The Role of the Gut Microbiome In Bone and Joint
Guss, Jason Daniel
Osteoporosis and osteoarthritis affect millions of people worldwide every year. Osteoporosis related fractures totaled 8.9 million worldwide annually and osteoarthritis affects over 30 million people in the US alone. Recently, the gut microbiome has been identified as a factor that can influence chronic conditions associated with bone and joint disease such as obesity, diabetes, metabolic syndrome, inflammatory bowel diseases, and malnutrition. Though the gut microbiome is studied extensively in relation to metabolic diseases and disorders, the role of the gut microbiome in the development and progression of bone and joint disease is largely unexplored. Recent evidence suggests that the gut microbiome can influence bone mass, however no studies have determined if the mechanical performance of the bone is influenced by the gut microbiome. Therefore, first, we characterize how alterations to the gut microbiome can influence whole bone mechanical performance at skeletal maturity. We evaluate alterations in the gut microbiome caused by genotypic alteration and chronic treatment with antibiotics. Our results demonstrate that disruption of the gut microbiome with antibiotics is associated with reductions in cortical bone mass and whole bone strength, as well as drastic shifts in the composition of the gut microbiome. Furthermore, the changes in whole bone strength are greater than can be explained by the associated changes in bone mass and geometry, suggesting impaired bone tissue material properties in mice with an altered gut microbiome due to genotypic alteration and chronic antibiotic treatment. Next, we evaluate the changes in bone tissue composition caused by alterations in the gut microbiome. Additionally, we investigate how the functional profile of the gut microbiome can influence bone tissue material properties through several potential pathways: 1) regulation of nutrient and vitamin absorption/synthesis; 2) regulation of the immune system; 3) translocation of bacterial products. Our results demonstrate that disruption of the gut microbiome with antibiotics causes changes in bone mineral crystallinity, and that the effect is different per mouse genotype. Furthermore, we show that the functional capacity of the gut microbiome is dramatically altered in mice treated with antibiotics. A pathway involving vitamin K, a factor important for bone health, and associated with fracture risk, is suspected as changes in microbial gene pathways for vitamin K synthesis are disrupted leading to reduced vitamin K levels in organs. Last, we evaluate how alterations in the gut microbiome may influence the development and severity of load-induced osteoarthritis. Here we investigate obesity and metabolic syndrome, two conditions associated with an altered gut microbiome and an increased risk of developing osteoarthritis (OA). We use a mouse model of metabolic syndrome dependent on the gut microbiome, a mouse model of severe obesity/diabetes, and an in vivo non-invasive loading model to induce osteoarthritis-like pathology. Our results demonstrate that metabolic syndrome in the current mouse model does not increase load-induced cartilage damage, while severe obesity leads to increases in cartilage damage, though only after a prolonged loading period. The increased cartilage damage in severely obese mice is associated with increased adiposity, systemic inflammation, and bacterial lipopolysaccharide. We also demonstrate that disruption of the gut microbiome in the metabolic syndrome mice is associated with decreased load-induced cartilage damage, as well as changes in subchondral bone properties. Together, the current work suggests the gut microbiome influences both the structure and composition of bone, and can influence the development of osteoarthritis. The current work helps to establish a promising foundation for future lines of investigation evaluating how the gut microbiome influences bone and joint and suggests that there may be a future use for manipulating the gut microbiome in therapies to treat and prevent bone and joint disease.
Biomechanics; bone; Biomedical engineering; Bone Quality; Gut Microbiome; Ostoeporosis
Hernandez, Christopher J.
van der Meulen, Marjolein; Goldring, Steven Reyburn
Ph. D., Biomedical Engineering
Doctor of Philosophy
dissertation or thesis