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: 10613570
• 负责人: Li Wen
• 金额: $ 39.69万
• 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/10613570
• 关键词: Acetates; Address; Animals; Autoimmune Diabetes; Autoimmune Diseases; Autoimmunity; Bacteria; Bacteriology; Biological Models; Cells; Collaborations; 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; 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.

抽象的 众所周知，患有1型自身免疫性糖尿病（T1D）的患者肠道微生物群改变了 增加的致病细菌已经研究了很多。但是，对影响很少 在宿主免疫系统上，尤其是在免疫调节上的细菌物种， 大幅减少。我们假设降低的细菌物种与缺乏 T1D中的免疫耐受性，尤其是肠道中通常存在的细菌物种 口腔。利用无菌动物的可用性和人类的纯V dispar strin 口腔，我们通过使用V. dispar定居于无菌（GF）小鼠并评估了该假设，并评估了该假设。 V. Dispar对免疫细胞的影响。令人着迷的是，我们发现V. dispar在大多数 所检查的周围淋巴组织和大多数Treg细胞表达神经蛋白酶和A Treg的频率较高是IL-10生产者。这些V. dispar的体内效应也可能是 在体外镜像，免疫细胞与V. dispar直接接触。 V. Dispar诱导的Treg已准备好 在体外抑制自然启动糖尿病的T细胞。更重要的是，V。DISPAR改善了严重性 点头小鼠的胰岛炎。此外，V. dispar产生高水平的短链脂肪酸（SCFAS）乙酸盐 和丙酸。此外，V。D。显着提高了肠道渗透性。此外，归纳 Tregs和IL-10生产商，以及测试时发现了V. dispar的肠道渗透性的提高 在GF-NOD和GF-B6小鼠菌株中，这表明V. dispar具有一般的免疫调节 效果..我们的初步数据令人信服，并使我们假设V. dispar在 维持免疫调节，从而维持免疫耐受性。我们提出了三个特定的目标，以测试我们的 使用GF点头和GF B6小鼠的假设以及树突状细胞或Tregs或 短链脂肪酸（SCFA）受体是针对靶向的（可商购的）。我们的方法 使用V. dispar作为模型系统也将使其他细菌物种的研究显着 T1D患者的肠道降低。如果我们的假设被证明是正确的，我们的研究将有助于 T1D和其他自身免疫性疾病的未来新颖疗法的设计，我们将“返回”人类 研究。