edited by Elisa Magnanelli M.D.
Recent trade growth in the USA as far as gluten-free products is concerned, partly endorsed by those needing a gluten-free diet, has brought into question the possible onset of gluten reaction different from Celiac disease and Wheat allergy. It is now getting clear that, in addition to Celiac disease and Wheat allergy, cases of gluten reaction in which neither allergic nor autoimmune mechanisms can be demonstrated also exist. They are generally defined as non-celiac gluten sensitivity forms or simply Gluten Sensitivity. Some people having ailments when they eat gluten-containing food and showing improvement going on a gluten-free diet, can be affected by Gluten Sensitivity rather than by Celiac disease. Gluten Sensitivity is a different pathology from Celiac disease and is not associated with the presence of anti-tTG2 autoantibodies or other autoimmune comorbidity. The small intestine of patients affected by Gluten Sensitivity is usually normal. Nevertheless, the two conditions can not be distinguished from a clinical point of view, because the symptoms experienced by patients suffering from Gluten Sensitivity are often present also in Celiac disease.
Gluten Sensitivity can be defined as gluten reaction excluding both allergic and autoimmune mechanisms (diagnosis by exclusion). Specifically, in these cases wheat immuno-allergic test and serological antibodies anti-EMA and/or anti-tTG test are negative, IgA deficiency is excluded and duodenal biopsy is normal; evidence of biomarkers of immune reaction to gluten (AGA+) is possible, and also symptoms overlapping those of Celiac disease or Wheat allergy. Symptom resolution is improved when patients go on a gluten-free diet, and blind testing procedures are carried out to prevent a possible placebo effect of the introduction of the above mentioned diet.
In physiological conditions, the first contact between food antigens and local immune system in bowel will happen through the'interaction between 'antigen presenting cells, specifically dendritic cells getting intestinal luminal content and promoting tolerating process towards food antigens which are present in the lumen, thus maintaining a disease free state. Toleration maintenance requires high differentiation and maturity regarding both epithelial and immune cellular behaviour and even a minimal alteration of this unstable equilibrium can lead to a pathological condition.
Unfortunately evidence based information in this context are poor, but the fact that non digested or partially digested gliadin can influence a wide range of human cell functions is broadly accepted. It has been recently demonstrated that an early introduction of gliadin-containing cereals in humans increases the risk of autoimmune mechanism activation against insular cells.
Studies carried out on non-obese diabetic mice (NOD - “Non-Obese Diabetic”) and BBDP rats (“BioBreeding Diabetic-Prone”) have defined wheat gliadin as food diabetogen factor. In BBDP rats, exposure to gliadin is associated with the increase of zonulin-dependent intestinal permeability, probably allowing food antigens to come in contact with underlying lamina propria. Zonulin is an important protein released by small bowel mucosa following a series of stimuli (i.e., food antigens, including gluten, or bacteria), involved in the regulation of intestinal paracellular permeability. A normal bowel epithelium is impervious to macromolecules, whereas Celiac disease is characterized by an increase in intestinal permeability and alterations in intercellular junctions; this lead to a compromised function of intestinal barrier. “Tight junctions” (tj) and the multiple proteins which make up such junctions (for instance, occludin, claudin family, “zonula occludens-1” (ZO-1) protein) play a pivotal role as far as the development of immune intestinal response is concerned. When the integrity of intestinal tj is compromised, an immune response can activate against external antigens which cross react with internal antigens, leading in this way to the onset of Celiac disease.
On the contrary, in a research carried out by Sapone et al., patients suffering from Gluten Sensitivity show a normal intestinal permeability, a normal protein claudin-1 e ZO-1 expression compared to celiac patients and significantly higher levels of claudin-4. In the same patients affected by Gluten Sensitivity, over-expression of claudin-4 is associated with an increased expression of “toll-like-2” receptor and an important reduction of FoxP3 T-regulatory cells marker in comparison with checked healthy individuals and celiac patients. Moreover, an increase in α and β IELs classes have been detected in case of Gluten Sensitivity in absence of an increase in the expression of genes, in the intestinal mucosa, involved in adaptive immunity, including those for interleukin IL)-6, IL-21 and interferon-γ. Wheat ATIs are a family of five or more small homolog proteins, which are highly resistant to intestinal proteolysis. They are known for being the main allergens responsible for baker's asthma. Preliminary tests indicate that the addition of 1 to 20 μg/mL ATIs to dendritic cells derived from monocytes stimulates dose-dependent release of IL-8 (Detlef Schuppan, data not published).
With the aim of testing the hypothesis that gluten may cause gastrointestinal symptoms in non-celiac patients, a randomized clinical "re-challenge" study in double-blind placebo has been recently carried out in patients with IBS satisfying the Rome III Criteria System, in which a diagnosis of Celiac disease has been excluded according to best clinical practice and whose symptoms improved thanks to a gluten-free diet. To randomize patients a computer generated list has been followed, or a random numbering kept by an observer who did not took part both to the gluten treatment and the placebo group. During the whole study period, pain scores, reduced faeces consistence and asthenia were significantly higher in the individuals who ate a gluten based diet as opposed to the placebo group, whereas neither evidence of inflammation nor bowel damage or latent Celiac disease have been detected to explain the worsening of symptoms caused by gluten. As a consequence, this study further support the hypothesis that non-celiac Gluten Sensitivity forms belong to the range of gluten-related disorders and confirm discoveries dating back to more than 30 years ago.
Gluten Sensitivity symptoms can be similar to those associated with Celiac disease, but with a prevalence of extraintestinal symptoms, such as behaviour changes, bone or articular pain, muscle cramps, numb legs, weight loss and chronic asthenia. Between 2004 and 2010, 5.896 cases of patients in the care of Center for Celiac Research, University of Maryland, have been studied. Criteria for Gluten Sensitivity have been satisfied by 347 (1:17; 6%) of analysed patients. Their symptoms included abdominal pain (68%), eczema and/or rash (40%), headache (35%), obnubilation (i.e. mental cloudiness) (34%), asthenia (33%), diarrhoea (33%), depression (22%), anaemia (20%), legs, arms and fingers numbness (20%) and articular pain (11%).
Whereas haplotypes MHC II HLA-DQ2 and HLA-DQ8 are present in almost all the patients with Celiac disease, these genes are present only in nearly 50% of patients affected by Gluten Sensitivity, however a higher percentage compared with general population. All the same, an association between haplotype HLA-DQ2 and Gluten Sensitivity has been noticed in the diarrhoea-predominant irritable bowel syndrome (IBS). Therefore, the involvement of an adaptive immune response MHC-dependent in Gluten Sensitivity still remains unclear and will require further investigation. During the last decade, several studies identified sign and symptoms associated with non-celiac forms of Gluten Sensitivity, in particular neuropsychiatric disorders. Schizophrenic patients have AGA antibodies titers, related with Celiac disease and Gluten Sensitivity, higher than expected, considering that the introduction of a gluten-free diet appear to improve the behaviour of a subgroup of children affected by Autistic Spectrum Disorder (ASD). Nevertheless, specific biomarkers for Gluten Sensitivity do not exist yet. Diagnosis is usually based on exclusion criteria; the elimination of gluten-containing food is more frequently used with the aim of evaluating a possible health improvement adopting a gluten-free or gluten-reduced diet.