Studies on gut microbiome-joint connections in arthritis

摘要 尽管关节的机械性超负荷与肥胖和肥胖症之间的共病关系有关， 和骨关节炎（OA）[1，2]，我们和其他人已经建立了肥胖相关的致病作用， 炎症[3-6]。我们在这种背景下进一步研究炎症的工作已经导致了新的数据， 肠道微生物组的生态失调是结肠、循环和滑膜炎症的根本原因， 最终导致关节加速OA变性[7]。变化包括结肠、血清和滑膜 炎性细胞因子的上调，这与消化球菌科的扩张平行， 肥胖肠道中的消化链球菌科成员。通过饮食纠正这种生态失调 补充不可消化的益生元纤维低聚果糖可消除这些促炎性细胞群 同时恢复在肥胖中丢失的放线菌分类群，假长双歧杆菌（B. pseudolongum）（B. 伪长）。这种矫正导致从结肠到关节的壁龛中的炎症减少， 减少滑膜中巨噬细胞和B细胞的数量，并防止OA的发展 在膝盖[7]。此外，我们已经发现口服递送B。假长链益生菌联合 保护和B。假长肌代谢组本身含有直接抑制炎症的分子。 基于这些发现，我们提出：1）肥胖的OA是由肠道微生物组生态失调引起的， 引发从肠道开始并辐射到关节的炎症级联反应，以及2）肥胖相关的OA 可以通过使用扩大B的方法纠正肥胖肠道生态失调来减轻。假舌或通过 征用其代谢物，以减少结肠上皮的炎症，其中肥胖相关的 炎症信号启动。为了研究这些概念，我们建议解决以下两个问题 具体目标。目的1是确定肠道微生物组生态失调是肥胖OA的原因， 假设肥胖的肠道微生物群是全身性炎症级联反应的启动者， 起始于结肠，辐射至关节，并加速OA。目的二是研究B.假长肌保护 对抗肥胖症关节退化的实验，旨在验证B.假长 减轻炎症，在肥胖症的情况下具有关节保护作用，其代谢组含有 炎症抑制剂。这些目标的完成将确定肥胖的OA是一种 由肠道微生物组生态失调驱动的炎症过程。B的扩展。假舌或其递送 代谢物可以代表新的治疗方法，以解决全球范围的疾病， 目前仅进行姑息治疗。

ABSTRACT Although mechanical overloading of joints has been implicated in the comorbid association between obesity and osteoarthritis (OA) [1, 2], we and others have established a pathogenic role for obesity-associated inflammation [3-6]. Our work to further study inflammation in this context has led to new data implicating dysbiosis of the gut microbiome as a root cause of inflammation in the colon, circulation, and synovium that culminates in accelerated OA degeneration in joints [7]. Changes include colonic, serum, and synovial upregulation of inflammatory cytokines, which parallel the expansion of Peptococcaceae and Peptostreptococcaceae family members in the obese gut. Correction of this dysbiosis via dietary supplementation with the indigestible prebiotic fiber oligofructose ablates these proinflammatory communities while restoring an Actinobacteria taxa that is lost in obesity, Bifidobacterium pseudolongum (B. pseudolongum). This correction leads to reduced inflammation in niches spanning from the colon to the joint, reduced numbers of macrophages and B cells in the synovium, and protection against the development of OA in the knee [7]. Moreover, we have discovered that oral delivery of a B. pseudolongum probiotic is joint protective and the B. pseudolongum metabolome itself contains molecules that directly inhibit inflammation. Based on these findings, we propose that 1) the OA of obesity is caused by a gut microbiome dysbiosis that triggers an inflammatory cascade starting in the intestine and radiating to the joint, and 2) obesity-related OA can be mitigated either by correcting the obese gut dysbiosis using methods to expand B. pseudolongum or by commandeering its metabolites to reduce inflammation in the colonic epithelium where the obesity-related inflammatory signature initiates. To investigate these concepts, we propose to address the following two Specific Aims. Aim 1 is to establish that gut microbiome dysbiosis is causal in the OA of obesity, with the hypothesis that the obese dysbiotic gut microbiome is the initiator of a systemic inflammatory cascade that initiates in the colon, radiates to joints, and accelerates OA. Aim 2 is to study how B. pseudolongum protects against joint degeneration in obesity, with experiments designed to test the hypothesis that B. pseudolongum mitigates inflammation and is joint protective in the context of obesity and its metabolome contains inflammation-suppressing agents. Completion of these aims will establish that the OA of obesity is an inflammatory process driven by gut microbiome dysbiosis. Expansion of B. pseudolongum or delivery of its metabolites could represent novel therapeutic approaches to address a disease of global scope that is currently only treated palliatively.