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，特征为不对称炎性关节炎、脊柱炎和附着点炎，有关节外并发症的风险。发病机制是未知的，然而，尽管最近的遗传进步，仍然有一个重要的作用，环境触发器。一个潜在的影响因素是肠道微生物群，其中异常与炎症性肠病有关。另一个重要的环境因素是芳香烃受体配体家族，它被错误地与关节炎的动物模型联系在一起，但尚未在脊椎关节炎中进行研究。我们的假设是，肠道微生物群和AHR配体都有助于脊柱关节炎，此外，微生物群可以减弱AHR配体的作用。本文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群喂给关节炎小鼠模型，以确定关节炎患者的微生物群是否更有效地诱导关节炎。其次，研究者将在产前用多种不同的AHR配体暴露相同的小鼠，以评估AHR配体暴露对关节炎发展的影响。AHR研究将在无菌状态下重复进行，以评估微生物群是否可以调节AHR配体暴露的影响。

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.