Identifying immunoregulatory gut bacteria in type 1 diabetes and autoimmunity

识别 1 型糖尿病和自身免疫性疾病中的免疫调节肠道细菌

• 批准号: 10467123
• 负责人: Li Wen
• 金额: $ 42.31万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10467123
• 关键词: Acetates; Address; Animals; Autoimmune Diabetes; Autoimmune Diseases; Autoimmunity; Bacteria; Bacteriology; Biological Models; Cells; Consultations; Data; Dendritic Cells; Derivation procedure; Frequencies; Future; Germ-Free; Human; Immune; Immune Tolerance; Immune system; In Vitro; Inbred NOD Mice; Insulin-Dependent Diabetes Mellitus; Interleukin-10; Intestinal permeability; Lead; Lymphoid Tissue; Metabolism; Modeling; Mouse Strains; Mus; Neuropilin-1; Oral; Oral cavity; Patients; Peripheral; Prevotella; Property; Propionates; Reagent; Regulatory T-Lymphocyte; Role; Severities; Sjogren' s Syndrome; T-Lymphocyte; Testing; The Jackson Laboratory; Therapeutic; Veillonella; Volatile Fatty Acids; commensal bacteria; design; diabetogenic; experience; germ free condition; gut bacteria; gut colonization; gut microbiota; immunoregulation; improved; in vivo; insulitis; novel; novel therapeutics; oral microbial community; pathogenic bacteria; receptor; stool sample; tool

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.

摘要 已知患有1型自身免疫性糖尿病（T1 D）的患者具有改变的肠道微生物群，并且可能 已经对增加的病原菌进行了大量研究。然而，人们对这种影响知之甚少， 对宿主免疫系统，特别是对细菌物种的免疫调节， 大幅减少。我们假设细菌种类的减少与缺乏 T1 D中的免疫耐受，特别是通常存在于肠道和 口腔利用无菌动物和来自人的纯舞毒菌株的可用性， 口腔，我们通过使用舞毒菌定殖无菌（GF）小鼠来验证这一假设，并评估 舞毒菌对免疫细胞的影响。有趣的是，我们发现舞毒菌在大多数小鼠中促进Treg细胞， 的外周淋巴组织检查和大多数的Treg细胞表达神经纤毛蛋白-1和一个神经纤毛蛋白-2。 IL-10产生者频率较高。舞毒菌的这些体内作用也可能是 反映在体外免疫细胞与舞毒菌的直接接触。舞毒菌诱导的Tvis准备好 在体外抑制天然引发的致糖尿病T细胞。更重要的是，舞毒菌改善了 NOD小鼠的胰岛炎。此外，舞毒菌产生高水平的短链脂肪酸（SCFAs）乙酸酯 和丙酸盐。此外，舞毒菌显著改善肠道通透性。此外， 当测试时，发现V. dispar产生TdR和IL-10，以及肠道通透性的改善 在GF-NOD和GF-B6小鼠品系中，表明舞毒菌具有一般的免疫调节作用， 影响..我们的初步数据是令人信服的，并使我们假设，舞毒蛾是重要的， 维持免疫调节，从而维持免疫耐受。我们提出了三个具体目标，以测试我们的 使用GF NOD和GF B6小鼠，以及其中树突状细胞或T细胞的小鼠品系， 短链脂肪酸（SCFA）受体是特异性靶向（可商购）。我们的方法 使用V. dispar作为模型系统也将标志着对其他细菌物种的研究， T1 D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 设计未来针对T1 D和其他自身免疫性疾病的新型疗法，为此，我们将“回归”人类 问题研究