1. Non Celiac Gluten Sensativity
Dr. Adnan M Hasan
Professor of pediatrics
College of Medicine
University of Sulaimani

2. Definition
A clinical entity induced by the ingestion of gluten leading to intestinal and/or extraintestinal symptoms that resolve once the gluten containing foodstuff is eliminated from the diet, and when celiac disease and wheat allergy have been ruled out.

3. Gluten
Complex of water insoluble proteins from wheat, rye and barley. The major seed proteins in cereals are the alcohol soluble prolamins, a complex group of alcohol-soluble polypeptides that make up about half of the protein in the mature grain.

4. Gluten
The term gluten indicates a broad group of prolamins gliadins and glutenins) found in wheat. Other prolamins showing similar immunogenic properties are found also in rye (secalins), barley (hordeins), and other closely related grains.

6. Pathogenesis
A number of in vitro studies have confirmed the cytotoxicity of gluten’s main antigen, gliadin The α gliadin proteins have agglutinating activity, reduce F-actin content, inhibit cell growth, induce apoptosis, alter redox equilibrium, cause rearrangements in the cytoskeleton via zonulin, and promote loss of tight junctions in the intestinal mucosa.

7. However, patients with NCGS have normal levels of intestinal permeability and expression of tight junction proteins, with the exception of overexpression of claudin-4.

8. Pathogenesis
Interestingly, compared with patients with celiac disease or controls, intestinal tissues from patients with NCGS have increased levels of the Toll-like receptor-2 (TLR2) and TLR4, increased numbers of intraepithelial lymphocytes, and reduced numbers of T-regulatory cells, whereas there are no differences in markers of adaptive immunity

9. Pathogenesis
These findings provide evidence that the intestinal innate immune system might be involved in the development of NCGS. The motifs of the gluten protein that are believed to activate innate immunity in the intestine differ from those that induce an adaptive immune response in subjects with celiac disease.

10. Map of indigestible α-gliadin peptide motifs
Map of indigestible α-gliadin peptide motifs. Peptide regions with apoptotic activity are red, those with immunodominant activity are yellow. Regions that mediate zonulin release and gut permeating activity are blue, and those that regulate CXCR3-dependent release of IL8 are green.

11. Pathogenesis
People can (and do) react to several other components of wheat above and beyond alpha gliadin, the component that is implicated in CD. These include other epitopes of gliadin (beta, gamma, omega), glutenin, wheat germ agglutinin, gluteomorphin, and deamidated gliadin. What’s more, people can react to other types of tissue transglutaminase, including type 3 primarily found in the skin and type 6 primarily found in the brain

12. Wheat ATIs (Amylase Trypsin inhibitors)
In vitro and in vivo studies have suggested that wheat ATIs induce innate immune responses that involve monocytes, macrophages, and dendritic cells activation of the TLR4 complex. Studies of biopsy specimens from patients with celiac disease showed that ATIs increase the gluten-specific T-cell response. Therefore, ATIs could be the long-sought inducers of innate immunity in patients with celiac disease or NCGS.

13. ATIs TLR4
Importantly, ATIs are present in commercial gluten and resist proteolytic digestion, such as by the gastric and enteric proteases pepsin and trypsin, maintaining the ability to activate TLR4 throughout oral ingestion and intestinal passage. Their resistance to proteases could derive from their compact secondary structure, maintained by 5 intrachain disulfide bonds

14. TLR4 signaling leads to the release of inflammatory cytokines and chemokines. ATIs also are adjuvants for adaptive immune reactions in the intestine and possibly nearby lymph nodes, where they also might promote extraintestinal T-cell responses.

15. Clinical features
Symptoms of NCGS usually occur within hours or days after ingestion of gluten-containing grains, and disappear rapidly when these grains are eliminated from the diet.

16. C/F
NCGS most frequently produces a combination of intestinal and extraintestinal symptoms. IBS-like symptoms, such as abdominal pain, gas, distension, and irregular bowel movements, frequently are reported and therefore make it difficult to distinguish NCGS from IBS induced by other causes.

17. C/F
The differential diagnosis is facilitated for patients who also experience extraintestinal symptoms, including headache or frank migraine, foggy mind, chronic fatigue, joint and muscle pain, tingling of the extremities, leg or arm numbness, eczema, anemia, depression, or for patients who report a reduction in immune-mediated symptoms on a GFD.

18. C/F
Children with NCGS mainly have intestinal symptoms such as abdominal pain and chronic diarrhea without weight loss Less frequently, they present with extraintestinal manifestations, including fatigue, autism and attention-deficit disorders

19. Diagnosis
Exclusion of CD and wheat allergy

20. Array 3 (from Cyrex Laboratories)

21. CD NCGS WA
Time interval from gluten exposure to weeks hours to days minutes to hours onset of symptoms Pathogenesis Adaptive Innate Allergic HLA DQ 2/8 restricted Not Not Autoantibodies Present ?? Absent Enteropathy Present always Absent IEL Absent Es LP Symptoms Intestinal and extraintestinal Complications Comorbidities Comorbidities No Comorbidities Long term comp ? Short term comp

22. Non-Celiac Gluten Sensitivity Has Narrowed the spectrum of Irritable Bowel Syndrome: A Double- Blind Randomized Placebo-Controlled Trial Bijan Shahbazkhani et al.
80 patients followed an “almost-gluten-free” diet (dietary compliance was considered optimal if consumption of gluten was below 100 mg/day, the equivalent of roughly 1/8 tsp of wheat flour).
Nutrients 2015, 7, ; doi: /nu

23. Bijan Shahbazkhani et al.
After six weeks, the 72 patients that complied with the diet and experienced significant improvement were then randomized into two groups: Group A, and Group B.
Group A (35 patients) was given a 100 g packet containing a gluten meal (free of FODMAPs). Group B (37 patients) was given a placebo packet (100 g) containing rice flour, corn starch, and glucose.
Patients in both groups consumed the powders for six weeks, while both groups continued on gluten-free diets.

24. Bijan Shahbazkhani et al.
After six weeks of the diet symptoms were controlled in only 26% of the gluten group, compared with 84% of the placebo group. In the gluten-containing group, all symptoms especially bloating and abdominal pain increased significantly one week after starting the gluten

25. Bijan Shahbazkhani et al.
The authors point out that it is important to properly identify gluten intolerance and distinguish it from FODMAP intolerance because some recent research suggests that long-term low FODMAP diets may have adverse effects on the gut microbiome.

26. Thank you