Abstract
Microbial metabolites have a profound effect on the development of type 1 diabetes (T1D). The cross-talk between the gut microbiota, the nervous system, and immune system is necessary to establish and maintain immune and gut tolerance. As quoted by Hippocrates, “All disease begins in the gut.” Although this has been recognized for 2,000 years, the connection between the gut and autoimmune T1D is not yet well-understood. Here, we outline new advances supported by our research and others that have contributed to elucidate the impact of microbial metabolites on the physiology of the pancreas and the gut through their remarkable effect on the immune and nervous system. Among many of the mechanisms involved in the gut–beta-cell–immune cross-talk, glial fibrillary acidic protein (GFAP)-expressing cells are critical players in the development of invasive insulitis. Besides, this review reveals a novel mechanism for microbial metabolites by stimulating IL-22, an essential cytokine for gut homeostasis and beta-cell survival. The close connections between the gut and the pancreas are highlighted through our review as microbial metabolites recirculate through the whole body and intimately react with the nervous system, which controls essential disorders associated with diabetes. As such, we discuss the mechanisms of action of microbial metabolites or short-chain fatty acids (SCFAs), IL-22, and GFAP on beta-cells, gut epithelial cells, neurons, and glial cells via metabolite sensing receptors or through epigenetic effects. The fine-tuned gut–neuro–immune network may be profoundly affected by SCFA deficiency related to dysbiosis and diet alterations at very early stages of the initiation of the disease. Thus, dampening the initial immune response or preventing the perpetuation of the immune response by maintaining the integrity of the gut is among the alternative approaches to prevent T1D.
Highlights
Type 1 diabetes (T1D) is a chronic autoimmune disease in which T cells destroy the insulin-producing beta-cells of the pancreas [1,2,3]
Antigenic targets for T cell priming are not solely expressed in betacells, and in multiple tissues distal to islets, and they can be found in food like insulin or produced by bacteria like glutamic acid decarboxylase (GAD) [6,7,8]
enteric glial cells (EGCs), with the help of their stellate projections, sample microbial antigens crossing the epithelial barrier and activate diabetogenic T cells. This is given under dysbiosis, predominant in T1D and many autoimmune diseases, and the release of microbial antigens such as LPS may break the tolerance of EGCs leading to overexpression of glial cell markers glial fibrillary acidic protein (GFAP) and S100B
Summary
Type 1 diabetes (T1D) is a chronic autoimmune disease in which T cells destroy the insulin-producing beta-cells of the pancreas [1,2,3]. Slattery’s group has recently shown that ablation of autoantigen presentation in GFAP-expressing cell types reduced the development of invasive insulitis in NOD mice [25]. We can speculate that reduction, but not total elimination of invasive infiltration, may be due to the absence of presentation of autoantigens other than insulin by GFAP-expressing cells, suggesting that Ag-derived ductal cell is one of the critical requirements in orchestrating the initiation of autoimmune responses to beta-cell antigens.
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