Triangulating Mechanisms of Microbiome-Joint Crosstalk

University Of California, San Francisco, San Francisco CA

Investigators

Abstract

7. PROJECT SUMMARY The proposed work focuses on interorgan communication between the gut microbiome and the joint in the pathogenesis of osteoarthritis (OA). Although historically viewed as a disease caused by mechanical overload, recent studies indicate that systemic factors are a major contributor to OA. The gut microbiome is a critical regulator of systemic inflammation and is readily modified in individuals, making it an enticing therapeutic target. Studies by our group and others indicate that the gut microbiome is a potent regulator of OA capable of enhancing or blunting trauma-induced osteoarthritis in animal models. Aging is associated with alterations in the composition of the gut microbiota, increased systemic inflammation and increased susceptibility to OA. In several cases, age-related changes in the gut microbiome are major contributors to disease. However, it is not known if the gut microbiome influences spontaneous age-related osteoarthritis, nor is it clear if age-related changes 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 the systemic circulation as regulators of the relationship between the gut microbiome and the joint. However, the association between microbiome-induced changes in musculoskeletal tissues and microbially-derived metabolites is currently limited to examination of fecal samples. Supported by robust PRELIMINARY STUDIES suggesting an effect of the gut microbiome on age-related OA and implicating key microbiota-dependent metabolites with severity of OA, we propose the global hypothesis that the gut microbiota regulates the effects of aging on joint degeneration. Specifically, we ask: Does the microbiome influence spontaneous, age-related joint degeneration? To what degree do age-related changes in the gut microbiota v. age-related changes in host physiology promote joint degeneration? Which of the circulating microbiota-dependent molecules link the gut microbiome to joint degeneration? How do these effects differ by sex? The proposed work has three aims explored using mouse models: 1) Determine the effects of the gut microbiome on age-related spontaneous osteoarthritis; 2) Determine the contribution of age-related changes in the gut microbiota to osteoarthritis; and 3) Determine the role of circulating microbiome-derived metabolites on the severity of osteoarthritis. At the completion of the proposed work, we will have addressed key interactions between the gut microbiome and aging in the context of joint degeneration and determined the effects of microbiota-derived molecules as signaling factors linking the gut microbiome to OA.