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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    • "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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