The "Perfect Storm" for Type 1 Diabetes: The Complex Interplay Between Intestinal Microbiota, Gut Permeability, and Mucosal Immunity

Laboratory for Immunobiology, Department of Viral Diseases and Immunology, National Public Health Institute, Helsinki, Finland.
Diabetes (Impact Factor: 8.1). 11/2008; 57(10):2555-62. DOI: 10.2337/db08-0331
Source: PubMed


It is often stated that type 1 diabetes results from a complex interplay between varying degrees of genetic susceptibility and environmental factors. While agreeing with this principal, our desire is that this Perspectives article will highlight another complex interplay potentially associated with this disease involving facets related to the gut, one where individual factors that, upon their interaction with each another, form a "perfect storm" critical to the development of type 1 diabetes. This trio of factors includes an aberrant intestinal microbiota, a "leaky" intestinal mucosal barrier, and altered intestinal immune responsiveness. Studies examining the microecology of the gastrointestinal tract have identified specific microorganisms whose presence appears related (either quantitatively or qualitatively) to disease; in type 1 diabetes, a role for microflora in the pathogenesis of disease has recently been suggested. Increased intestinal permeability has also been observed in animal models of type 1 diabetes as well as in humans with or at increased-risk for the disease. Finally, an altered mucosal immune system has been associated with the disease and is likely a major contributor to the failure to form tolerance, resulting in the autoimmunity that underlies type 1 diabetes. Herein, we discuss the complex interplay between these factors and raise testable hypotheses that form a fertile area for future investigations as to the role of the gut in the pathogenesis and prevention of type 1 diabetes.

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Available from: Outi Vaarala, Feb 23, 2014
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    • "T1D represents around 5–10% (Atkinson et al., 2014) and T2D accounts for about 90% of the diabetic cases worldwide (Wild et al., 2004). Autoimmune destruction of beta cells has multiple genetic predispositions (Onengut-Gumuscu et al., 2015) and effect of environmental factors is still being understood in T1D (Knip et al., 2005; Vaarala et al., 2008). However, markers of immune destruction like islet cell auto-antibodies, auto-antibodies to insulin, GAD65, and tyrosine phosphatases IA-2 and IA-2b and rise in circulating levels of C-peptide help in reasonably accurate diagnosis of T1D and determine their clinical course (Arvan et al., 2012; American Diabetes Association, 2014; Atkinson et al., 2014). "
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    Frontiers in Genetics 08/2015; 6:251. DOI:10.3389/fgene.2015.00251
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    • "Viral infections, dietary factors, and changes in gut microbiome lead to intestinal inflammation and may contribute to the increased permeability of the gut [16]. Vaarala et al. showed that the complex interactions between gut microbiome, intestinal permeability , and mucosal immunity contribute to the pathogenesis of T1D [22] [23]. These authors suggested that leaky gut allows entry to certain proteins present in cow's milk and wheat and as such leads to T1D autoimmunity in at risk subjects [22] "
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    ABSTRACT: Complex interactions between a series of environmental factors and genes result in progression to clinical type 1 diabetes in genetically susceptible individuals. Despite several decades of research in the area, these interactions remain poorly understood. Several studies have yielded associations of certain foods, infections, and immunizations with the onset and progression of diabetes autoimmunity, but most findings are still inconclusive. Environmental triggers are difficult to identify mainly due to (i) large number and complex nature of environmental exposures, including bacteria, viruses, dietary factors, and environmental pollutants, (ii) reliance on low throughput technology, (iii) less efforts in quantifying host response, (iv) long silent period between the exposure and clinical onset of T1D which may lead to loss of the exposure fingerprints, and (v) limited sample sets. Recent development in multiplex technologies has enabled systematic evaluation of different classes of molecules or macroparticles in a high throughput manner. However, the use of multiplex assays in type 1 diabetes research is limited to cytokine assays. In this review, we will discuss the potential use of multiplex high throughput technologies in identification of environmental triggers and host response in type 1 diabetes.
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    • "One possible indirect mechanism by which L. reuteri 6475 could impact the suppression of bone loss in Ovx animals is by alteration of the immune response by changing intestinal microbial communities found in Ovx animals. Dysbiosis of gut communities can promote or exacerbate diseases including obesity, diabetes and IBD (Kuhbacher et al., 2006; Oakley et al., 2008; Sartor, 2008; Vaarala et al., 2008; Wen et al., 2008) while alterations in the host immune system can also modify the structure and function of the intestinal microbiota to promote disease. Interestingly, bone density can be enhanced by the absence of luminal bacteria (Sjogren et al., 2012). "
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