Triangulating Mechanisms of Microbiome-Joint Crosstalk

The proposed work focuses on interorgan communication between the gut microbiome and the joint in thepathogenesis of osteoarthritis (OA). Although historically viewed as a disease caused by mechanical overloadrecent studies indicate that systemic factors are a major contributor to OA. The gut microbiome is a criticalregulator of systemic inflammation and is readily modified in individuals making it an enticing therapeutictarget. Studies by our group and others indicate that the gut microbiome is a potent regulator of OA capable ofenhancing or blunting trauma-induced osteoarthritis in animal models. Aging is associated with alterations inthe composition of the gut microbiota increased systemic inflammation and increased susceptibility to OA. Inseveral cases age-related changes in the gut microbiome are major contributors to disease. However it is notknown if the gut microbiome influences spontaneous age-related osteoarthritis nor is it clear if age-relatedchanges in OA are due to age-related changes in host physiology or age-related changes in the gut microbiota.Clinical and preclinical studies have implicated microbially-derived molecules that transit from the gut into thesystemic circulation as regulators of the relationship between the gut microbiome and the joint. However theassociation between microbiome-induced changes in musculoskeletal tissues and microbially-derivedmetabolites is currently limited to examination of fecal samples. Supported by robust PRELIMINARY STUDIESsuggesting an effect of the gut microbiome on age-related OA and implicating key microbiota-dependentmetabolites with severity of OA we propose the global hypothesis that the gut microbiota regulates the effectsof aging on joint degeneration. Specifically we ask: Does the microbiome influence spontaneous age-relatedjoint degeneration? To what degree do age-related changes in the gut microbiota v. age-related changes inhost physiology promote joint degeneration? Which of the circulating microbiota-dependent molecules link thegut microbiome to joint degeneration? How do these effects differ by sex? The proposed work has three aimsexplored using mouse models: 1) Determine the effects of the gut microbiome on age-related spontaneousosteoarthritis; 2) Determine the contribution of age-related changes in the gut microbiota to osteoarthritis; and3) Determine the role of circulating microbiome-derived metabolites on the severity of osteoarthritis. At thecompletion of the proposed work we will have addressed key interactions between the gut microbiome andaging in the context of joint degeneration and determined the effects of microbiota-derived molecules assignaling factors linking the gut microbiome to OA.