Large Gliadin Peptides Detected in the Pancreas of NOD and Healthy Mice following Oral Administration

Abstract

Gluten promotes type 1 diabetes in nonobese diabetic (NOD) mice and likely also in humans. In NOD mice and in non-diabetes-prone mice, it induces inflammation in the pancreatic lymph nodes, suggesting that gluten can initiate inflammation locally. Further, gliadin fragments stimulate insulin secretion from beta cells directly. We hypothesized that gluten fragments may cross the intestinal barrier to be distributed to organs other than the gut. If present in pancreas, gliadin could interact directly with the immune system and the beta cells to initiate diabetes development. We orally and intravenously administered 33-mer and 19-mer gliadin peptide to NOD, BALB/c, and C57BL/6 mice and found that the peptides readily crossed the intestinal barrier in all strains. Several degradation products were found in the pancreas by mass spectroscopy. Notably, the exocrine pancreas incorporated large amounts of radioactive label shortly after administration of the peptides. The study demonstrates that, even in normal animals, large gliadin fragments can reach the pancreas. If applicable to humans, the increased gut permeability in prediabetes and type 1 diabetes patients could expose beta cells directly to gliadin fragments. Here they could initiate inflammation and induce beta cell stress and thus contribute to the development of type 1 diabetes.

Gluten‐free diet during pregnancy alleviates signs of diabetes and celiac disease in NOD mouse offspring

“…The presence of gliadin peptides in islets may induce beta‐cell hyperactivity and inflammatory stress, which could increase expression and activity of tTG, PTMs of islet autoantigens, T cell activation, destruction of the beta cells, and type 1 diabetes . In the present study, we found no difference in the islet TG activity in mice that were on GF and STD diet in utero.…”

“…We have provided evidence that gliadin peptides localize to the pancreas after oral gavage in mice and that gliadin peptides increase the glucose‐stimulated insulin secretion in rat islets by closure of ATP‐sensitive K‐channels . Therefore, gliadin peptides might induce beta‐cell hyperactivity and increased expression of surface antigens .…”

Are Non-Celiac Autoimmune Diseases Responsive to Gluten-Free Diet?

“…Autoimmune thyroiditis, rheumatoid arthritis, IgA nephropathy, dermatitis herpetiformis and gluten ataxia are some of the examples [58][59][60][61][62][63]. On the other hand, gluten/gliadin peptides are internalized systemically and are secreted in the human urine [64,65], or appear in the mice pancreas following oral administration [66]. One wonders if in the absence of gluten, no immunogenic or neo-epitopes' complexes will be available to drive autoimmunity.…”

Dietary gluten and type 1 diabetes

“…These studies generally consider the timing of introduction of gluten into the diet, and do not report the amount of gluten consumed 56789. Physiological mechanisms that could explain an association between gluten and type 1 diabetes are unknown in humans, but studies done in animal models of the disease suggest that gluten could affect gut permeability (so-called leakiness of the gut), affect gut microbiota, and cause low grade inflammation 101112…”