The "perfect storm" for type 1 diabetes: the complex interplay between intestinal microbiota, gut permeability, and mucosal immunity

Abstract

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.

FIG. 1.

Constituents of the intestine.

FIG. 2.

Hypothetical model of the contribution of various gut components to the pathogenesis of type 1 diabetes.

FIG. 3.

Immunoperoxidase stainings for HLA-DR (A and B) and HLA-DP (C and D) in jejunal biopsy specimens from a healthy control (A and C) and from a type 1 diabetic patient with normal jejunal mucosa (B and D). Intensive, positive HLA-DR staining is seen throughout the epithelial cells of the villi and also in many crypt cells in the type 2 diabetic specimen (B), whereas the control specimen shows only faint HLA-DR staining in the apical parts of the epithelial cells at the tip of the villi (A). The biopsy specimen from a control patient treated with HLA-DP antibody shows scattered positive granules in the apical parts of the epithelial cells at the tip of the villi (C), whereas strong positive staining is seen throughout the villous epithelial cells in the specimen from a type 1 diabetic patient (D). No positive staining is seen with either HLA-DR or HLA-DP in crypt cells in the control specimen (A and C). AEC-hematoxylin stain, original magnification ×50. (Please see http://dx.doi.org/10.2337/db08-0331 for a high-quality digital representation of this figure.)