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

Sonam Verma, Lucy S. Cohen, I. Olin, P. Kendall
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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
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嗜粘杆菌与btk缺乏症协同预防1型糖尿病
缺乏btk可消除自身反应性B细胞,但不能消除正常B细胞,并可预防1型糖尿病(T1D)。令人惊讶的是,我们最近发现,将Btk - / - /NOD小鼠重新衍生为更清洁的“屏障”设施导致疾病保护丧失。这表明Btk - / -小鼠的T1D保护依赖于微生物组。Akkermansia muciniphila (A。与未受保护的WT和Btk - / - /NOD相比,受保护的Btk - / - /NOD小鼠中muciniphila)的表达增加。尽管因果关系和机制尚不清楚,但在某些情况下,嗜粘单胞杆菌与人类和小鼠的疾病保护有关。我们之前的研究表明,缺乏Btk的K/BxN小鼠肠道IgA减少,因此假设A. muciniphilaas在Btk−/−/NOD中逃脱了次优的IgA涂层,并与自身反应性B细胞的损失协同作用,以防止T1D。无菌雌性WT NOD和Btk−/−/NOD灌胃3-4周。每周对老鼠进行糖尿病检测,直到30周龄。另外的小鼠在9-10周平行治疗并安乐死,以检查对胰岛粘膜免疫和自身免疫攻击的影响。与单定殖的WT NOD相比,嗜粘芽孢杆菌单定殖Btk−/−/NOD对T1D具有显著的保护作用。Peyer’s patches的CD19 +GL7 +染色显示Btk−/−/NOD的生发中心比WT NOD小。因此,a . muciniphila对Btk−/−/NOD的T1D有保护作用,但对WT NOD无保护作用,表明其具有协同作用。总之,这些数据表明,btk在维持肠道健康方面发挥着一种以前未被认识到的作用,这种作用可能对T1D的预后有下游影响。美国国家卫生研究院资助R01-DK-084246I退伍军人事务I01-BX-002882华盛顿大学医学院
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