Do systemic metabolites drive the chondroprotective effects of the IL18-/- gut microbiome in osteoarthritis?

骨关节炎（OA）是最常见的关节疾病，在我们生活中的某个时候影响了大约50%的人。但是为什么其他50%的人没有得OA呢？我们认为我们已经发现了一种新的机制，它依赖于我们肠道中的饮食和细菌，可能能够保护我们免受OA的影响。我们已经发现了这种机制与小鼠的遗传变化，强烈保护他们从发展实验OA。在研究了这种保护的一些潜在机制后，我们发现遗传变化影响了这些小鼠肠道中的细菌平衡。我们发现，这些小鼠的肠道细菌负责观察到的保护作用，如果我们将正常小鼠和转基因小鼠放在同一个笼子里，转基因小鼠与正常小鼠共享肠道细菌，这转移了对OA的保护作用。换句话说，这些小鼠的OA保护是传染性的！这种由肠道细菌改变介导的益处在其他疾病领域如糖尿病和炎症性肠病中越来越多地得到认可。这些研究表明，一组关键的分子介导了这种保护。这些都是分解产物，所谓的代谢物，膳食物质，如脂肪和碳水化合物。细菌在肠道中分解这些分子，然后进入血液，在那里它们可以到达身体的其他部位，发挥有益（有时是有害）的作用。它们与一大类称为G蛋白偶联受体（GPR）的受体结合。其中一些存在于关节细胞上，重要的是在关节损伤后增加，这是OA发展的重要风险因素。在这个项目中，我们将通过确定联合保护的机制是否是由于代谢物的增加。我们将研究出哪些细菌专门驱动这些代谢物，以及它们与哪些受体结合以保护关节。我们将确定如何使用饮食来增强正常小鼠的细菌和代谢产物谱，以驱动关节保护。最后，我们将检查一组在急性膝关节损伤时收集的患者样本。从以前的研究中我们知道，这些人中有50%将在5年内发展为OA，50%将得到保护。我们将测量这些个体血液中的代谢物，并询问代谢物水平是否可以预测关节损伤后的OA结果。最终，我们希望这项工作将确定利用特定膳食补充剂的益处来保护我们的关节免受OA的影响的方法。

Osteoarthritis (OA) is the most common disease of the joint, affecting around 50% of us at some point in our lives. But why do the other 50% of individuals not get OA? We think that we have discovered a new mechanism which is dependent upon the diet and the bacteria in our gut that may be able to protect us from developing OA. We have uncovered this mechanism working with mice with a genetic change that strongly protects them from developing experimental OA. After studying a number of potential mechanisms for this protection, we found that the genetic change affected the bacterial balance in the guts of these mice. We showed that gut bacteria from these mice were responsible for the protection observed by demonstrating that if we put normal mice and genetically changed mice together in the same cage, the genetically changed mice shared their gut bacteria with the normal mice and this transferred the protection against OA. In other words OA protection in these mice was contagious! This type of benefit, mediated by altered gut bacteria, is increasingly recognised in other disease areas such as diabetes and inflammatory bowel disease. These studies suggest that a key group of molecules mediate this protection. These are breakdown products, so called metabolites, of dietary substances such as fats and carbohydrates. Bacteria break down these molecules in the gut and they then access the blood stream where they can travel to other parts of the body to exert beneficial (or sometime detrimental) effects. They bind to a broad class of receptors called G-protein coupled receptors (GPRs). Several of these are present on cells of the joint and importantly are increased after joint injury, an important risk factor in the development of OA. In this project we will unravel the mechanism of joint protection by establishing whether it is due to increased metabolites. We will work out which bacteria specifically drive these metabolites and which receptors they bind to to protect the joint. We will determine how diet could be used to enhance the bacterial and metabolite profile in normal mice to drive joint protection. Finally, we will examine a group of patient samples that have been collected at the time of an acute knee injury. From previous studies we know that 50% of these individuals will develop OA over 5 years, and 50% will be protected. We will measure the metabolites in the blood of these individuals and ask whether metabolite levels predict OA outcome after joint injury.Ultimately we hope that this work will identify ways of harnessing the benefits of specific dietary supplements to protect our joints from OA.