Akkermansia muciniphilaacts synergistically with Btk-deficiency to prevent Type 1 Diabetes

Abstract

Btk-deficiency eliminates autoreactive B cells, but not normal ones, and protects against Type 1 diabetes (T1D). Surprisingly, we recently found that rederivation of Btk−/−/NOD mice into a cleaner, “barrier” facility resulted in loss of disease protection. This suggests that T1D protection is microbiome dependent in Btk−/−mice. Akkermansia muciniphila(A. muciniphila)was found to be increased in Btk−/−/NOD mice that were protected against disease compared to WT and Btk−/−/NOD that were not protected. A. muciniphilahas previously been associated with disease protection in humans and mice under some conditions, although causality and mechanisms are unknown. We previously showed that Btk-deficient K/BxN mice have reduced intestinal IgA, and therefore hypothesized that A. muciniphilaescapes suboptimal IgA-coating in Btk−/−/NOD and works synergistically with the loss of autoreactive B cells to protect against T1D. Germ-free female WT NOD and Btk−/−/NOD were gavaged with A. muciniphilaat 3–4 weeks. Mice were tested weekly for diabetes to 30 weeks of age. Additional mice were treated in parallel and euthanized at 9–10 weeks to examine the effects on mucosal immunity and autoimmune attack on pancreatic islets. Monocolonization of Btk−/−/NOD with A. muciniphilaprotected significantly against T1D compared to monocolonized WT NOD. CD19 +GL7 +staining of Peyer’s patches showed small germinal centers in Btk−/−/NOD compared to WT NOD. Thus, A. muciniphilaprotects against T1D in Btk−/−/NOD but not WT NOD, indicating a synergistic effect. Altogether, the data show that Btkplays a previously unrecognized role in the maintenance of gut health that can have downstream effects on T1D outcomes. National Institutes of Health Grants R01-DK-084246I Veteran’s Affairs I01-BX-002882 Washington University School of Medicine