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: 10132989
• 负责人: Kristine A. Kuhn
• 金额: $ 33.1万
• 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/10132989
• 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 新兴数据表明，调节宿主免疫的宿主 - 微生物相互作用可能会起着重要的作用 在类风湿关节炎（RA）发展中的作用。使用良好的胶原蛋白诱导的关节炎 （CIA）模型，我们发表了我们的发现，这些发现是通过给予广泛的，对微生物群的耗尽 自身抗体正在发展时疾病阶段的光谱抗生素，但可观察到的关节炎是 不存在疾病严重程度降低> 95％的结果。我们的小组生成的初步数据已确定 细菌生产的代谢产物吲哚，源自饮食色氨酸，与发展 中央情报局。口服对CIA诱导的抗生素处理的小鼠的吲哚导致疾病增加 严重程度。因此，我们假设产生吲哚的细菌的扩张加剧了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 碳氢化合物受体信号传导。要了解微生物衍生的吲哚如何调节CIA，在AIM 1中，我们 将首先通过使用选择性定植在CIA过程中鉴定吲哚的细菌来源 无细菌小鼠。在AIM 2中，我们将评估吲哚影响特异性TFH和B的机制 CIA过程中的细胞分化。 AIM 3然后将重点关注吲哚如何影响胶原蛋白自身抗体 通过刺激B细胞糖基化酶的致病性。这些研究的完成将提供 一个新的了解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 RA人类的翻译研究。