Bruton’s tyrosine kinase impacts IgA repertoire and microbiome composition in non-obese diabetic mice

Abstract

Abstract The microbiome has emerged as a contributor to type 1 diabetes (T1D), but how interactions between the microbiome and the mucosal immune system lead to or prevent T1D is not clear. Previously, we found that deletion of the B cell signaling protein Bruton’s Tyrosine Kinase (BTK) selectively eliminates autoreactive B cells and autoantibodies, preventing T1D development. However, we discovered that this disease protection is microbiome-dependent, as it disappears in cleaner facilities. We hypothesize that disruption of BTK-mediated B cell receptor (BCR) signaling promotes the growth of particular microbes that are protective against T1D by altering IgA production. Thus, the objective of this study is to determine how BTK-deficiency affects the IgA repertoire, shapes the gut microbiome, and synergistically prevents T1D. First, we performed IgA-seq to assess how BTK-deficiency alters IgA-coating of the microbiota. Then, we characterized the microbiomes of non-obese diabetic (NOD) mouse colonies living in distinct environments using 16S sequencing and conducted disease studies to track T1D development. We found that BTK-deficiency altered the ability of IgA to coat microbiota in the small intestine and colon. We also found that BTK-deficiency significantly impacts the composition of the microbiome in NOD mice living in distinct facilities. BTK-deficient mice have increased commensal diversity and enrichment of specific microbes. Based on these findings, we conclude that disruption of BTK-mediated BCR signaling alters IgA production and microbiome composition, with downstream effects on T1D pathogenesis. Supported by grants from NIH (R01-DK-084246I) and Veteran's Affairs (101-BX-002882)