients with CD are exposed to gluten, despite their best efforts at dietary modifications. It has been demonstrated that both natural and certified gluten-free foods can be heavily contaminated with gluten well above the commonly accepted threshold of 20 mg/kg. Moreover, meals from food services such as restaurants, workplaces, and schools remain a significant risk for inadvertent gluten exposure. Other possible sources of gluten are non-certified oat products, numerous composite foods, medications, and cosmetics that unexpectedly contain “hidden” vital gluten, a proteinaceous by-product of wheat starch production. A number of immunochemical assays are commercially available worldwide to detect gluten. Each method has specific features, such as format, sample extraction buffers, extraction time and temperature, characteristics of the antibodies, recognition epitope, and the reference material used for calibration. Due to these differences and a lack of official reference material, the results of gluten quantitation may deviate systematically. In conclusion, incorrect gluten quantitation, improper product labeling, and poor consumer awareness, which results in the inadvertent intake of relatively high amounts of gluten, can be factors that compromise the health of patients with CD.     

Challenges of Monitoring the Gluten-Free Diet Adherence in the Management and Follow-Up of Patients with Celiac Disease

Celiac disease (CD) is a chronic gluten-responsive immune mediated enteropathy and is treated with a gluten-free diet (GFD). However, a strict diet for life is not easy due to the ubiquitous nature of gluten. This review aims at examining available evidence on the degree of adherence to a GFD, the methods to assess it, and the barriers to its implementation. The methods for monitoring the adherence to a GFD are comprised of a dietary questionnaire, celiac serology, or clinical symptoms; however, none of these methods generate either a direct or an accurate measure of dietary adherence. A promising advancement is the development of tests that measure gluten immunogenic peptides in stools and urine. Causes of adherence/non-adherence to a GFD are numerous and multifactorial. Inadvertent dietary non-adherence is more frequent than intentional non-adherence. Cross-contamination of gluten-free products with gluten is a major cause of inadvertent non-adherence, while the limited availability, high costs, and poor quality of certified gluten-free products are responsible for intentionally breaking a GFD. Therefore, several studies in the last decade have indicated that many patients with CD who follow a GFD still have difficulty controlling their diet and, therefore, regularly consume enough gluten to trigger symptoms and damage the small intestine.     

Influence of Mediterranean Diet Adherence and Physical Activity on Bone Health in Celiac Children on a Gluten-Free Diet

We aimed to assess the influence of the Mediterranean Diet adherence and physical activity (PA) on body composition, with a particular focus on bone health, in young patients with celiac disease (CD). The CD group (n = 59) included children with CD with a long (>18 months, n = 41) or recent (<18 months, n = 18) adherence to a gluten-free diet (GFD). The non-celiac group (n = 40) included non-celiac children. After adjusting for potential confounders, the CD group showed lower body weight (p = 0.034), lean mass (p = 0.003), bone mineral content (p = 0.006), and bone Z-score (p = 0.036) than non-celiac children, even when the model was further adjusted for adherence to a GFD for at least 18 months. Among CD children, spending greater time in vigorous physical activity was associated with higher lean mass (p = 0.020) and bone mineral density with evidence of statistical significance (p = 0.078) regardless of the time they followed a GFD. In addition, a greater Mediterranean Diet adherence was associated with a higher bone Z-score (p = 0.020). Moreover, lean mass was strongly associated with bone mineral density and independently explained 12% of its variability (p < 0.001). These findings suggest the importance of correctly monitoring lifestyle in children with CD regarding dietary habits and PA levels to improve lean mass and, consequently, bone quality in this population.     

Prevalence of Wheat/Gluten-Related Disorders and Gluten-Free Diet in Paraguay: An Online Survey-Based Study

Gluten-related disorders (GRDs) are increasing around the world, but their magnitude and relevance remain unknown in most Latin American countries. Thus, an online survey was conducted to estimate the prevalence of GRDs as well as adherence to a gluten-free diet (GFD) in Paraguayan adult population. There were 1058 individuals surveyed using a validated questionnaire (response rate of 93.9%). The self-reported prevalence rates were as follows (95% CI): gluten sensitivity (GS), 10.30% (8.53–12.29); non-celiac GS (NCGS), 5.19% (3.94–6.71); physician-diagnosed celiac disease (PD-CD), 3.11% (2.15–4.35); wheat allergy (WA), 2.07% (1.30–3.13); and adherence to GFD, 15.69% (13.55–18.02). Excluding CD, more women than men met the criteria for GRDs, adverse food reactions, and GFD (p < 0.05). Eight respondents reported the coexistence of NCGS with PD-CD and/or WA. Most cases on a GFD indicated medical/dietitian advice for following the diet (68.07%). Non-self-reported GS individuals indicated weight control (46.4%) and the notion that the GFD is healthier (20.2%) as the main motivations for following the diet. GRDs are not uncommon in Paraguayan adult population. It seems that there is awareness about GRDs and the GFD, but training about the diagnosis of GRDs is desirable because of the informed overlapping diagnoses of CD or WA with NCGS. Future studies involving face-to-face interviews are necessary.     

Expanded Role of a Dietitian in Monitoring a Gluten-Free Diet in Patients with Celiac Disease: Implications for Clinical Practice

Access to a registered dietitian experienced in celiac disease (CD) is still limited, and consultation when available focuses primarily on the elimination of gluten from the diet. Thus, the aim of this study was to evaluate the nutritional value of a gluten-free diet (GFD) in adult CD patients before, and one year after, the standard dietary education. The study included 72 CD patients on a GFD and 30 healthy controls. The dietary intake of both groups was assessed through a 3-day food diary, while adherence to a GFD in celiac subjects was assessed using Standardized Dietician Evaluation (SDE). Subsequently, all CD patients received detailed education on gluten sources, and 48 of them participated in a one-year follow-up. Results: Comparison with the control group showed that consumption of plant protein in CD patients was significantly lower, whereas fat and calories were higher. At baseline, only 62% of CD patients adhered to a GFD, but the standard dietary education successfully improved it. However, the nutritional value of a GFD after one year did not change, except for a reduced sodium intake. The CD subjects still did not consume enough calcium, iron, vitamin D, folic acid or fiber. In conclusion, while the standard dietary education improved GFD adherence, it did not significantly alter its nutritional value. Therefore, it is necessary to increase the role of a dietitian in the treatment of CD.     

Prototype Gluten-Free Breads from Processed Durum Wheat: Use of Monovarietal Flours and Implications for Gluten Detoxification Strategies

In this investigation, we reported the production of prototype breads from the processed flours of three specific Triticum turgidum wheat genotypes that were selected in our previous investigation for their potential low toxic/immunogenic activity for celiac disease (CD) patients. The flours were subjected to sourdough fermentation with a mixture of selected Lactobacillus strains, and in presence of fungal endoproteases. The breads were characterized by R5 competitive enzyme linked immunosorbent assay in order to quantify the residual gluten, and the differential efficacy in gluten degradation was assessed. In particular, two of them were classified as gluten-free (<20 ppm) and very low-gluten content (<100 ppm) breads, respectively, whereas the third monovarietal prototype retained a gluten content that was well above the safety threshold prescribed for direct consumption by CD patients. In order to investigate such a genotype-dependent efficiency of the detoxification method applied, an advanced proteomic characterization by high-resolution tandem mass spectrometry was performed. Notably, to the best of our knowledge, this is the first proteomic investigation which benefitted, for protein identification, from the full sequencing of the Triticum turgidum ssp. durum genome. The differences of the proteins’ primary structures affecting their susceptibility to hydrolysis were investigated. As a confirmation of the previous immunoassay-based results, two out of the three breads made with the processed flours presented an exhaustive degradation of the epitopic sequences that are relevant for CD immune stimulatory activity. The list of the detected epitopes was analyzed and critically discussed in light of their susceptibility to the detoxification strategy applied. Finally, in-vitro experiments of human gastroduodenal digestion were carried out in order to assess, in-silico, the toxicity risk of the prototype breads under investigation for direct consumption by CD patients. This approach allowed us to confirm the total degradation of the epitopic sequences upon gastro-duodenal digestion.     

Physico-chemical and sensory characteristics of gluten-free breads made with pine nuts (Araucaria angustifolia) associated to other flours

Pine nuts are the seeds of Araucaria angustifolia, which have a good nutritional value and relevance to be investigated in food technology, especially in bakery products for celiac people. This study aimed to evaluate physico-chemical and sensory properties of gluten-free breads made with pine nuts. Four different formulations (T1, T2,T3, and T4) of bread were prepared, varying the percentages flours, and were submitted to physical, chemical, and sensory analysis. The formulation made with pine nut and potato starch and the one made with pine nuts associated with potato starch and rice flour are promising alternatives for celiac patients.     

Analysis of ingredient and nutritional labeling of commercially available gluten-free bread in Brazil

This study aimed at evaluating the ingredients and nutritional information of commercially-available gluten-free bread (GFB) in Brazil. A total of 128 products were studied, of which 87% presented the sandwich loaf shape. Traditional GFBs (n?=?114) had as main ingredient the refined rice flour and starches, whereas alternative ones (n?=?14) presented whole rice flour. Raw materials suggested by science to improve nutrients and bioactive compounds of gluten-free foodstuffs were observed in the ingredient list of most products (n?=?86); however, they were used in lower levels, thus no significant differences were observed for nutritional information between the different categories of GFB. No products with added vitamins or minerals were found, though 77% of them included hydrocolloids in their formulations – other food additives were also observed. Despite the increased gluten-free food market, there is still a gap between science and market, especially regarding the approaches to improve the GFB diversity and nutritional quality.     

2013 Update on Celiac Disease and Eosinophilic Esophagitis

Celiac disease is a chronic, immune-mediated disorder, characterized by small intestinal inflammation and villous atrophy after the ingestion of gluten by genetically susceptible individuals. Several extraintestinal manifestations have been associated to celiac disease. Eosinophilic esophagitis is a primary disorder of the esophagus characterized by upper gastrointestinal symptoms, absence of gastroesophageal reflux disease and more than 15 eosinophils per high-power field in biopsy specimens. Both celiac disease and eosinophilic esophagitis are caused by aberrant, but distinct, immune responses to ingested antigens and can be responsive to restricted food intake. The aim of this review is to assess whether there is an association between these two pathologies. In the majority of the studies examined, including the studies in pediatric population, the prevalence of eosinophilic esophagitis in subjects with celiac disease was about 10-times that of the general population. We suggest searching for eosinophilic esophagitis in all children undergoing endoscopy for suspicious celiac disease.     

Relationship between Persistent Gastrointestinal Symptoms and Duodenal Histological Findings after Adequate Gluten-Free Diet: A Gray Area of Celiac Disease Management in Adult Patients

A gluten-free diet (GFD) leads to a rapid improvement in gastrointestinal (GI) symptoms, biochemical alterations and duodenal histological damage in the majority of celiac disease (CD) patients. This study aimed to assess the frequency and factors associated with the persistence of GI symptoms/malabsorption signs and their relationship with duodenal histological findings among CD patients on an adequate GFD (mean duration 16 months, range 12–28 months). This longitudinal cohort study included 102 adult CD patients (median age 38.5 years, range 18–76 years, F = 71.6%) diagnosed between 2012 and 2018. A total of 36.3% of the included patients had persistent GI symptoms and/or malabsorption signs (Group 1), while the remaining patients had complete GI well-being without malabsorption signs (Group 2) at the time of histological re-evaluation. The persistence of GI symptoms/signs was associated with a long duration of symptoms/signs before CD diagnosis (≥5 years) (OR 5.3; 95% CI 1.3–21.8) and the presence of constipation at the time of CD diagnosis (OR 7.5; 95% CI 1.3–42) while for other variables, including age at CD diagnosis, sex, duration of GFD, comorbidities, CD serology positivity and severity of duodenal damage at histological re-evaluation, no association was found. According to our results, the persistence of symptoms/signs is not associated with histological findings, and their relationship could be a gray area in CD management.