Translational Chemistry Meets Gluten‐Related Disorders

Abstract

Gluten‐related disorders are a complex group of diseases that involve the activation of the immune system triggered by the ingestion of gluten. Among these, celiac disease, with a prevalence of 1 %, is the most investigated, but recently, a new pathology, named nonceliac gluten sensitivity, was reported with a general prevalence of 7 %. Finally, there other less‐prevalent gluten‐related diseases such as wheat allergy, gluten ataxia, and dermatitis herpetiformis (with an overall prevalence of less than 0.1 %). As mentioned, the common molecular trigger is gluten, a complex mixture of storage proteins present in wheat, barley, and a variety of oats that are not fully degraded by humans. The most‐studied protein related to disease is gliadin, present in wheat, which possesses in its sequence many pathological fragments. Despite a lot of effort to treat these disorders, the only effective method is a long‐life gluten‐free diet. This Review summarizes the actual knowledge of gluten‐related disorders from a translational chemistry point of view. We discuss what is currently known from the literature about the interaction of gluten with the gut and the critical host responses it evokes and, finally, connect them to our current and novel molecular understanding of the supramolecular organization of gliadin and the 33‐mer gliadin peptide fragment under physiological conditions.

Large supramolecular structures of 33-mer gliadin peptide activate toll-like receptors in macrophages

“…They are named according to clinical symptoms and immunological response as wheat allergy, celiac disease (CD), gluten ataxia, dermatitis herpetiformis and non-celiac gluten sensibility. 1 In wheat, gliadin and glutenin are the major components of gluten. 2 It is known that humans do not fully degrade gliadin and after its digestion, some large peptic fragments remain unprocessed.…”

The Effect of Gluten-Free Diet on Health and the Gut Microbiota Cannot Be Extrapolated from One Population to Others

“…Interestingly, other autoantibodies may also be involved, especially in extraintestinal manifestations, such as anti-ganglioside, anti-synapsin I and anti-actin antibodies [ 18 ]. Patients with CD present either typical or atypical symptoms [ 19 ] and CD is believed to perpetuate other maladies and often presents simultaneously with other autoimmune diseases [ 20 , 21 , 22 , 23 ]. Despite the great progress in CD research, new key emerging findings suggest previously unknown features of CD pathogenesis, for example at the transcriptome level of immune cells [ 24 ].…”

“…The fact that genetic susceptibility is not determinant for the presentation of CD (30–40% of the population have the required genotype but the prevalence of CD is only about 1%) has prompted research to discover what other factors can predict the clinical manifestation of the disease [ 21 ]. For example, there is enough evidence to suggest that the gut microbiota (especially Bacteria) plays a role in the onset and clinical manifestations of CD [ 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ] and probably other GRD.…”

Molecular mechanisms of 33-mer gliadin peptide oligomerisation

“…The 33-mer gliadin peptide, LQLQPFPQPQLP 69 YPQPQLP 76 Y PQPQLP 83 YPQPQPF, is a proteolytical resistant fragment of gliadin, which is a dietary protein found in the gluten of wheat, rye, barley and some varieties of oats. 1,2 The incomplete proteolysis of 33-mer in humans was demonstrated by an analysis of human stool and urine, of subjects under glutencontaining diet, by using different ELISA methods. 3 It has been found that the 33-mer is the immunodominant peptide that triggers the adaptive immune response in celiac disease 4 , but the early events of the disease, as well as the role of 33-mer in other gluten-related disorders, remain elusive.…”

“…In the case of well-established amylogenic diseases, different modelling approaches were applied to their studies, such as 2 | J. Name., 2012, 00, [1][2][3] This journal is © The Royal Society of Chemistry 20xx…”