Identifying immunoregulatory gut bacteria in type 1 diabetes and autoimmunity

摘要 众所周知，1型自身免疫性糖尿病(T1D)患者的肠道微生物区系发生了变化，并可能 随着病原菌的增多，人们对其进行了大量的研究。然而，人们对其影响知之甚少。 对宿主免疫系统的影响，特别是对细菌的免疫调节，这些细菌是 显著减少。我们推测，减少的细菌种类与缺乏 T1D的免疫耐受性，尤其是肠道和肠道中普遍存在的细菌种类 口腔。利用可获得的无菌动物和来自人类的纯V毒株 口腔，我们通过使用致病弧菌定植无菌(GF)小鼠来验证这一假设，并评估了 致病弧菌对免疫细胞的影响。有趣的是，我们发现，迪帕尔弧菌在大多数情况下促进了Treg细胞 在所检测的外周淋巴组织中，大多数Treg细胞表达NeuroPilin-1和a Tregs频率较高的是IL-10产生者。迪帕尔弧菌的这些体内效应也可能是 通过免疫细胞与致病弧菌的直接接触，在体外形成镜像。V.迪帕尔诱导的树已经准备好 体外抑制天然诱生的糖尿病T细胞。更重要的是，迪帕尔病毒减轻了严重程度。 NOD小鼠患上了胰岛炎症。此外，致病弧菌还能产生高水平的短链脂肪酸(SCFAs)醋酸酯 还有丙酸。此外，迪帕尔弧菌还能显著改善肠道通透性。此外，诱导 当测试时，发现Tregs和IL-10产生者，以及肠道通透性的改善。 在GF-NOD和GF-B6两个品系的小鼠中，表明致病弧菌具有普遍的免疫调节作用 效果..我们的初步数据是令人信服的，并引导我们提出假设，即迪帕尔病毒在 维持免疫调节，从而维持免疫耐受性。我们提出了三个具体目标，以测试我们的 假设使用了GF nod和GF B6小鼠，以及树突状细胞或树突状细胞或 短链脂肪酸(SCFA)受体是专门针对(商业上可以买到的)的。我们的方法 使用迪帕尔弧菌作为模式系统也将标志着对其他显著 在T1D患者的肠道中减少。如果我们的假设被证明是正确的，我们的研究将有助于 未来针对T1D和其他自身免疫性疾病的新疗法的设计，对于这些疾病，我们将回到人类 学习。

Abstract It is known that patients with type 1 autoimmune diabetes (T1D) have altered gut microbiota, and potentially pathogenic bacteria, which are increased, have been much studied. However, less is known of the impact on the host immune system, and in particular on immune regulation, of the bacterial species, which are significantly reduced. We hypothesized that the reduced bacterial species are associated with the lack of immune tolerance in T1D, especially the bacterial species that are commonly present in both the gut and oral cavity. Taking advantage of availability of germ free animals and a pure V dispar strain from human oral cavity, we tested this hypothesis by using V. dispar to colonize germ-free (GF) mice and assessed the effect of V. dispar on immune cells. It is intriguing that we found that V. dispar promoted Treg cells in most of the peripheral lymphoid tissues examined and the majority of the Treg cells expressed neuropilin-1 and a higher frequency of the Tregs were IL-10 producers. These in vivo effects of V. dispar could also be mirrored in vitro with direct contact of immune cells to V. dispar. V. dispar induced Tregs are ready to suppress naturally primed diabetogenic T cells in vitro. More importantly, V. dispar ameliorated the severity of insulitis in NOD mice. Further, V. dispar produce high level of short chain fatty acids (SCFAs) acetate and propionate. In addition, V. dispar markedly improved gut permeability. Moreover, the induction of Tregs and IL-10 producers, as well as improvement of gut permeability by V. dispar were found when tested in both GF-NOD and GF-B6 mouse strains, suggesting that V. dispar has a general immune regulatory effect.. Our preliminary data are compelling, and lead us to hypothesize that V. dispar are important in maintaining immune regulation, and hence immune tolerance. We propose the 3 specific aims to test our hypothesis using GF NOD and GF B6 mice, as well as the mouse strains in which dendritic cells or Tregs or short chain fatty acid (SCFA) receptor are specifically targeted (commercially available). Our approach using V. dispar as a model system will also signpost the study of other bacteria species that were markedly reduced in the gut of patients with T1D. If our hypothesis is proved to be correct, our study will help with the design of future novel therapy for T1D and other autoimmune disorders, for which, we will “return“ to human studies.