The Dexi gene has a protective effect in autoimmune diabetes and influences circulating microbial metabolites

Background: Genome-wide association studies have demonstrated that variations in intron 19 of CLEC16A, in the 16p13.13 region of the human genome, are associated with risk of type 1 diabetes (T1D). This region is also associated with IgA deficiency and microbial diversity in the human gut. No consensus has been reached on the causal T1D gene(s) in this region, but we have previously identified DEXI, of unknown function, as a candidate causal gene. We hypothesized that disruption of Dexi in a mouse model of T1D would accelerate spontaneous diabetes, associated with a change in serum IgA and gut microbiome.

Methods: The non-obese diabetes (NOD) mouse develops spontaneous diabetes from 11 weeks. We used CRISPR mutagenesis in NOD oocytes to generate two NOD mouse lines with mutations in the Dexi coding sequence (12bp deletion and 1bp insertion). Female mice were evaluated weekly for glycosuria. Kaplan-Meier diabetes-free survival analysis was performed and a log-rank Mantel-Cox test used to compare survival. Faecal microbiome was evaluated using the Axiom microarray (n=44 mice) and metabolomic profiling of >2000 metabolites in blood, liver and spleen was undertaken using Metabolon mass-spectrometry (n=18 mice). Serum IgA was measured by ELISA.

Results: Homozygous Dexi-disrupted NOD mice in both lines were viable and of normal macroscopic and microscopic appearance. As predicted, disruption of Dexi significantly decreased diabetes-free survival in the NOD mouse. Dexi disruption also increased serum IgA compared to wild-type NOD mice. This was accompanied by changes in the gut microbiome and in circulating markers of microbial metabolism. These findings identify DEXI as a novel target in T1D prevention and are consistent with the protective effect of DEXI in T1D being mediated via the microbiome.