Leaky gut and diabetes mellitus: what is the link?

Kort, Sander de; Keszthelyi, Dániel; Masclee, Ad

doi:10.1111/j.1467-789x.2010.00845.x

Cited by 205 publications

(180 citation statements)

References 67 publications

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“…The 'leaky gut' theory has been suggested as a potential mechanism by which increased exposure of the immune system to luminal microbial antigens could result in the stimulation of autoimmune responses leading to T1D (de Kort et al, 2011). However, we did not find that antibiotic-induced diabetes was associated with barrier dysfunction (Supplementary data Figure 3).…”

Section: Discussioncontrasting

confidence: 45%

“…The 'hygiene hypothesis' proposes that insufficient microbial exposure during infancy drives autoimmunity, and certain intestinal microbes and their antigens are hypothesized to induce autoimmune responses. Increased exposure to intestinal microbial antigens or metabolites through the gut could be involved in triggering diabetogenic immune responses (reviewed in (de Kort et al, 2011)). …”

Section: Introductionmentioning

confidence: 99%

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Prolonged antibiotic treatment induces a diabetogenic intestinal microbiome that accelerates diabetes in NOD mice

Brown

Godovannyi

Ma³

et al. 2015

The ISME Journal

146

110

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Accumulating evidence supports that the intestinal microbiome is involved in Type 1 diabetes (T1D) pathogenesis through the gut-pancreas nexus. Our aim was to determine whether the intestinal microbiota in the non-obese diabetic (NOD) mouse model played a role in T1D through the gut. To examine the effect of the intestinal microbiota on T1D onset, we manipulated gut microbes by: (1) the fecal transplantation between non-obese diabetic (NOD) and resistant (NOR) mice and (2) the oral antibiotic and probiotic treatment of NOD mice. We monitored diabetes onset, quantified CD4+T cells in the Peyer's patches, profiled the microbiome and measured fecal short-chain fatty acids (SCFA). The gut microbiota from NOD mice harbored more pathobionts and fewer beneficial microbes in comparison with NOR mice. Fecal transplantation of NOD microbes induced insulitis in NOR hosts suggesting that the NOD microbiome is diabetogenic. Moreover, antibiotic exposure accelerated diabetes onset in NOD mice accompanied by increased T-helper type 1 (Th1) and reduced Th17 cells in the intestinal lymphoid tissues. The diabetogenic microbiome was characterized by a metagenome altered in several metabolic gene clusters. Furthermore, diabetes susceptibility correlated with reduced fecal SCFAs. In an attempt to correct the diabetogenic microbiome, we administered VLS#3 probiotics to NOD mice but found that VSL#3 colonized the intestine poorly and did not delay diabetes. We conclude that NOD mice harbor gut microbes that induce diabetes and that their diabetogenic microbiome can be amplified early in life through antibiotic exposure. Protective microbes like VSL#3 are insufficient to overcome the effects of a diabetogenic microbiome.

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Section: Discussioncontrasting

confidence: 45%

Section: Introductionmentioning

confidence: 99%

Prolonged antibiotic treatment induces a diabetogenic intestinal microbiome that accelerates diabetes in NOD mice

Brown

Godovannyi

Ma³

et al. 2015

The ISME Journal

146

110

View full text Add to dashboard Cite

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“…Comparatively, islets from mice receiving supplementation with butyrate (CB and HFB groups) displayed a tendency of an increase, although not statistically significant, in insulin secretion at the supraliminal concentration of glucose (16.7 mM) (Figure 2(b)). This change resulted in a significantly higher (P ¼ 0.012) fold increase in glucose-induced insulin secretion in HFB islets (56.5 AE 18.8 (10) fold as compared to basal secretion) than HF islets (10.5 AE 3.4 (13) fold as compared to basal secretion), which, in turn, displayed a significant lower (P ¼ 0.02) secretory response to glucose as compared to control (C) islets (32.4 AE 7.9 (14) fold as compared to basal secretion).…”

Section: Resultsmentioning

confidence: 99%

“…22,25,45,59,60 Based on clinical and experimental evidence, the current hypothesis postulates that a disruption of the intestinal epithelial barrier induced by a modified microbiota or altered luminal content would lead to an increased intestinal permeability to antigens from dietary, viral or bacterial origin, that in turn could activate autoimmune reactions against insulin-producing beta cells (in T1DM) and/or elicit secretion of pro-inflammatory cytokines, locally and systemically, leading to insulin resistance (in T2DM). 14,48,61,62 Given our current knowledge, one may assume that reinforcing the intestinal barrier can offer and open new therapeutic horizons in the treatment of these two types of diabetes. Taken all into consideration, we went to investigate the effect of butyrate supplementation on intestinal barrier function in our animal model of T2DM, ....................................................................................................................... focusing on the structure and function of the intestinal TJ, an essential element of this barrier.…”

Section: Discussionmentioning

confidence: 99%

“…4,6,9,10 In addition, it has been recently proposed that microbiota-derived lipopolysaccharides, crossing a leaky intestinal epithelium, may also play a role in the long-term development of insulin resistance in T2DM. [11][12][13][14] In order to compensate the permanent state of insulin resistance, pancreatic beta cells are capable of an adaptive response that involves changes in their secretory function and mass in the endocrine pancreas. [15][16][17][18] At initial stages, beta cells increase insulin biosynthesis and release but, subsequently, due to the continuous resistance of biological tissues to insulin, beta cell mass expands to promote a further increase in secretion of this hormone necessary for the maintenance of normoglycemia.…”

Section: Introductionmentioning

confidence: 99%

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Butyrate reduces high-fat diet-induced metabolic alterations, hepatic steatosis and pancreatic beta cell and intestinal barrier dysfunctions in prediabetic mice

Matheus

Monteiro

Oliveira

et al. 2017

Exp Biol Med (Maywood)

130

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Butyrate is a short-chain fatty acid produced by the intestinal microbiota through the fermentation of non-absorbable carbohydrates and proteins (e.g. fibers). Sodium butyrate incorporated into the diet displayed a protective action on metabolic, hepatic, pancreatic and intestinal alterations induced by high-fat diet in mice, resulting in significant inhibition of the development of a prediabetic state. Thus, our data suggest that butyrate may have a potential therapeutic use in the treatment of type 2 diabetes and related disorders. AbstractIn this study, we investigated the effect of diet supplementation with sodium butyrate (5% w/w), a short-chain fatty acid produced by the intestinal microbiota, on metabolic parameters, body adiposity, hepatic and pancreatic lipid accumulation, beta cell function/mass as well as on the structure and function of the tight junction-mediated intestinal epithelial barrier in both normal and obese/prediabetic C57 mice fed a regular (control) or high-fat diet for 60 days, respectively. Butyrate treatment significantly inhibited all the high-fat-induced metabolic dysfunctions evaluated, i.e. significantly reduced the weight gain and body adiposity as well as the insulin resistant state, hyperglycemia and hyperinsulinemia, without changing food intake. In addition, high-fat-fed mice treated with this short-chain fatty acid displayed no compensatory hyperplasia of pancreatic beta cells nor marked hepatic steatosis as seen in prediabetic mice after high-fat diet only. Isolated pancreatic islets from high-fat-fed mice treated with butyrate showed improvement of the insulin secretion, which was associated with a significant decrease in lipid accumulation within the pancreas. Butyrate enhanced the intestinal epithelial barrier, as revealed by the FITC-Dextran permeability assay, which was accompanied by a significant increase in the junctional content of the tight junction-associated claudin-1 in intestinal epithelia of jejunum, ileum, and colon of both control and high-fat mice. In conclusion, our results showed that diet supplementation with butyrate inhibits the deleterious effects of high-fat diet intake on metabolic parameters and structure/function of several tissues/ organs associated with type 2 diabetes mellitus in a mouse model, suggesting a potential use of this short-chain fatty acid in the treatment of this endocrine-metabolic disorder.

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