Contribution of Phosphate to Inflammatory Bone Loss

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Project Summary/Abstract Objectives: The median age of veterans in 2018 was 65 and women make up the fastest growing share of veterans, estimated at 17% by 2040 (American Community Survey). Almost 25% are over 75 years old and 68% are 55 and older. Aging is associated with an increased vulnerability to a number of diseases including osteoporosis with the associated increased risk of fracture. Fractures have serious health consequences including lengthy rehabilitation and the most serious, hip fractures, may cause prolonged or permanent disability and almost always require hospitalization and major surgery. A recent retrospective, secondary analysis of National Veterans Health Administration Medicare beneficiaries concluded that one in three elderly male veterans who sustain a hip fracture die within one year. Another retrospective study of 41,331 veterans determined that approximately 18.3% of hip fracture patients were readmitted within 30 days and of those 48.5% died within one year. Therefore, prevention of fractures would represent a significant health intervention, improving longevity as well as quality of life in the veteran population. Nutritional intervention as a means to modulate health and disease represents a promising area of opportunity to improve health although sufficient data does not currently exist to optimally take advantage of this strategy. Research Plan: We have identified inorganic phosphate that is consumed in great excess by Americans as a nutritional element that strongly influences inflammation and bone quality and might be manipulated for improvement of bone mass and quality. Therefore, the goals of this study are to further investigate the value of controlling phosphate intake for the improvement of bone quality and reduction of inflammation. Our published and preliminary data strongly support the working model and hypothesis that high dietary Pi intake results in changes in the microbiome, compromised intestinal integrity, and chronic inflammation leading to bone loss, while a reduced Pi diet is beneficial to bone volume and reduces inflammation. Growing evidence strongly suggests that the gut microbiota can have profound systemic influence on health and disease although the details are only beginning to be uncovered. How, individual environmental elements such as nutrients alter the gut microbiota is even less understood. Pi is required for cell and bacterial growth and excess Pi is known to positively influence cell growth, and in some cases cause deregulated growth, leading to our general hypothesis that a sustained high Pi diet results in changes to the microbiome composition which results in inflammation and bone loss. Methods: Proposed studies will utilize a comprehensive series of innovative mouse models including Germ- Free, antibiotic treated, and T cell tracking mice to; 1) To determine if a sustained high phosphate diet generates increased intestinal inflammation, 2) To identify the mechanisms whereby the gut microbiome influences high dietary phosphate-induced bone loss including intestinal permeability and changes in microbiome content, and 3) To determine if the microbiome can be manipulated to modulate Pi homeostasis and bone metabolism. Clinical Relevance: Prevention of fractures will greatly reduce both the personal and financial burden to veterans relative to post-fracture treatment. These studies will be the first to investigate the effect of the common nutritional element particularly relevant to the dietary habits of Americans in Pi on gut inflammation and long-term changes to the gut microbiome. Results could unveil new clinically relevant prevention strategies to modulate mineral homeostasis that have broad consequences on health and disease.