Low Incidence of Spontaneous Type 1 Diabetes in Non-Obese Diabetic Mice Raised on Gluten-Free Diets Is Associated with Changes in the Intestinal Microbiome

Abstract

Human and animal studies strongly suggest that dietary gluten could play a causal role in the etiopathogenesis of type 1 diabetes (T1D). However, the mechanisms have not been elucidated. Recent reports indicate that the intestinal microbiome has a major influence on the incidence of T1D. Since diet is known to shape the composition of the intestinal microbiome, we investigated using non-obese diabetic (NOD) mice whether changes in the intestinal microbiome could be attributed to the pro- and anti-diabetogenic effects of gluten-containing and gluten-free diets, respectively. NOD mice were raised on gluten-containing chows (GCC) or gluten-free chows (GFC). The incidence of diabetes was determined by monitoring blood glucose levels biweekly using a glucometer. Intestinal microbiome composition was analyzed by sequencing 16S rRNA amplicons derived from fecal samples. First of all, GCC-fed NOD mice had the expected high incidence of hyperglycemia whereas NOD mice fed with a GFC had significantly reduced incidence of hyperglycemia. Secondly, when the fecal microbiomes were compared, Bifidobacterium, Tannerella, and Barnesiella species were increased (p = 0.03, 0.02, and 0.02, respectively) in the microbiome of GCC mice, where as Akkermansia species was increased (p = 0.02) in the intestinal microbiomes of NOD mice fed GFC. Thirdly, both of the gluten-free chows that were evaluated, either egg white based (EW-GFC) or casein based (C-GFC), significantly reduced the incidence of hyperglycemia. Interestingly, the gut microbiome from EW-GFC mice was similar to C-GFC mice. Finally, adding back gluten to the gluten-free diet reversed its anti-diabetogenic effect, reduced Akkermansia species and increased Bifidobacterium, Tannerella, and Barnesiella suggesting that the presence of gluten is directly responsible for the pro-diabetogenic effects of diets and it determines the gut microflora. Our novel study thus suggests that dietary gluten could modulate the incidence of T1D by changing the gut microbiome.

Early infant feeding and risk of developing islet autoimmunity and type 1 diabetes

“…The mechanisms by which early gluten exposure influences the immune system are not fully understood. Evidence from animal models suggests a complex interplay between dietary factors and gut microbiome being relevant in the disease pathogenesis [7]. Results from the BABYDIET cohort further support these findings by demonstrating that the gut microbiome changes markedly during the first year of life and is strongly affected by breastfeeding and solid food introduction [8].…”

Effects of microcystin-LR on gut microflora in different gut regions of mice

“…Interestingly, a similar microbial shift was shown in a study of diabetic mice, which found 28% reduction in the Lachnospiraceae family and a 54% reduction in the Oscillibacter genus in diabetic versus nondiabetic mice (McDermid, 2012). At the meantime, previous studies also found increased Barnesiella in dietary gluten induced hyperglycemia and Type 1 diabetes of non-obese diabetic mice (Marietta et al, 2013), and in NASH-prone mice which developed hepatic macrovesicular steatosis (Le Roy et al, 2013). Most notably, it should be mentioned that the mice in the MC-LR-treated group did show signs of NASH (unpublished data).…”

The intestinal microbiome in type 1 diabetes

“…However, in a recent study, NOD mice were raised on either gluten-containing chows (GCC) or gluten-free chows (GFC). GFC-fed mice had a significantly reduced incidence of hyperglycaemia, which was associated with changes in bacterial genera compared to the GCC-fed mice [51]. While the effects of gluten on disease development in a human trial were different than in the NOD study, these studies show the feasibility of early dietary interventions in T1D and the further need to study whether and if these interventions alter the microbiota and associated effects on immunoregulation and disease development.…”