Graduate Student University of British Columbia Vancouver, British Columbia, Canada
Abstract Text: Environmental factors including enterovirus infection and microbiome dysbiosis have been independently linked to type 1 diabetes in both humans and in mouse models. However, it is unknown whether these risk factors are able to engage in cross-communication to influence predisposition to diabetes development by skewing host physiology and immune homeostasis. Non-obese diabetic (NOD) mice were infected with coxsackievirus B4 (CVB4) and microbial community profiling using 16S rRNA sequencing as well as targeted metabolomics was used to determine how infection longitudinally alters the intestinal microbiome profile. Upon infection, CVB4 induced rapid onset of diabetes, immune infiltration into the pancreatic islets, an increased abundance of autoreactive CD8+ T cells, as well as reorganisation of the intestinal microbiota community composition. The dysbiosis resembled that of mice which spontaneously developed diabetes and resulted in reduced production of short chain fatty acid metabolites. Accompanying this dysbiosis, disruption of intestinal barriers caused increased intestinal permeability and bacterial translocation to promote inflammation. Furthermore, host antibody IgG and IgA responses to commensal bacterial antigens were increased both systemically and within the gut of infected mice. Finally, performing a fecal microbiome transfer (FMT) of the CVB4-induced “diabetogenic” microbiome to antibiotic-depleted NOD recipients was sufficient to promote diabetes onset in the absence of virus infection by reducing regulatory T cell responses in the intestinal environment. These findings signify virus infection can drive dysbiosis and disrupt intestinal immune homeostasis in a way that contributes to diabetes autoimmunity.
