Ultrastructural mucosal alterations and increased intestinal permeability in non-celiac, type I diabetic patients

Secondulfo, Mario; Iafusco, Dario; Carratù, R.; deMagistris, L.; Sapone, Anna; Generoso, M.; Mezzogiorno, Antonio; Sasso, Ferdinando Carlo; Cartenı̀, Maria; Rosa, Roberto De; Prisco, Francesco; Esposito, Vincenzo

doi:10.1016/j.dld.2003.09.016

Cited by 167 publications

(116 citation statements)

References 38 publications

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“…Although there are no definitive clinical studies linking enteric bacterial infections to the development of human type 1 diabetes, there are a growing number of reports of type 1 diabetes patients who concomitantly present with intestinal enteropathies [8][9][10][11][12]35]. Our results demonstrate that intestinal barrier dysfunction, in this case mediated by the enteric bacterial pathogen, C. rodentium, is a catalyst for the accelerated development of insulitis and for the priming of CD8 + T cells that are potentially diabetogenic.…”

Section: Discussionmentioning

confidence: 64%

“…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%

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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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Section: Discussionmentioning

confidence: 64%

Section: Introductionmentioning

confidence: 99%

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

et al. 2009

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“…More recently, an enteropathy with similar characteristics has also been described in the non-obese diabetic mouse [4]. In patients with type 1 diabetes, increased intestinal permeability [5][6][7], intestinal biopsy-documented signs of enhanced immune activation [8], ultrastructural changes [9] and increased concentrations of circulating zonulin [7] have been shown. In the BB rat, these features, detectable before the onset of clinical diabetes, are thought to be related to the systemic immune disorder; in human type 1 diabetes the natural history and the pathogenetic implications of these alterations remain to be clarified.…”

Section: Introductionmentioning

confidence: 76%

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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“…21 Similarly, intestinal mucosa from individuals at risk for T1D or with T1D exhibit abnormalities in intestinal permeability as evaluated by functional tests or electron microscopy studies. [22][23][24] In experimentally induced diabetes in rats or mice, changes in intestinal permeability are also detected before the onset of diabetes; increased intestinal permeability in these cases has been shown to be dependent on increased zonulin expression, which regulates tight junctions in the intestinal mucosa. [25][26][27] Additionally, mucosal biopsy, fecal microbiota and serological studies have indicated that the composition of intestinal microbiota may influence the immune mechanisms that participate in the development of CD 28,29 and T1D.…”

Section: Introductionmentioning

confidence: 99%

Celiac disease in patients with type 1 diabetes: a condition with distinct changes in intestinal immunity?

et al. 2011

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Two common chronic childhood diseases-celiac disease (CD) and type 1 diabetes (T1D)-result from complex pathological mechanisms where genetic susceptibility, environmental exposure, alterations in intestinal permeability and immune responses play central roles. In this study, we investigated whether these characteristics were universal for CD independently of T1D association. For this purpose, we studied 36 children with normal small-bowel mucosa and 26 children with active CD, including 12 patients with T1D. In samples from the small-bowel mucosa, we detected the lowest expression of tight junction protein 1 (TJP1) mRNA in CD patients with T1D, indicating an increase in intestinal permeability. Furthermore, these samples displayed the highest expression of forkhead box P3 (FoxP3) mRNA, a marker for regulatory T cells, as compared with other patient groups. At the same time, serum levels of IgA antibodies specific for the CD-related antigens deamidated gliadin and tissue transglutaminase (tTG) were the highest in CD patients with T1D. In contrast, no significant differences were found in IgA or IgG antibodies specific for bovine beta-lactoglobulin or Bifidobacterium adolescentis DSM 20083-derived proteins. There were also no differences in the transamidating activity of serum autoantibodies between patients and control individuals. Our results show that patients with T1D and newly detected CD exhibit severely altered intestinal permeability, strong local immune activation and increased immunoregulatory mechanisms in the small bowel. Further study is required to determine whether these extreme changes in this CD subgroup are due to some specific environmental factors (virus infections), unknown genetic effects or autoimmune reactions to antigenic targets in intracellular tight junctions. INTRODUCTIONWith an approximate prevalence of 1.0% in Western countries, celiac disease (CD) is one of the most common lifelong chronic disorders. 1 CD and type 1 diabetes (T1D) form a significant sector of childhood diseases with high rate of co-occurrence. 2 Both diseases are autoimmune in origin and develop as a result of complex pathological mechanisms, involving several common genetic, environmental and immunological factors. Among these, the common susceptibility loci of HLA and other immune system-related genes, 3 permeability changes in the small-bowel mucosa, 4 and association with wheat consumption 4,5 are prominent. Both diseases are increasing in most regions of the world, 6,7 as are several other autoimmune diseases, but the actual cause of the disease remains unknown. However, several recent studies have highlighted the role of environmental and social changes that have taken place over the last several decades. 8,9 The central event in the pathogenesis of CD is damage to the small intestinal mucosa that occurs after ingestion of gluten or related prolamins in genetically susceptible individuals. During this process, several morphological and immunological alterations have been demonstrated in the small-bowel mucos...

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Ultrastructural mucosal alterations and increased intestinal permeability in non-celiac, type I diabetic patients

Cited by 167 publications

References 38 publications

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

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

Increased intestinal permeability precedes clinical onset of type 1 diabetes

Celiac disease in patients with type 1 diabetes: a condition with distinct changes in intestinal immunity?

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