Interactions between AHR ligands and the gut microbiota in murine arthritis

描述(由申请人提供)：脊柱关节炎(SpA)影响美国0.5%-2%的人口，其特征是非对称性炎性关节炎、脊柱炎和终端炎，并有关节外并发症的风险。发病机制尚不清楚；然而，尽管最近在遗传方面取得了进展，但环境因素仍然发挥着重要作用。一个潜在的因素是肠道微生物区系，其中的异常与炎症性肠病有关。另一个被错误地与关节炎动物模型联系在一起但尚未在脊柱性关节炎中研究的重要环境因素是芳烃受体配体家族。我们的假设是，肠道微生物区系和AHR配体都有助于脊柱性关节炎，而且微生物区系可以减弱AHR配体的影响。这里提出的研究将对这些潜在的触发因素提供重要的启示。首先，研究人员将人类受试者的肠道微生物区系喂给关节炎小鼠模型，以确定关节炎患者的微生物区系是否在引发关节炎方面更有效。其次，研究人员将在产前将同一小鼠暴露于多种不同的AHR配体，以评估AHR配体暴露对关节炎发生的影响。AHR的研究将在无菌状态下重复进行，以评估微生物区系是否可以调节AHR配体暴露的效果。

DESCRIPTION (provided by applicant): Spondyloarthritis (SpA) affects 0.5-2% of the population in the United States and is characterized by an asymmetric inflammatory arthritis, spondylitis, and enthesitis, with risk of extra-articular complications. The pathogenesis is unknown; however, despite recent genetic advances, there remains an important role for environmental triggers. One potential contributing factor is the intestinal microbiota, abnormalities in which are linked to inflammatory bowel disease. Another important environmental factor that is wrongly linked to animal models of arthritis but has not yet been studied in spondyloarthritis is the family of aryl hydrocarbon receptor ligands. It is our hypothess that both the enteric microbiota and AHR ligands contribute towards spondyloarthritis, and furthermore that the microbiota can attenuate the effects of the AHR ligands. The studies proposed herein will shed important light on these potential triggers. First, the investigators wil feed enteric microbiota from human subjects to a mouse model of arthritis, to determine whether the microbiota from arthritis patients is more effective at inducing arthritis. Second, the investigators will expose the same mice prenatally with multiple different AHR ligands to evaluate the effect of AHR ligand exposure on development of arthritis. The AHR studies will be repeated in the germ-free state, to evaluate whether the microbiota can modulate the effect of AHR ligand exposure.