Advances in Gluten Hypersensitivity: Novel Dietary-Based Therapeutics in Research and Development.

Gluten hypersensitivity is characterized by the production of IgE antibodies against specific wheat proteins (allergens) and a myriad of clinical allergic symptoms including life-threatening anaphylaxis. Currently, the only recommended treatment for gluten hypersensitivity is the complete avoidance of gluten. There have been extensive efforts to develop dietary-based novel therapeutics for combating this disorder. There were four objectives for this study: (i) to compile the current understanding of the mechanism of gluten hypersensitivity; (ii) to critically evaluate the outcome from preclinical testing of novel therapeutics in animal models; (iii) to determine the potential of novel dietary-based therapeutic approaches under development in humans; and (iv) to synthesize the outcomes from these studies and identify the gaps in research to inform future translational research. We used Google Scholar and PubMed databases with appropriate keywords to retrieve published papers. All material was thoroughly checked to obtain the relevant data to address the objectives. Our findings collectively demonstrate that there are at least five promising dietary-based therapeutic approaches for mitigating gluten hypersensitivity in development. Of these, two have advanced to a limited human clinical trial, and the others are at the preclinical testing level. Further translational research is expected to offer novel dietary-based therapeutic options for patients with gluten hypersensitivity in the future.

Outcomes of Serum Food-Specific Immunoglobulin G 4 to Guide Elimination Diet in Patients With Eosinophilic Esophagitis.

INTRODUCTION: Eosinophilic esophagitis (EoE) is associated with atopy; however, recent studies have identified an association with food-specific immunoglobulin G 4 (FS-IgG 4 ) rather than immunoglobulin E antibodies. This study aimed to evaluate the role of serum FS-IgG 4 in guiding an elimination diet and its outcomes. METHODS: Patients with and without EoE were enrolled in a prospective, controlled, single tertiary center trial. Serum FS-IgG 4 titers, esophageal eosinophil counts, and dysphagia symptom questionnaire scores were assessed, and participants with elevated FS-IgG 4 (ImmunoCAP, cutoff of 10 mgA/L) commenced 6-week targeted elimination diet. Repeat serum FS-IgG 4 and endoscopic and histologic examination were performed at 6-week follow-up. RESULTS: Twenty-two patients with active EoE and 13 controls were recruited. Serum FS-IgG 4 to milk, wheat, soy, eggs, and nuts was significantly higher in EoE ( P = 0.0002, P = 0.002, P = 0.003, P = 0.012, and P < 0.001, respectively). Elevated serum FS-IgG 4 to 1 or more food groups (median 2) was identified in 21/22 (95.4%) patients with EoE; 20/21 underwent 6-week dietary elimination. Median reductions in dysphagia symptom questionnaire score and EoE endoscopic reference score after elimination were 8 ( P = 0.0007) and 1 ( P = 0.002), respectively. Nine (45%) patients had histological remission (<15 eosinophils per high-power field). Fall in median esophageal eosinophil count was not statistically significant (50 vs 23; P = 0.068). Serum FS-IgG 4 did not decline by 6-week follow-up. DISCUSSION: Serum FS-IgG 4 to milk, wheat, soy, egg, and nuts was present at higher levels in EoE, with targeted elimination resulting in 45% histologic remission rate. Serum FS-IgG 4 has potential as a noninvasive biomarker in EoE. When successful, FS-IgG 4 -led elimination diet can negate need for medications and be viewed more favorably by patients because of its smaller endoscopic burden compared with empirical elimination diets.

Eosinophilic Esophagitis: A Review.

Importance: Eosinophilic esophagitis (EoE) is a chronic immune-mediated inflammatory disease of the esophagus that affects an estimated 34.4/100 000 people in Europe and North America. EoE affects both children and adults, and causes dysphagia, food impaction of the esophagus, and esophageal strictures. Observations: EoE is defined by symptoms of esophageal dysfunction, such as vomiting, dysphagia, or feeding difficulties, in a patient with an esophageal biopsy demonstrating at least 15 eosinophils per high-power field in the absence of other conditions associated with esophageal eosinophilia such as gastroesophageal reflux disease or achalasia. Genetic factors and environmental factors, such as exposure to antibiotics early in life, are associated with EoE. Current therapies include proton pump inhibitors; topical steroid preparations, such as fluticasone and budesonide; dietary therapy with amino acid formula or empirical food elimination; and endoscopic dilation. In a systematic review of observational studies that included 1051 patients with EoE, proton pump inhibitor therapy was associated with a histologic response, defined as less than 15 eosinophils per high-power field on endoscopic biopsy, in 41.7% of patients, while placebo was associated with a 13.3% response rate. In a systematic review of 8 randomized trials of 437 patients with EoE, topical corticosteroid treatment was associated with histologic remission in 64.9% of patients compared with 13.3% for placebo. Patients with esophageal narrowing may require dilation. Objective assessment of therapeutic response typically requires endoscopy with biopsy. Conclusions and Relevance: EoE has a prevalence of approximately 34.4/100 000 worldwide. Treatments consist of proton pump inhibitors, topical steroids, elemental diet, and empirical food elimination, with esophageal dilation reserved for patients with symptomatic esophageal narrowing.

Grains on the brain: A survey of dog owner purchasing habits related to grain-free dry dog foods.

Grain-free pet food options abound in the pet food market today, representing more than 40% of available dry dog foods in the United States. There is currently a dearth of information about the factors that contribute to a dog owner's choice of a grain-free dry dog food and if those factors are similar among countries. Therefore, the primary objective of the current survey was to identify the variables that are predictive of a dog owner's choice of a grain-free dry food across North America (Canada and the United States) and Europe (France, the United Kingdom and Germany). The survey consisted of 69 questions, took less than 15 minutes to complete and was distributed virtually via Qualtrics (Qualtrics XM, Utah, USA). A total of 3,298 responses were collected, equally distributed between countries. Multinomial logistic regression was performed in SPSS Statistics (Version 26, IBM Corp, North Castle, New York, USA). Male respondents, people from France, people who ranked the importance of ingredients in a pet food in the lower quartiles and people who do not rotate their dog's diet to provide variety were less likely to select 'no grain' when choosing a pet food. In contrast, people who believe that their dog has a food allergy, follow more than 5 specific dietary routines in their own diet, do not try to include grains in their own diet, get their information about pet food from online resources or pet store staff and look for specific claims on pet food (such as 'no fillers'), were all more likely to select 'no grain' when choosing a pet food. This survey provides insight into the similarities and differences in decision making among dog owners in North America and Europe and should be considered when exploring the effects of grain-free dog foods on canine health and well-being.

The practical dietary management of food protein-induced enterocolitis syndrome.

OBJECTIVE: Food protein-induced enterocolitis syndrome (FPIES) is a non-immunoglobulin E-mediated food allergy with potential risk of malnutrition related to the early onset of disease, frequent avoidance of cow's milk, and the possibility of multiple food triggers. This publication is aimed at providing an evidence-based, practical approach to the dietary management of FPIES. DATA SOURCES: This is a narrative review summarizing information from national and international guidelines, retrospective studies, population studies, review articles, case reports, and case series to evaluate for nutritional risk and develop guidance for risk reduction in children with FPIES. STUDY SELECTIONS: We have included retrospective clinical cohort studies, population-based studies, case reports, and case studies. We did not exclude any studies identified owing to the small number of studies addressing the nutritional management of individuals with FPIES. RESULTS: Children with FPIES are at risk of malnutrition owing to suboptimal oral intake, limited food choices, and knowledge deficits related to feeding. In particular, children with 3 or more FPIES triggers seem to be at increased risk for poor weight gain and developing food aversion. Caregivers of children with FPIES also report a high degree of psychosocial burden. CONCLUSION: Appropriate dietary management entails the following 3 essential components: supporting normal growth and development, avoidance of allergens, and advancement of complementary foods. Education to avoid the trigger food and assisting caregivers in creating an individualized, well-designed complementary feeding plan to meet the infant's nutritional needs for optimal growth and development are essential management strategies.

Test-guided dietary management of eczema in children: A randomized controlled feasibility trial (TEST).

BACKGROUND: Parents commonly ask about food allergy tests, to find a cause for their child's eczema, yet the value of routine testing is uncertain. OBJECTIVE: To determine whether a clinical trial comparing test-guided dietary advice versus usual care, for the management of eczema, is feasible. METHODS: Children (>3 months and <5 years) with mild-to-severe eczema, recruited via primary care, were individually randomized (1:1) to intervention or usual care. Intervention participants underwent structured allergy history and skin prick tests (SPT) with dietary advice for cow's milk, hen's egg, wheat, peanut, cashew and codfish. All participants were followed up for 24 weeks. A sample of doctors and parents was interviewed. Registration ISRCTN15397185. RESULTS: From 1059 invitation letters sent to carers of potentially eligible children, 84 were randomized (42 per group) with mean age of 32.4 months (SD 13.9) and POEM of 8.7 (4.8). Of the 42, 6 (14%) intervention participants were advised to exclude one or more foods, most commonly egg, peanut or milk. By participant, 1/6 had an oral food challenge (negative); 3/6 were told to exclude until review in allergy clinic; and 6/6 advised a home dietary trial (exclusion and reintroduction of food over 4-6 weeks) - with 1/6 partially completing it. Participant retention (four withdrawals) and data completeness (74%-100%) were acceptable and contamination low (two usual care participants had allergy tests). There were three minor SPT-related adverse events. During follow-up, 12 intervention and 8 usual care participants had minor, unrelated adverse events plus one unrelated hospital admission. CONCLUSIONS: It is possible to recruit, randomize and retain children with eczema from primary care into a trial of food allergy screening and to collect the outcomes of interest. Changes to recruitment and inclusion criteria are needed in a definitive trial, to ensure inclusion of younger children from more diverse backgrounds.

Food Elimination in the Management of Refractory Chronic Rhinosinusitis: A Pilot Study.

BACKGROUND: Chronic rhinosinusitis (CRS) is one of the most commonly reported chronic diseases. Refractory CRS represents a subgroup of patients who continue to be symptomatic even after adequate medical and surgical therapy. These patients started to form a significant portion of patients with CRS. Food elimination as a therapeutic method to control symptoms of different chronic diseases, such as eosinophilic esophagitis, asthma, and atopic dermatitis, has been described in the literature with variable success rates. OBJECTIVES: To evaluate the effectiveness of food elimination therapy as adjuvant treatment in refractory patients having CRS with positive food sensitization. DESIGN: Prospective open-label study. SETTING: Tertiary academic center. METHODS: Consecutive adult patients with refractory nonobstructive CRS (patients who had persistent sinonasal symptoms despite endoscopic sinus surgery and patent sinuses ostia with adequate medical treatment) with positive food sensitization were included. Subjects were asked to eliminate the sensitized food from their diet. Clinical outcome was assessed using the Lund-Kennedy symptom and Lund-Kennedy endoscopic appearance scores. RESULTS: Twenty-two patients were initially enrolled in the study. Six patients were excluded; 4 were lost to follow-up, and 2 did not eliminate the causal food for the required period. The average age of the patients was 36 years old. There were 10 female and 6 male patients. Nasal discharge and facial pressure were the most common presenting symptoms. Shellfish, egg, and meat mix were the most common eliminated foods. There was a significant difference in the patients' Lund-Kennedy symptom and Lund-Kennedy endoscopic appearance scores at 6 and 12 weeks after food elimination therapy. CONCLUSIONS: Food elimination in refractory CRS is an effective adjuvant treatment and should be considered in the treatment algorithm of patients with persistent symptoms after successfully performed sinus surgery.

Retinoic Acid Ameliorates the Severity of Food Allergy under Allergen Exposure in a Mouse Model with Food Allergy.

Effectiveness of retinoic acid (RA) in treating food allergy is not yet clear. Using an allergic mouse model, we examined the amelioration of the severity of food allergy by daily RA intake with allergen or without. Female Balb/c mice were systemically sensitized to egg white (EW) and alum by intraperitoneal injection. Sensitized mice were provided diets supplemented with 0% (non-treated group), 0.1% EW (allergen group), 0.0017% RA (RA group), or 0.1% EW plus 0.0017% RA (RA+allergen group) with 20% casein for 4 wk. Oral food challenge (OFC) and allergic biomarkers were quantified. The decrease in rectal temperature post-OFC was significantly suppressed in the RA and RA+allergen groups compared to those in the non-treated and allergen groups, respectivety. The plasma levels of ovalbumin-specific IgE, IgA and IgG1 at the study endpoint were higher in the allergen and RA+allergen groups than those in the non-treated and RA+allergen groups, respectivety. Plasma ovalbumin-specific IgG2a levels at the study endpoint were significantly higher in the RA+allergen group than those in the RA groups. The supernatant concentrations of interleukin-10 and interferon-γ in the cultured spleen lymphocytes were highest in the RA+allergen group compared to those in the other groups. Thus, continuous intake of RA under allergen exposure ameliorated the severity of food allergy in a mouse model with food allergy.

Elimination diets for eosinophilic esophagitis: making the best choice.

INTRODUCTION: Dietary elimination therapy has long been an option for patients with eosinophilic esophagitis (EoE). Multiple diets have been reported, with variable efforts involved, efficacy rates, costs, and long-term management plans. Although the pros and cons of dietary elimination therapy have been described, a clear method for deciding on who is the right candidate for a diet, and which diet is best for that candidate, has not been clearly delineated. AREAS COVERED: This article covers the benefits and challenges of dietary elimination therapies for patients with EoE. It outlines factors to consider before opting for an elimination diet, and for choosing which specific elimination diet to follow. Efficacy rates and pros and cons of each specific elimination diet are also discussed. Peer-reviewed published studies testing various elimination diets in patients with EoE were used for that purpose. EXPERT OPINION: Dietary elimination therapy is a long-term management option for patients with EoE. Shared decision making involving the patient and the medical provider is important. Multiple factors including demographics, diet, nutritional status, social and financial support, and acceptance of multiple endoscopies need to be considered. Ongoing multi-disciplinary support during the initiation and maintenance phases of the diet is crucial to ensure good outcomes.

Technical Review on the Management of Eosinophilic Esophagitis: A Report From the AGA Institute and the Joint Task Force on Allergy-Immunology Practice Parameters.

Eosinophilic esophagitis (EoE) is a chronic inflammatory condition of the esophagus. Many new studies have been reported recently that describe EoE management. An expert panel was convened by the American Gastroenterological Association Institute and the Joint Task Force on Allergy-Immunology Practice Parameters to provide a technical review to be used as the basis for an updated clinical guideline. This technical review was developed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. Eighteen focused EoE management questions were considered, with 15 answered using the GRADE framework and 3 with a narrative summary. There is moderate certainty in the evidence that topical glucocorticosteroids effectively reduce esophageal eosinophil counts to <15 per high-power field over a short-term treatment period of 4-12 weeks, but very low certainty about the effects of using topical glucocorticosteroids as maintenance therapy. Multiple dietary strategies may be effective in reducing esophageal eosinophil counts to <15 per high-power field over a short-term treatment period, with moderate certainty for elemental diets, low certainty for empiric 2-, 4-, and 6-food elimination diets, and very low certainty that allergy-based testing dietary eliminations have a higher failure rate compared to empiric diet elimination. There is very low certainty for the effect of proton pump inhibitors in patients with esophageal eosinophilia. Although esophageal dilation appears to be relatively safe, there is no evidence that it reduces esophageal eosinophil counts. There is very low certainty in the effects of multiple other medical treatments for EoE: anti-interleukin-5 therapy, anti-interleukin-13 therapy, anti-IgE therapy, montelukast, cromolyn, and anti-TNF therapy.

Pilot study on non-celiac gluten sensitivity: effects of Bifidobacterium longum ES1 co-administered with a gluten-free diet.

BACKGROUND: Bifidobacterium longum ES1 is a strain probiotic, colonizing the human gut and capable of a degradative action on gliadin. In an attempt to find new nutritional solutions aimed at improving the quality of life of patients with non-celiac gluten sensitivity (NCGS) we evaluated the effectiveness of this strain, in association with a gluten-free diet, comparing its efficacy versus diet therapy alone. METHODS: The experimental design included a non-randomized, open-label, 1:1 intervention study in parallel groups. Enrolled patients with symptoms attributable to NCGS, and with negative diagnoses of both wheat allergy and celiac disease, were included in this three-month trial divided into four outpatient visits (baseline, T1, T2 and T3). Fifteen patients for each group completed the experimental protocol. RESULTS: Our results showed that a combination of diet and probiotic determined a more significant reduction in the frequency and intensity of intestinal and extra-intestinal symptoms, and a clear improvement in stool consistency. CONCLUSIONS: Although the study was carried out on a small number of patients, the results of our pilot trial suggest that a combined strategy of naturally gluten-free diet therapy with administration of the probiotic strain ES1 appears to offer a greater advantage than the dietary regime alone in improving the clinical symptomatic picture and in stabilizing the intestinal microbiota.

LTP allergy/sensitization in a pediatric population.

Plant lipid transfer proteins (LTPs) are widespread plant food allergens, highly resistant to food processing and to the gastrointestinal environment, which have been described as the most common food allergens in the Mediterranean area. LTP allergy is widely described in adults, but it represents an emerging allergen also in the pediatric population. Little is known about the real prevalence and the clinical features of this allergy in children and it still often remains underdiagnosed in these patients. An early identification and a deeper knowledge of this allergy in childhood can avoid severe systemic reactions and improve the child's quality of life. Pediatricians should always consider the possibility of LTP involvement in cases of plant-derived food allergy.

Cytokine release after gluten ingestion differentiates coeliac disease from self-reported gluten sensitivity.

BACKGROUND: Diagnosing coeliac disease (CD) in patients on a gluten-free diet (GFD) is difficult. Ingesting gluten elevates circulating interleukin (IL)-2, IL-8 and IL-10 in CD patients on a GFD. OBJECTIVE: We tested whether cytokine release after gluten ingestion differentiates patients with CD from those with self-reported gluten sensitivity (SR-GS). METHODS: Australian patients with CD (n = 26) and SR-GS (n = 18) on a GFD consumed bread (estimated gluten 6 g). Serum at baseline and at 3 and 4 h was tested for IL-2, IL-8 and IL-10. Separately, Norwegian SR-GS patients (n = 49) had plasma cytokine assessment at baseline and at 2, 4 and 6 h after food bars containing gluten (5.7 g), fructan or placebo in a previous double-blind crossover study. RESULTS: Gluten significantly elevated serum IL-2, IL-8 and IL-10 at 3 and 4 h in patients with CD but not SR-GS. The highest median fold-change from baseline at 4 h was for IL-2 (8.06, IQR: 1.52-24.0; P < 0.0001, Wilcoxon test). The two SR-GS cohorts included only one (1.5%) confirmed IL-2 responder, and cytokine responses to fructan and placebo were no different to gluten. Overall, cytokine release after gluten was present in 22 (85%) CD participants, but 2 of the 4 non-responders remained clinically well after 1 y on an unrestricted diet. Hence, cytokine release occurred in 22 (92%) of 24 'verified' CD participants. CONCLUSIONS: Gluten challenge with high-sensitivity cytokine assessment differentiates CD from SR-GS in patients on a GFD and identifies patients likely to tolerate gluten reintroduction. Systemic cytokine release indicating early immune activation by gluten in CD individuals cannot be detected in SR-GS individuals.

Strategy for Food Reintroduction Following Empiric Elimination and Elemental Dietary Therapy in the Treatment of Eosinophilic Gastrointestinal Disorders.

PURPOSE OF REVIEW: This review presents the available data regarding efficacy of nutritional therapy, highlighting clinical decision points and a strategy for reintroduction of foods following an elemental diet for treatment of eosinophilic gastrointestinal disorders. RECENT FINDINGS: Elemental and empiric elimination diets are highly effective treatments for eosinophilic gastrointestinal diseases. Standardization in the reintroduction phase, after utilizing the diet for disease remission, is lacking. Clinicians are confronted with multiple challenges regarding the best practice for food reintroduction and identification of potential dietary triggers including order of foods being challenged and duration between endoscopic procedures. Individualization is required for preference and adherence to optimize quality of life and treatment success for this burdensome and life altering immune driven gastrointestinal disorder. Age specific concerns for children, teenagers, and adults should be assessed using a patient centric approach.