Modulation of the gut microbiome by dietary fiber to improve calcium absorption and bone health in older men

Osteoporosis and associated fractures are key health problems in older male Veterans due to high morbidity and mortality, yet little is known about the pathogenesis of accelerated bone loss in men. Emerging evidence points to dietary fiber as an important modifiable risk factor, likely through increased intestinal calcium absorption as suggested by studies in adolescents, young men, and postmenopausal women. It remains unknown whether dietary fiber augments calcium absorption and bone health in older men, in part because we do not have a clear mechanistic understanding of how it influences calcium and bone metabolism. The gut microbiome, which is crucial for host nutrient metabolism and hormone modulation, is an underexplored mechanism. Dietary fiber intake is associated with increases in short chain fatty acids (SCFA) that are produced by microbiota fermentation of dietary fiber in the lower intestine. Among other effects, SCFA can induce host insulin-like growth factor 1 (IGF-1) synthesis, which is a regulator of calcium absorption and bone metabolism. Therefore, our central hypothesis is that dietary fiber augments SCFA production by the gut microbiome, which modulates the production of systemic IGF-1 to increase calcium absorption and bone mass. To test this hypothesis, we will first evaluate the effects of soluble corn fiber on intestinal calcium absorption and gut microbiome composition and function in older male Veterans. With a crossover intervention study, we will measure fractional calcium absorption using dual isotopic tracers and characterize the gut microbiome with shotgun metagenomics and metabolomics after 4 weeks of soluble corn fiber and placebo (Aim 1). Second, we will determine the causal role of the gut microbiome in calcium homeostasis and bone. We will measure the differences in calcium absorption and bone microarchitecture, assessed by an in situ ligated intestinal loop procedure and microcomputed tomography, between an antibiotic-induced microbiota-depleted mouse model vs. control after 8 weeks on soluble corn fiber-supplemented diet, fiber-free diet, or control diet (Aim 2). Third, we will explore the mediating role of IGF-1 by measuring the change in serum IGF-1 level while on soluble corn fiber in the older male Veterans studied in Aim 1, and then with a transgenic mouse model with intestinal IGF-1 receptor knockout (Aim 3). Results from the proposed research are expected to provide valuable insights into the effects of dietary fibers on calcium and bone metabolism and the mediating role of the gut microbiome. Further, the proposed activities will promote the career development of Dr. Wu, a staff endocrinologist at the San Francisco VA Health Care System (SFVAHCS) with the long-term career goal of becoming a clinical/translational VA investigator of the interactions between nutrition, gut microbiome, and skeletal metabolism. To achieve this goal, Dr. Wu will gain crucial training in (1) interventional study designs, (2) advanced techniques for assessing calcium metabolism, (3) integration of multi-omics microbiome data and computational analysis, and (4) use of mouse models for translational microbiome and metabolic research. Dr. Wu will thrive with the support of a renowned clinical and translational mentorship team; experiential and formal didactic training; and the outstanding scientific environment of the SFVAHCS Endocrine Research Unit, the Benioff Center for Microbiome Medicine at the University of California, San Francisco (UCSF), and the UCSF Clinical and Translational Science Institute. By the end of this award, Dr. Wu will have the necessary skills and preliminary data to compete successfully for Merit Review funding and to establish an independent VA research career.