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The "Perfect Storm" for Type 1 Diabetes

The Complex Interplay Between Intestinal Microbiota, Gut Permeability, and Mucosal Immunity

¹ Laboratory for Immunobiology, Department of Viral Diseases and Immunology, National Public Health Institute, Helsinki, Finland
² Department of Clinical and Experimental Medicine, Division of Pediatrics and Diabetes Research Center, Linköping University, Linköping, Sweden
³ Department of Pathology, University of Florida College of Medicine, Gainesville, Florida
⁴ Department of Pediatrics, University of Florida College of Medicine, Gainesville, Florida

Corresponding author: Outi Vaarala, outi.vaarala{at}ktl.fi

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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