Enteropathy precedes type 1 diabetes in the BB rat

Graham, Shirley A.

doi:10.1136/gut.2004.042481

Cited by 77 publications

(75 citation statements)

References 52 publications

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“…The natural history of intestinal abnormalities associated with human type 1 diabetes looks similar to that observed in diabetes-prone BB rats, in which the increased intestinal permeability precedes hyperglycaemia and lymphocytic insulitis, indicating enteropathy as a very early pathogenetic event [1][2][3]. In human type 1 diabetes the genesis and significance of the increased intestinal permeability is unknown.…”

Section: Discussionmentioning

confidence: 69%

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Increased intestinal permeability precedes clinical onset of type 1 diabetes

et al. 2006

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Aims/hypothesis Recent observations have shown subclinical intestinal abnormalities in human type 1 diabetes. Whether these are related to the pathogenetic process or secondary to the diabetes remains to be clarified. The aim of this study was to investigate this issue by examining intestinal permeability to sugars in subjects at different stages of type 1 diabetes: preclinical, new-onset and longterm established disease. Methods Eighty-one subjects with islet autoimmunity (18 preclinical, 28 new-onset and 35 long-term type 1 diabetes) and 40 healthy control subjects were investigated by a lactulose-mannitol test, consisting of oral administration of the two sugars and measurement of their urinary excretion.Results All groups of subjects with islet autoimmunity showed an increase in intestinal permeability (p≤0.009 vs controls) to the disaccharide lactulose, indicative of a damaged barrier, but a similar permeability to the monosaccharide mannitol (NS vs controls), indicative of an integral surface mucosa; consequently there was an increase in the lactulose:mannitol excretion ratio (p≤0.025 vs controls). Conclusions/interpretation These findings indicate the presence of a subclinical enteropathy associated with type 1 diabetes that is already detectable before clinical onset of the disease, and suggest that the small intestine is an organ participating in the pathogenetic process of type 1 diabetes.

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Section: Discussionmentioning

confidence: 69%

“…In the bio-breeding (BB) rat, a model of spontaneous autoimmune diabetes, increased intestinal permeability, mucosal lymphocytic infiltration and morphological changes have been reported [1][2][3]. More recently, an enteropathy with similar characteristics has also been described in the non-obese diabetic mouse [4].…”

Section: Introductionmentioning

confidence: 98%

Increased intestinal permeability precedes clinical onset of type 1 diabetes

et al. 2006

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“…We show that prediabetic NOD mice develop an intrinsic 'leaky' gut. This finding has been well characterised in the BioBreeding rat model of type 1 diabetes [3,5,6]. Watts et al [7] have suggested that intrinsic gut leakiness in BioBreeding rats may be caused by an increase in endogenous zonulin, a protein involved in modulating intestinal tight junctions.…”

Section: Discussionmentioning

confidence: 72%

“…Disruption of this delicate barrier promotes the initiation and development of intestinal autoimmune diseases such as coeliac disease [1] and inflammatory bowel disease [2]. Impaired intestinal barrier function has also been detected in rodent models of type 1 diabetes [3][4][5][6][7] and in type 1 diabetes patients and their relatives [8][9][10][11][12]. Changes in the intestine, induced by dietary or enteric antigens, have been proposed as causative factors in the course of type 1 diabetes [13,14]; however, the role of the gut and enteric microbes in type 1 diabetes remains unclear.…”

Section: Introductionmentioning

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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“…Our group recently identified a wheat storage globulin-like protein as a candidate diabetes-related antigen in diabetic rats and human patients [4]. There is evidence that the gut is mildly inflamed and abnormally permeable to lumen antigens in BBdp rats [10][11][12][13][14] and in human patients with type 1 diabetes [15][16][17][18]. However, remarkably little is known about the immune state of the gut-associated lymphoid tissue (GALT) in animals or humans that spontaneously develop type 1 diabetes.…”

Section: Introductionmentioning

confidence: 99%

Wheat protein-induced proinflammatory T helper 1 bias in mesenteric lymph nodes of young diabetes-prone rats

Chakir¹,

Lefebvre

Wang³

et al. 2005

Diabetologia

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Aims/hypothesis: Type 1 diabetes is the result of an inflammatory T helper 1 (Th1) lymphocyte-mediated beta cell destructive process. The majority of diabetesprone BioBreeding (BBdp) rats fed wheat protein-based diets, such as NTP-2000, develop type 1 diabetes and display a mild coeliac-like enteropathy. Mesenteric lymph nodes (MLNs), which drain the gut, are the major inductive site where dietary antigens are recognised in the gut-associated lymphoid tissue (GALT). We hypothesised that this compartment could be a site of abnormal wheat proteininduced Th1 cell activation. Methods: MLN cells were isolated from BBdp and BB control (BBc) rats that were fed NTP-2000 or a hydrolysed casein (HC)-based diet at ages that pre-date classic insulitis. The inflammatory status, phenotype and proliferation of these cells in response to wheat protein were determined. Results: The expression ratio of T-bet : Gata3, master transcription factors for Th1 and Th2 cytokines, was increased in the MLN from NTP-2000-fed BBdp rats compared with that from BBc rats, mainly due to decreased Gata3 expression. CD3 + CD4 + IFN-γ + T cells were more prevalent in the MLN of wheatfed BBdp rats, but remained at control levels in BBdp rats fed a diabetes-retardant HC diet. BBdp MLN cells proliferated in response to wheat protein antigens in a specific, dose-dependent manner, and >93% of cells were CD3 + CD4 + T cells. This proliferation was associated with a low proportion of CD4 + CD25 + T cells and a high proportion of dendritic cells in the MLN of BBdp rats. Conclusions/ interpretation: Before insulitis is established, the MLNs of wheat-fed BBdp rats contain an unusually high proportion of Th1 cells that proliferate specifically in response to wheat protein antigens.

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Enteropathy precedes type 1 diabetes in the BB rat

Cited by 77 publications

References 52 publications

Increased intestinal permeability precedes clinical onset of type 1 diabetes

Increased intestinal permeability precedes clinical onset of type 1 diabetes

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

Wheat protein-induced proinflammatory T helper 1 bias in mesenteric lymph nodes of young diabetes-prone rats

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