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

摘要 新出现的数据表明，调节宿主免疫力的宿主-微生物相互作用可能起到重要作用 在类风湿性关节炎(RA)的发展中起着重要作用。利用具有良好特性的胶原蛋白诱导的关节炎 (CIA)模型，我们已经发表了我们的发现，通过给药广泛的- 在疾病阶段，当自身抗体正在发展，但可观察到的关节炎 在疾病严重程度降低95%的情况下没有出现结果。由我们小组生成的初步数据确定 细菌产生的代谢物吲哚，来自饮食中的色氨酸，与糖尿病的发展有关 中情局。给抗生素治疗的小鼠口服吲哚可增加CIA的发病率 严肃性。因此，我们假设产生吲哚的细菌的扩张通过 吲哚通过芳基刺激抗体糖基化的粘膜生发中心的发育 碳氢化合物受体信号。为了了解微生物衍生的吲哚是如何调节CIA的，在目标1中，我们 将首先通过选择性定植确定吲哚在CIA过程中的细菌来源(S) 无菌小鼠。在目标2中，我们将评估吲哚影响胶原特异性TfH和B的机制 CIA发病过程中的细胞分化。然后，目标3将重点研究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。这些研究的完成将提供 肠道细菌如何调节自身免疫性关节炎的发展并提示未来 类风湿性关节炎患者的翻译研究。

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.