A Maternal Gluten-Free Diet Reduces Inflammation and Diabetes Incidence in the Offspring of NOD Mice

Abstract

Early-life interventions in the intestinal environment have previously been shown to influence diabetes incidence. We therefore hypothesized that a gluten-free (GF) diet, known to decrease the incidence of type 1 diabetes, would protect against the development of diabetes when fed only during the pregnancy and lactation period. Pregnant nonobese diabetic (NOD) mice were fed a GF or standard diet until all pups were weaned to a standard diet. The early-life GF environment dramatically decreased the incidence of diabetes and insulitis. Gut microbiota analysis by 16S rRNA gene sequencing revealed a pronounced difference between both mothers and their offspring on different diets, characterized by increased numbers of Akkermansia, Proteobacteria, and TM7 in the GF diet group. In addition, pancreatic forkhead box P3 regulatory T cells were increased in GF-fed offspring, as were M2 macrophage gene markers and tight junction-related genes in the gut, while intestinal gene expression of proinflammatory cytokines was reduced. An increased proportion of T cells in the pancreas expressing the mucosal integrin a4b7 suggests that the mechanism involves increased trafficking of gut-primed immune cells to the pancreas. In conclusion, a GF diet during fetal and early postnatal life reduces the incidence of diabetes. The mechanism may involve changes in gut microbiota and shifts to a less proinflammatory immunological milieu in the gut and pancreas.Gluten has previously been shown to affect the development of type 1 diabetes (T1D) in animal models. A gluten-free (GF) diet decreased the incidence of diabetes from 64% to 15% when nonobese diabetic (NOD) mice were fed a GF diet after weaning (1), and eating a GF diet decreased the incidence of diabetes to just 6% in the offspring in two generations, which indicates that the interplay between gut antigens and immune pathways leading to diabetes is particularly important in the preweaning period when insulitis starts to progress (2).Accumulating evidence suggests that gut immune reactivity is skewed in human and murine diabetic patients. Studies in young human patients with T1D have demonstrated increased numbers of interferon-g (IFN-g)-producing, interleukin (IL)-1a-producing, and IL-4-producing cells in the small intestinal lamina propria, reflecting T1D preceded by intestinal immune activation (3). Similarly in NOD mice, a diabetes-promoting diet induced proinflammatory cytokines IFN-g and tumor necrosis factor-a in the small intestinal lamina propria (4), and an antidiabetogenic diet decreased the high numbers of CD11b + CD11c+ dendritic cells (DCs) found in the colon lamina propria (5). Under germ-free conditions, reduced expression of forkhead box P3 (FoxP3) in the ileum, colon, and the draining lymph node was associated with accelerated development of insulitis in NOD mice (6), and, likewise in humans, Badami et al. (7) found that jejunal biopsy samples from T1D patients showed reduced frequency of CD42 regulatory T cells (Tregs). The link between the gut and pancreas has also...

Dietary gluten increases natural killer cell cytotoxicity and cytokine secretion

“…We have previously shown that a SGF diet reduces incidence of T1D in NOD mice to 6% compared to 15% in GF [1,51]. Recently, it was shown in NOD mice that a maternal GF diet reduces diabetes incidence in the offspring [52]. Thus, our data indicate that a GF diet may prevent diabetes, by generally reducing the number of NKp46 + NK cells, cellular proliferation, and downregulating the activating receptor NKG2D on NK cells, making them less autoreactive.…”

Intervention for Dysbiosis in Children Born by C-Section

“…Studies in mice demonstrate that a maternal glutenfree diet increases the number of Akkermansia, Proteobacteria, in the offspring's gut microbiota and reduces the incidence of diabetes and low-grade inflammation [18]. It has also been shown in humans that an "unhealthy" mother's diet during pregnancy or poor early childhood nutrition can lead to the establishment of a defective intestinal microbiota [19].…”

Type 1 diabetes and gut microbiota: Friend or foe?

“…Other components from cow’s milk, such as casein, can alter gut permeability and potentially promote the incidence of T1D (22, 23). Food-derived gluten has also been shown to modify gut permeability and again potentially affect the development of T1D (20, 21). Interestingly, mice treated with a gluten-free diet showed modifications in gut microbiota and protection from T1D (20, 21).…”

“…Food-derived gluten has also been shown to modify gut permeability and again potentially affect the development of T1D (20, 21). Interestingly, mice treated with a gluten-free diet showed modifications in gut microbiota and protection from T1D (20, 21). Consistently, accumulating studies showed in recent years the involvement of environment factors, particularly an association with gut microbiota, in the pathogenesis of T1D.…”