Studies on gut microbiome-joint connections in arthritis

摘要 尽管关节机械负荷过重与肥胖之间的共病联系有关 和骨关节炎[1，2]，我们和其他人已经确定了肥胖相关的致病作用 炎症[3-6]。我们在这一背景下进一步研究炎症的工作导致了新的数据 肠道微生物群失调是结肠、循环和滑膜炎症的根本原因 最终导致关节骨关节炎加速退变[7]。变化包括结肠、血清和滑膜。 炎性细胞因子的上调，这与消化球菌科和 肥胖肠道中的消化链球菌家族成员。通过饮食纠正这种生物失调 补充难以消化的益生素纤维低聚果糖可消融这些促炎群落 在修复因肥胖而丢失的放线菌类群的同时，伪龙双歧杆菌(B. 伪龙属)。这种矫正导致从结肠到关节的壁龛炎症减轻， 减少滑膜中巨噬细胞和B细胞的数量，防止骨性关节炎的发生 在膝盖上[7]。此外，我们还发现，口服假单胞菌益生菌是联合 具有保护性的假单胞菌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)肥胖的骨性关节炎是由肠道微生物群失调引起的 引发从肠道开始并向关节辐射的炎症级联反应，以及2)肥胖相关的骨性关节炎 可以通过使用扩展假单胞菌的方法纠正肥胖的肠道生物失调或通过 征用其代谢产物以减轻与肥胖相关的结肠上皮的炎症 炎性征兆启动。为了研究这些概念，我们建议解决以下两个问题 明确的目标。目标1是确定肠道微生物群失调是肥胖骨性关节炎的原因， 假设肥胖的肠道微生物群是全身炎症性级联反应的发起者 起始于结肠，辐射至关节，加速骨性关节炎。目标2是研究假单胞菌是如何保护 对抗肥胖症的关节退行性变，实验旨在验证假单胞菌的假说 减轻炎症，对肥胖及其代谢物含有的关节具有保护作用 消炎药。这些目标的完成将确立肥胖的OA是一种 肠道微生物群失调所驱动的炎症过程。假单胞菌的扩展或ITS的交付 代谢物可以代表新的治疗方法来应对一种全球范围的疾病 目前只接受姑息治疗。

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.