A wheat-based, diabetes-promoting diet induces a Th1-type cytokine bias in the gut of NOD mice

Flohé, Stefanie B.; Wasmuth, Hermann E.; Kerad, J.B; Beales, P. E.; Pozzilli, Paolo; Elliott, Robert B.; Hill, J. P.; Scott, Fraser W.; Kolb, Hubert

doi:10.1016/s1043-4666(02)00486-6

Cited by 47 publications

(28 citation statements)

References 16 publications

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“…It seems reasonable to assume that gluten and certain microbes have a synergistic effect on the development of T1D, as was also recently suggested by Patrick et al (17). Cytokine profiles of gutassociated lymphoid tissue have revealed a strong association between intestinal IFN-g production and the incidence of diabetes, especially in several gluten intervention studies (4,11,(17)(18)(19)(20). Also, type 1 T-helper cells proliferated specifically in the mesenteric lymph node (MLN) in response to wheat protein antigens (19).…”

Section: Cd11cmentioning

confidence: 77%

“…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 +…”

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confidence: 99%

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

et al. 2014

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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...

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Section: Cd11cmentioning

confidence: 77%

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confidence: 99%

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

et al. 2014

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“…Wheat gluten has been identified as a main contributor of gut barrier dysfunction in coeliac disease and as a potential source of gut barrier dysfunction in type 1 diabetes [2,13]. NOD mice fed a wheat gluten diet develop a Th1 cytokine bias in the gut [30]. This diet promotes small intestinal enteropathy [31], and increases the incidence of diabetes [31].…”

Section: Discussionmentioning

confidence: 99%

Gut barrier disruption by an enteric bacterial pathogen accelerates insulitis in NOD mice

et al. 2009

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Aims/hypothesis Increased exposure to enteric microbes as a result of intestinal barrier disruption is thought to contribute to the development of several intestinal inflammatory diseases; however, it less clear whether such exposure modulates the development of extra-intestinal inflammatory and autoimmune diseases. The goal of this study was to examine the potential role of pathogenic enteric microbes and intestinal barrier dysfunction in the pathogenesis of type 1 diabetes. Methods Using NOD mice, we assessed: (1) intrinsic barrier function in mice at different ages by measuring serum levels of FITC-labelled dextran; and (2) the impact on insulitis development of infection by strains of an enteric bacterial pathogen (Citrobacter rodentium) either capable (wild-type) or incapable (lacking Escherichia coli secreted protein F virulence factor owing to deletion of the gene [ΔespF]) of causing intestinal epithelial barrier disruption. Results Here we demonstrate that prediabetic (12-weekold) NOD mice display increased intestinal permeability compared with non-obese diabetes-resistant and C57BL/6 mice. We also found that young (4-week-old) NOD mice infected with wild-type C. rodentium exhibited accelerated development of insulitis in concert with infection-induced barrier disruption. In contrast, insulitis development was not altered in NOD mice infected with the non-barrier-disrupting ΔespF strain. Moreover, C. rodentium-infected NOD mice demonstrated increased activation and proliferation of pancreatic-draining lymph node T cells, including diabetogenic CD8 + T cells, compared with uninfected NOD mice. Conclusions/interpretation This is the first demonstration that a loss of intestinal barrier integrity caused by an enteric bacterial pathogen results in the activation of diabetogenic CD8 + T cells and modulates insulitis.

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“…More intriguing is the enhanced mucosal immune response to gliadin observed in biopsies from type 1 diabetic patients. Both an increased risk of diabetes (10) and intestinal inflammation have been reported in rodent models of type 1 diabetes in response to dietary gluten (19). In type 1 diabetic patients, peripheral lymphocyte proliferation increases in response to gliadin (13), and, at the intestinal level, rectal challenge with gliadin results in local mucosal recruitment of lymphocytes (14).…”

Section: Discussionmentioning

confidence: 99%

In Vitro–Deranged Intestinal Immune Response to Gliadin in Type 1 Diabetes

Auricchio¹,

Paparo²,

Maglio³

et al. 2004

Diabetes

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Dietary gluten has been associated with an increased risk of type 1 diabetes. We have evaluated inflammation and the mucosal immune response to gliadin in the jejunum of patients with type 1 diabetes. Small intestinal biopsies from 17 children with type 1 diabetes without serological markers of celiac disease and from 50 age-matched control subjects were examined by immunohistochemistry. In addition, biopsies from 12 type 1 diabetic patients and 8 control subjects were cultured with gliadin or ovalbumin peptic-tryptic digest and examined for epithelial infiltration and lamina propria T-cell activation. The density of intraepithelial CD3 ؉ and ␥␦ ؉ cells and of lamina propria CD25 ؉ mononuclear cells was higher in jejunal biopsies from type 1 diabetic patients versus control subjects. In the patients' biopsies cultured with peptic-tryptic gliadin, there was epithelial infiltration by CD3 ؉ cells, a significant increase in lamina propria CD25 ؉ and CD80 ؉ cells and enhanced expression of lamina propria CD54 and crypt HLA-DR. No such phenomena were observed in control subjects, even those with celiac disease-associated HLA haplotypes. In conclusion, signs of mucosal inflammation were present in jejunal biopsies from type 1 diabetic patients, and organ culture studies indicate a deranged mucosal immune response to gliadin.

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A wheat-based, diabetes-promoting diet induces a Th1-type cytokine bias in the gut of NOD mice

Cited by 47 publications

References 16 publications

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

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

Gut barrier disruption by an enteric bacterial pathogen accelerates insulitis in NOD mice

In Vitro–Deranged Intestinal Immune Response to Gliadin in Type 1 Diabetes

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