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

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.

Osteoarthritis (OA) will affect around 50% of us over our lifetime and yet we still have no disease modifying drugs nor effective analgesics to reduce its societal burden. We have observed that deletion of IL18, and its down stream adaptor protein MyD88, strongly protects mice from developing experimental OA (induced by surgical destabilisation of the joint). We were unable to demonstrate a direct inflammatory role for IL18 in the joint. Rather, it radically changed the gut microbiome and we showed that this mediated the observed joint protection, as wild type mice co-housed with IL18-/- animals displayed reduced OA after joint destabilisation. Furthermore IL18-/- gut microbiome transferred to germ free mice (in our gnotobiotic unit) was able to suppress disease suggesting that the microbiome was releasing something systemically that could drive protection of the joint. Much of the published literature in recent years points to the role of gut microbes generating metabolites from dietary substances which drive systemic anti-inflammatory and protective responses. We propose that a similar mechanism exists in OA.

This project will seek to confirm that metabolites are involved in IL18-/- joint protection by metabolomic screening of IL18-/- and WT mice, and careful dissection of the gut microbe species that confer this protection. We will recolonise mice with individual microbes and test the efficacy of candidate metabolites either by giving them directly (in the drinking water) or by optimising their release from specialised chow. Metabolites signal through specific G protein coupled receptors (GPRs), several of which are regulated in articular cartilage. These will be investigated through relevant knockout mice and available agonists/antagonists. Finally we will explore whether differences in metabolites are measurable in human OA and their role as prognostic biomarkers in OA risk following joint injury.