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Autoimmune diabetes mellitus and the leaky gut

Over the past decade, our understanding of the immune reactivity and, in particular, of autoimmune disorders has witnessed a silent revolution. It has become clear that many, if not all autoimmune diseases entertain an intimate connection to the bacterial gut flora, a cosmos of trillions of different bacteria, forming diverse consortia distributed along the length of the intestinal tube. However, the microbiota’s role seems to be remarkably ambiguous, depending on the particular autoimmune disease. Experimental studies of disease models indicate that, for example, in autoimmune diseases of the brain and the eye microbiota are essentially required to trigger and maintain autoimmunity (1, 2), while in stark contrast, in autoimmune type 1 diabetes (T1D), gut bacteria may protect from disease (3⇓⇓–6). Local interactions between luminal microbes with the surrounding gut-associated lymphoid tissue (GALT) drive the immune system into either direction. In PNAS, Sorini et al. (7) describe an alternative interactive mechanism. They observe that in 2 models of T1D changes in the luminal gut wall precede onset of clinical autoimmune diabetes. These changes are most evident in the mucus layer of the large intestine, where they allow translocation of bacteria from the lumen into extraluminal tissues and where they enable activated self-reactive T cells to home to the pancreatic islets and ultimately destroy the insulin-forming β cells (Fig. 1).



Fig. 1. 
A compromised intestinal barrier triggers activation of diabetogenic T cells in the GALT. An intact intestinal barrier ( Left ) is composed of a thick mucus layer and an epithelial layer with tight junctions (orange). The rare diabetogenic T cells in the underlying lamina propria remain quiescent. In contrast, a compromised intestinal barrier ( Right ) characterized by a thin and discontinuous mucus layer and a breached epithelial barrier allows invasion of microbiota into the lamina propria. This results in … 



[↵][1]1To whom correspondence may be addressed. Email: hwekerle{at}neuro.mpg.de.

 [1]: #xref-corresp-1-1