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

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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.