Proteins from Modern and Ancient Wheat Cultivars: Impact on Immune Cells of Healthy Individuals and Patients with NCGS

In non-celiac gluten sensitivity (NCGS), the elimination of wheat results in a clear symptom improvement, but gluten has still not been proven as (the sole) trigger. Due to the increase in the prevalence of gluten-related diseases, the breeding of high-performance wheat cultivars is discussed as a trigger. To analyze the immune stimulation and signal pathways, the immune cells of healthy subjects and patients with NCGS were stimulated with gliadins from wheat, and the expression and secretion of interleukin 1ß (IL1ß) and interleukin 6 (IL6) were studied. To determine the impact of wheat breeding, the monocyte cell line THP1 and human immune cells were stimulated with gliadin, glutenin, and albumin/globulin fractions of ancient and modern cereals, and expression of inflammatory molecules was checked. Immune cells of patients with NCGS showed an increased expression of IL1ß and IL6 after stimulation with gliadins compared to immune cells of healthy controls. Gliadins caused a strong activation of P-STAT3 in immune cells of healthy controls, and inhibitors of JAK and NFκB pathways considerably reduced this response. In addition to gliadins, we further showed that glutenins and albumin/globulins from all wheat cultivars from the last century, and especially from einkorn and spelt, also markedly induced the expression of inflammatory genes in THP1 and human immune cells. There was no correlation between enhanced immune stimulation and ancient or modern cultivars. This does not support the hypothesis that modern wheat breeding is responsible for the increase in gluten-related diseases. An altered immune situation is suggested in patients with NCGS

Whole-Body Electromyostimulation Combined With Individualized Nutritional Support Improves Body Composition in Patients With Hematological Malignancies – A Pilot Study

Patients undergoing the complex treatment for hematological malignancies are exposed to a high physiological and psychological distress inducing fatigue and physical inactivity. In line with cancer-related metabolic changes patients are predisposed for skeletal muscle mass loss that leads to a functional decline, affects therapeutic success, and quality of life. Benefits of physical exercise and nutritional interventions on muscle maintenance are observed in solid cancer patients, but marginally investigated in patients with hematological cancer. We here studied the effects of a combined supportive exercise and nutrition intervention using whole-body electromyostimulation (WB-EMS) training and individualized nutritional support in patients actively treated for hematological malignancy. In a controlled pilot trial, 31 patients (67.7% male; 58.0 ± 16.7 years) with various hematological cancers were allocated to a control group (n = 9) receiving nutritional support of usual care regarding a high protein intake (>1.0 g/kg/d) or to a physical exercise group (n = 22) additionally performing WB-EMS training twice weekly for 12 weeks. Bodyweight and body composition assessed by bioelectrical impedance analysis were measured every 4 weeks. Physical function, blood parameters, quality of life and fatigue were assessed at baseline and after 12 weeks. No WB-EMS-related adverse effects occurred. Patients attending the exercise program presented a higher skeletal muscle mass than controls after 12-weeks (1.51 kg [0.41, 2.60]; p = 0.008). In contrast, patients of the control group showed a higher fat mass percentage than patients of the WB-EMS group (-4.46% [-7.15, -1.77]; p = 0.001) that was accompanied by an increase in serum triglycerides in contrast to a decrease in the WB-EMS group (change ± SD, control 36.3 ± 50.6 mg/dl; WB-EMS -31.8 ± 68.7 mg/dl; p = 0.064). No significant group differences for lower limb strength, quality of life, and fatigue were detected. However, compared to controls the WB-EMS group significantly improved in physical functioning indicated by a higher increase in the 6-min-walking distance (p = 0.046). A combined therapeutic intervention of WB-EMS and protein-rich nutritional support seems to be safe and effective in improving skeletal muscle mass and body composition in hematological cancer patients during active oncological treatment.Clinical Trial Registration:www.ClinicalTrials.gov, identifier NCT02293239

Muscle-derived cytokines reduce growth, viability and migratory activity of pancreatic cancer cells

The evidence that regular physical exercise reduces the risk of developing cancer is well described. However, the interaction between physical exercise and cancer is not fully clarified yet. Several myokines released by skeletal muscle appear to have a direct anti-tumour function. There are few data on myokine secretion after exercise in patients with advanced tumours. Pancreatic cancer (PC) is a very aggressive and usually fatal cancer. To investigate the effects of exercise in PC, the blood of advanced-stage PC patients was analysed after 12 weeks of resistance training using whole-body electromyostimulation. After the 12-week training period, the patient serum inhibited the proliferation and the motility of PC cells and enhanced PC cell apoptosis. The impact of exercise training was also investigated in an exercise-mimicking in vitro model using electric pulse stimulation of human myotubes and revealed similar anti-tumour effects on PC cells, clearly indicating direct cancer-protective properties of activated skeletal muscle. Protein and gene expression analyses in plasma from exercise-trained patients and in myotube cultures after in vitro exercise showed that interleukin 10 (IL10), C-X-C motif ligand 1 (CXCL1) and C-C motif chemokine ligand 4 (CCL4) are myokines released from activated skeletal muscle. In accordance with the effects of serum from exercise-trained patients, the supplementation with recombinant IL10, CXCL1 and CCL4 impaired growth and migration of PC cells. Treatment of PC cells with these myokines upregulated caspase 3/7 expression and the cleavage of poly(ADP-ribose) polymerase, leading to enhanced PC cell death. The identification of myokines with anti-tumour properties in advanced-stage PC patients after exercise opens a new perspective in supportive therapy with sports and exercise for cancer patients

The Overlapping Area of Non-Celiac Gluten Sensitivity (NCGS) and Wheat-Sensitive Irritable Bowel Syndrome (IBS): An Update

Gluten-related disorders have recently been reclassified with an emerging scientific literature supporting the concept of non-celiac gluten sensitivity (NCGS). New research has specifically addressed prevalence, immune mechanisms, the recognition of non-immunoglobulin E (non-IgE) wheat allergy and overlap of NCGS with irritable bowel syndrome (IBS)-type symptoms. This review article will provide clinicians with an update that directly impacts on the management of a subgroup of their IBS patients whose symptoms are triggered by wheat ingestion

Diagnosis of Non-Celiac Gluten Sensitivity (NCGS): The Salerno Experts' Criteria

Non-Celiac Gluten Sensitivity (NCGS) is a syndrome characterized by intestinal and extra-intestinal symptoms related to the ingestion of gluten-containing food, in subjects that are not affected by either celiac disease or wheat allergy. Given the lack of a NCGS biomarker, there is the need for standardizing the procedure leading to the diagnosis confirmation. In this paper we report experts’ recommendations on how the diagnostic protocol should be performed for the confirmation of NCGS. A full diagnostic procedure should assess the clinical response to the gluten-free diet (GFD) and measure the effect of a gluten challenge after a period of treatment with the GFD. The clinical evaluation is performed using a self-administered instrument incorporating a modified version of the Gastrointestinal Symptom Rating Scale. The patient identifies one to three main symptoms that are quantitatively assessed using a Numerical Rating Scale with a score ranging from 1 to 10. The double-blind placebo-controlled gluten challenge (8 g/day) includes a one-week challenge followed by a one-week washout of strict GFD and by the crossover to the second one-week challenge. The vehicle should contain cooked, homogeneously distributed gluten. At least a variation of 30% of one to three main symptoms between the gluten and the placebo challenge should be detected to discriminate a positive from a negative result. The guidelines provided in this paper will help the clinician to reach a firm and positive diagnosis of NCGS and facilitate the comparisons of different studies, if adopted internationally

Diagnosis of Non-Celiac Gluten Sensitivity (NCGS)

Non-Celiac Gluten Sensitivity (NCGS) is a syndrome characterized by intestinal and extra-intestinal symptoms related to the ingestion of gluten-containing food, in subjects that are not affected by either celiac disease or wheat allergy. Given the lack of a NCGS biomarker, there is the need for standardizing the procedure leading to the diagnosis confirmation. In this paper we report experts’ recommendations on how the diagnostic protocol should be performed for the confirmation of NCGS. A full diagnostic procedure should assess the clinical response to the gluten-free diet (GFD) and measure the effect of a gluten challenge after a period of treatment with the GFD. The clinical evaluation is performed using a self-administered instrument incorporating a modified version of the Gastrointestinal Symptom Rating Scale. The patient identifies one to three main symptoms that are quantitatively assessed using a Numerical Rating Scale with a score ranging from 1 to 10. The double-blind placebo-controlled gluten challenge (8 g/day) includes a one-week challenge followed by a one-week washout of strict GFD and by the crossover to the second one-week challenge. The vehicle should contain cooked, homogeneously distributed gluten. At least a variation of 30% of one to three main symptoms between the gluten and the placebo challenge should be detected to discriminate a positive from a negative result. The guidelines provided in this paper will help the clinician to reach a firm and positive diagnosis of NCGS and facilitate the comparisons of different studies, if adopted internationally

A randomized trial of a transglutaminase 2 inhibitor for celiac disease

BACKGROUND In celiac disease, small intestinal transglutaminase 2 causes deamidation of glutamine residues in gluten peptides, which enhances stimulation of T cells and leads to mucosal injury. Inhibition of transglutaminase 2 is a potential treatment for celiac disease. METHODS In a proof-of-concept trial, we assessed the efficacy and safety of a 6-week treatment with ZED1227, a selective oral transglutaminase 2 inhibitor, at three dose levels as compared with placebo, in adults with well-controlled celiac disease who underwent a daily gluten challenge. The primary end point was the attenuation of gluten-induced mucosal damage, as measured by the ratio of villus height to crypt depth. Secondary end points included intraepithelial lymphocyte density, the Celiac Symptom Index score, and the Celiac Disease Questionnaire score (for assessment of health-related quality of life). RESULTS Of the 41 patients assigned to the 10-mg ZED1227 group, the 41 assigned to the 50-mg group, the 41 assigned to the 100-mg group, and the 40 assigned to the placebo group, 35, 39, 38, and 30 patients, respectively, had adequate duodenal-biopsy samples for the assessment of the primary end point. Treatment with ZED1227 at all three dose levels attenuated gluten-induced duodenal mucosal injury. The estimated difference from placebo in the change in the mean ratio of villus height to crypt depth from baseline to week 6 was 0.44 (95% confidence interval [CI], 0.15 to 0.73) in the 10-mg group (P=0.001), 0.49 (95% CI, 0.20 to 0.77) in the 50-mg group (P<0.001), and 0.48 (95% CI, 0.20 to 0.77) in the 100-mg group (P<0.001). The estimated differences from placebo in the change in intraepithelial lymphocyte density were -2.7 cells per 100 epithelial cells (95% CI, -7.6 to 2.2) in the 10-mg group, -4.2 cells per 100 epithelial cells (95% CI, -8.9 to 0.6) in the 50-mg group, and -9.6 cells per 100 epithelial cells (95% CI, -14.4 to -4.8) in the 100-mg group. Use of the 100-mg dose may have improved symptom and quality-of-life scores. The most common adverse events, the incidences of which were similar across all groups, were headache, nausea, diarrhea, vomiting, and abdominal pain. Rash developed in 3 of 40 patients (8%) in the 100-mg group. CONCLUSIONS In this preliminary trial, treatment with ZED1227 attenuated gluten-induced duodenal mucosal damage in patients with celiac disease.publishedVersionPeer reviewe

Dietary Effects on Microbiota—New Trends with Gluten-Free or Paleo Diet

A well-balanced diet is the basis for a healthy life. Both the western diet and special diets can have a relevant impact on the microbiome and promote the development of various diseases. There has been an increase in food-related disorders in recent years, largely associated with dramatic changes in food consumption trends and main nutrients. A major response to food intolerances has been the adoption of new dietary trends involving the reduction or exclusion of specific food ingredients. Especially gluten-containing, but also gluten-free cereals are in the cross-fire. Supporters of the gluten-free diet argue that gluten triggers inflammation and related diseases, while followers of the Paleo diet drastically impeach all cereals as dangerous for human health. To date, no controlled studies support or reject a positive health effect of a gluten-free or cereal-free diet. Future large-scale studies need to evaluate the effect of gluten-containing and gluten-free cereals and the various diets on human health, inflammatory parameters, clinical symptoms, and the gut microbiota (including the bacteria, fungi, and viruses). Dietary-associated changes in compositional and functional microbiota traits should be correlated with the health status for the future development of dietary recommendations and potential clinical interventions

Microbiota in the Gastrointestinal Tract

Gut microbiota are permanent residents of humans with the highest concentrations being found in human colon. Humans get the first contact with bacteria at delivery, and microbiota are subject of permanent change during the life. The individual microbiota pattern is highly variable and varying environmental conditions, e.g., diets, antigen exposure, infections, or medication, as well as genetics, age, or hygiene factors, strongly influence the bacterial community. A fine interaction between the host and microbiota determines the outcome of health or disease. The gut immune system is constantly challenged to distinguish between commensal non-invasive bacteria and potential pathogens. Goblet cells produce mucins that prevent most gut bacteria from penetrating through intestinal epithelial barrier, and Paneth cells are the main supplier of anti-microbial defensins. Gut epithelial and immune cells recognize bacteria via surface markers and they initiate an adequate immune answer. A dysbiosis is noticed in several diseases, but the crucial role in pathogenesis has to be proven. Prebiotics or probiotics are discussed as valuable tools to preserve or restore a healthy gut community