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: 10597597
• 负责人: Kristine A. Kuhn
• 金额: $ 34.12万
• 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/10597597
• 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; Phase; Plasmablast; Play; Population; Populations at Risk; Prevention strategy; Publishing; Receptor Signaling; Rheumatoid Arthritis; Risk; Role; Severities; Severity of illness; Signal Transduction; Source; Stains; Structure of germinal center of lymph node; Surface; T-Cell Immunologic Specificity; 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; pharmacologic; pre-clinical; receptor; 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.

摘要 新出现的数据表明，调节宿主免疫的宿主-微生物相互作用可能在调节宿主免疫方面发挥重要作用。 类风湿性关节炎（RA）的发病机制利用胶原蛋白诱导的关节炎 (CIA)模型，我们已经发表了我们的研究结果，通过广泛的管理， 在疾病阶段，当自身抗体正在发展，但可观察到的关节炎， 不存在导致疾病严重程度降低>95%。我们小组得出的初步数据表明， 细菌产生的代谢物吲哚，来自饮食色氨酸，与发展相关， 中情局经口给予吲哚治疗的CIA诱导小鼠导致疾病增加 严重性。因此，我们假设吲哚产生细菌的扩张通过以下途径加剧CIA： 粘膜生发中心的发展，其中吲哚通过芳基刺激抗体糖基化 烃受体信号传导。为了了解微生物来源的吲哚如何调节CIA，在目标1中，我们 将首先通过使用选择性定殖来鉴定CIA过程中吲哚的细菌来源。 无菌小鼠在目的2中，我们将评估吲哚影响胶原特异性Tfh和B的机制 细胞分化过程中的CIA。目标3然后将集中在吲哚如何影响胶原自身抗体 通过刺激B细胞糖基化酶而致病。完成这些研究将提供 肠道细菌如何调节自身免疫性关节炎的发展并为未来提供信息 在RA患者中的转化研究。