Abstract
The incidence of type 1 diabetes (T1D) has been increasing among children and adolescents, in which environmental factors, including gut microbiota, play an important role. However, the underlying mechanisms are yet to be determined. Here, we show that patients with newly diagnosed T1D displayed not only a distinct profile of gut microbiota associated with decreased short-chain fatty acids (SCFAs) production, but also an altered IgA-mediated immunity compared with healthy control subjects. Using germ-free NOD mice, we demonstrate that gut microbiota from patients with T1D promoted different IgA-mediated immune responses compared with healthy control gut microbiota. Treatment with the SCFA, acetate, reduced gut bacteria-induced IgA response accompanied by decreased severity of insulitis in NOD mice. We believe our study provides new insights into the functional effects of gut microbiota on inducing IgA immune response in T1D, suggesting that SCFAs might be potential therapeutic agents in T1D prevention and/or treatment.
Highlights
Type 1 diabetes (T1D) is an immune-mediated disease resulting from the destruction of insulin-producing pancreatic β cells
The level of these IgA-bound bacteria was negatively correlated with the concentration of stool short-chain fatty acids (SCFAs), including acetate, butyrate, and propionate (Figure 2, C–E), and we observed a higher proportion of IgA-bound gut bacteria and lower concentrations of 3 SCFAs
The altered gut microbiota promoted an increased IgA response to the bacterial targets, and there were more IgA-bound gut bacteria in patients with T1D. These results suggest that SCFAs may regulate bacteria-reactive IgA immune responses
Summary
Type 1 diabetes (T1D) is an immune-mediated disease resulting from the destruction of insulin-producing pancreatic β cells. Changes in the environment, including the gut microbiota, have been suggested to modulate the susceptibility to T1D Studies in both NOD mice and humans have identified microbial composition changes between those that develop T1D and those that do not [5,6,7,8,9]. In humans, altered gut microbial composition in early life and microbial immunogenicity have been linked with islet β cell autoimmunity [10, 11]. It has been shown in both NOD mouse model and patients with T1D that bacterial mimics of pancreatic autoantigens can be recognized by autoreactive T cells [12,13,14]. Understanding the functional interactions between the gut microbiota and the immune system in T1D beyond the composition is important
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