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，在我们生活的某个阶段影响着大约50%的人。但为什么另外50%的人没有患OA呢？我们认为我们已经发现了一种新的机制，它依赖于我们的饮食和肠道中的细菌，这可能能够保护我们免受OA的影响。我们已经发现了这一机制，并与具有强烈保护它们免受实验性OA的遗传变化的小鼠一起工作。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。我们证明了这些老鼠的肠道细菌起到了保护作用如果我们把正常老鼠和基因改变的老鼠放在同一个笼子里，基因改变的老鼠和正常老鼠分享了它们的肠道细菌这就转移了对OA的保护。换句话说，这些小鼠的OA保护具有传染性！这种由肠道细菌改变介导的益处，在糖尿病和炎症性肠病等其他疾病领域得到越来越多的认识。这些研究表明，一组关键的分子介导了这种保护作用。这些是脂肪和碳水化合物等膳食物质的分解产物，即所谓的代谢物。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。它们与一大类叫做g蛋白偶联受体（GPRs）的受体结合。其中一些存在于关节细胞中，重要的是在关节损伤后增加，这是OA发展的一个重要危险因素。在这个项目中，我们将通过确定是否由于代谢物增加来揭示联合保护的机制。我们将找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。根据之前的研究，我们知道50%的人会在5年内患上OA，而50%的人会得到保护。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能预测关节损伤后的OA结局。最终，我们希望这项工作将确定利用特定膳食补充剂的好处来保护我们的关节免受OA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.