The role of bacteria-produced indole in the development of autoimmune arthritis

细菌产生的吲哚在自身免疫性关节炎发展中的作用

• 批准号: 10377936
• 负责人: Kristine A. Kuhn
• 金额: $ 33.78万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-10 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10377936
• 关键词: Address; Affect; Antibiotics; Antibodies; Antigens; Arthritis; Aryl Hydrocarbon Receptor; Autoantibodies; Autoantigens; Autoimmune Diseases; B cell differentiation; B-Cell Activation; B-Lymphocytes; Bacteria; Collagen; Collagen Arthritis; Complement; Data; Development; Disease; Enzymes; Evaluation; Feces; Flow Cytometry; Future; Galactosyltransferases; Generations; Genetic; Germ-Free; Human; Immunity; Immunofluorescence Immunologic; Immunoglobulin A; Individual; Indoles; Inflammation; Intestines; Knowledge; Kynurenine; Microbe; Modeling; Mucous Membrane; Mus; Oral; Oral Administration; Pathogenicity; Pathway interactions; Pattern; Pharmacology; Phase; Plasmablast; Play; Population; Prevention strategy; Publishing; Receptor Signaling; Rheumatoid Arthritis; Risk; Role; Severities; Severity of illness; Signal Transduction; Source; Specificity; Stains; Structure of germinal center of lymph node; Surface; T-Lymphocyte; Testing; Therapeutic; Tryptophan; Tryptophan 2,3 Dioxygenase; Tryptophan Metabolism Pathway; autoimmune arthritis; citrullinated protein; commensal bacteria; dietary; dysbiosis; glycosylation; gut microbiota; high risk; host-microbe interactions; insight; metabolome; microbiota; microorganism interaction; novel; pathogenic autoantibodies; pre-clinical; translational study

ABSTRACT Emerging data suggest that host-microbe interactions, which modulate host immunity, may play an important role in the development of rheumatoid arthritis (RA). Using the well-characterized collagen-induced arthritis (CIA) model, we have published our findings that depletion of the microbiota through administration of broad- spectrum antibiotics during the phase of disease when autoantibodies are developing but observable arthritis is not present results in >95% reduction in disease severity. Preliminary data generated by our group identified the bacteria-produced metabolite indole, derived from dietary tryptophan, correlated with the development of CIA. Oral administration of indole to antibiotic-treated mice induced for CIA resulted in increased disease severity. Therefore, we hypothesize that the expansion of indole-producing bacteria exacerbate CIA through the development of mucosal germinal centers in which indole stimulates antibody glycosylation through aryl hydrocarbon receptor signaling. To understand how the microbe-derived indole modulates CIA, in Aim 1, we will first identify the bacterial source(s) of indoles during the course of CIA by using selective colonization of germ free mice. In Aim 2, we will evaluate the mechanism by which indole affects collagen-specific Tfh and B cell differentiation during the course of CIA. Aim 3 will then focus on how indole affects collagen autoantibody pathogenicity through the stimulation of B cell glycosylation enzymes. Completion of these studies will provide a novel insight into how intestinal bacteria modulate the development of autoimmune arthritis and inform future translational studies in humans with RA.

抽象的 新数据表明，调节宿主免疫的宿主-微生物相互作用可能发挥重要作用。 在类风湿性关节炎（RA）的发展中发挥作用。使用充分表征的胶原蛋白诱导的关节炎 （CIA）模型，我们发表了我们的研究结果，通过广泛的管理来消耗微生物群 在自身抗体正在形成但可观察到关节炎的疾病阶段使用谱抗生素 不存在导致疾病严重程度降低>95%。我们小组生成的初步数据确定 细菌产生的代谢产物吲哚，源自膳食色氨酸，与 中央情报局。经抗生素治疗的小鼠口服吲哚导致 CI​​A 小鼠病情加重 严重程度。因此，我们假设产生吲哚的细菌的扩张通过以下方式加剧了 CIA 粘膜生发中心的发育，其中吲哚通过芳基刺激抗体糖基化 碳氢化合物受体信号传导。为了了解微生物来源的吲哚如何调节 CIA，在目标 1 中，我们 将首先在 CIA 过程中通过使用选择性定植来识别吲哚的细菌来源 无菌小鼠。在目标 2 中，我们将评估吲哚影响胶原蛋白特异性 Tfh 和 B 的机制 CIA 过程中的细胞分化。目标 3 将重点关注吲哚如何影响胶原蛋白自身抗体 通过刺激 B 细胞糖基化酶产生致病性。完成这些研究将提供 关于肠道细菌如何调节自身免疫性关节炎发展并为未来提供信息的新见解 RA 人类转化研究。