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bioRxiv · 10.1101/393421

Dexi disruption depletes gut microbial metabolites and accelerates autoimmune diabetes

Davison, L. J.·Wallace, M. D.·Preece, C.·Hughes, K.·Todd, J. A.·Davies, B.·O'Callaghan, C. A.
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Abstract

Non-coding genetic variants in the CLEC16A gene on human chromosome 16p13.13 are associated with risk of autoimmune diseases, including type 1 diabetes and multiple sclerosis. In this region, we previously identified DEXI, a candidate causal gene of unknown function, which alters the risk of type 1 diabetes, where the T1D predisposing allele is associated with lower DEXI expression. Here, we demonstrate by CRISPR mutagenesis in vivo and deep phenotyping that disrupted Dexi expression accelerates diabetes in the non-obese diabetic (NOD) mouse, a spontaneous model of autoimmune pancreatic beta-cell destruction. Mutant mice have increased serum IgM and IgA concentrations compared to wild-type NOD mice, as well as changes in both the gut microbiome and molecular metabolites associated with microbial metabolism. These findings suggest that the mechanism by which DEXI alters diabetes risk involves the composition and function of the microbiome and its impact on host metabolites. Such metabolites, including short chain fatty acids such as butyrate, have been shown to alter the activity of the immune cells involved in beta-cell destruction and susceptibility of the beta cells to autoimmune attack.\n\nOne Sentence Summary: Disruption of the Dexi gene leads to accelerated diabetes in the non-obese diabetic (NOD) mouse, accompanied by changes in serum immunoglobulins, gut microbiome and microbial metabolites.

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Davison, L. J., Wallace, M. D., Preece, C., Hughes, K., Todd, J. A., Davies, B., O'Callaghan, C. A.. 2018-08-16. Dexi disruption depletes gut microbial metabolites and accelerates autoimmune diabetes. https://doi.org/10.1101/393421

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