Failure to replicate the diabetes alleviating effect of a maternal gluten-free diet in non-obese diabetic mice.

Type 1 diabetes (T1D) is an autoimmune disease with an unexplained rising incidence for which environmental factors like gluten may play a role. Previously, we showed that a gluten-free (GF) diet provided strictly in utero reduces the autoimmune diabetes incidence in Non-Obese Diabetic (NOD) mice compared to a gluten-containing standard (STD) diet. The current study was initiated to elucidate possible mechanisms behind the diabetes-alleviating effect of the same diet intervention. NOD mice received either a GF Altromin diet or a STD Altromin diet during pregnancy. Female offspring from both groups were fed a STD diet throughout life and their diabetes incidence was recorded for 200 days. The following parameters were measured in 13-week-old female offspring: insulitis degree, glucose and insulin tolerance, and plasma insulin autoantibody titer. The diet intervention showed no reduction in autoimmune diabetes incidence, insulitis degree, glucose nor insulin tolerance and plasma insulin autoantibody titer. In conclusion, this study could not replicate the previously observed diabetes alleviative effects of a maternal gluten-free diet in NOD mouse offspring and could therefore not further elucidate potential mechanisms.

Reduced phosphatidylcholine level in the intestinal mucus layer of prediabetic NOD mice.

Type 1 diabetes (T1D) is an autoimmune disease with rising incidence. Pre- and manifest T1D is associated with intestinal barrier dysfunction, skewed microbiota composition, and serum dyslipidemia. The intestinal mucus layer protects against pathogens and its structure and phosphatidylcholine (PC) lipid composition may be compromised in T1D, potentially contributing to barrier dysfunction. This study compared prediabetic Non-Obese Diabetic (NOD) mice to healthy C57BL/6 mice by analyzing the intestinal mucus PC profile by shotgun lipidomics, plasma metabolomics by mass spectrometry and nuclear magnetic resonance, intestinal mucus production by histology, and cecal microbiota composition by 16 S rRNA sequencing. Jejunal mucus PC class levels were decreased in early prediabetic NOD vs C57BL/6 mice. In colonic mucus of NOD mice, the level of several PC species was reduced throughout prediabetes. In plasma, similar reductions of PC species were observed in early prediabetic NOD mice, where also increased beta-oxidation was prominent. No histological alterations were found in jejunal nor colonic mucus between the mouse strains. However, the ß-diversity of the cecal microbiota composition differed between prediabetic NOD and C57BL/6 mice, and the bacterial species driving this difference were related to decreased short-chain fatty acid (SCFA)-production in the NOD mice. This study reports reduced levels of PCs in the intestinal mucus layer and plasma of prediabetic NOD mice as well as reduced proportions of SCFA-producing bacteria in cecal content at early prediabetes, possibly contributing to intestinal barrier dysfunction and T1D.

Intestinal permeability in type 1 diabetes: An updated comprehensive overview.

The etiopathogenesis of the autoimmune disease type 1 diabetes (T1D) is still largely unknown, however, both genetic and environmental factors contribute to the development of the disease. A major contact surface for environmental factors is the gastrointestinal (GI) tract, where barrier defects in T1D likely cause diabetogenic antigens to enter the body tissues, contributing to beta-cell autoimmunity. Human and animal research imply that increased intestinal permeability is an important disease determinant, although the underlying methodologies, interpretations and conclusions are diverse. In this review, an updated comprehensive overview on intestinal permeability in patients with T1D and animal models of T1D is provided in the categories: in vivo permeability, ex vivo permeability, zonulin, molecular permeability and blood markers. Across categories, there is consistency pointing towards increased intestinal permeability in T1D. In animal models of T1D, the intestinal permeability varies with age and strains implying a need for careful selection of method and experimental setup. Furthermore, dietary interventions that affect diabetes incidence in animal models does also impact the intestinal permeability, suggesting an association between increased intestinal permeability and T1D development.