Role of Gut Microbiota in Bone Mass Heritability and Skeletal Response to PTH

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SUMMARY Low bone mineral density (BMD) is a key feature of osteoporosis that is caused by deficient skeletal development and/or accelerated bone loss. Interestingly, there is a high degree of variation in BMD within populations, with about half of the differences in BMD attributed to genetic factors. However, the remaining causes of BMD variance within populations remain enigmatic. With the help of the Human Microbiome Project, we now understand that the microbiome plays a critical role in health and wellness. Implicating the microbiome as a regulator of BMD are established reports that mice raised in germ-free (GF) conditions have altered bone density compared to conventional mice. A number of elements influence the composition of the microbiota, including both genomic and non-genomic factors. Of the non-genomic factors, a recently realized prevalent influence is cohabitation with family members, where microbes transfer horizontally between co-inhabitants, or vertically from parent to offspring. These observations are the basis of our compelling hypothesis that the microbiome is a non-genomic contributor to BMD heretability, which affects the efficiency of skeletal mass development. Corroborating this hypothesis is our data showing that BMD levels, and the frequency of osteoclastogenic Th17 cells differ between isogenic mice with varying microbiome compositions. Critically, we also show that equalization of the microbiota by co-housing these mice balances the frequency of Th17 cells, and balances the bone density between the two groups. In this proposal, we will identify how microbiome diversity acquired following birth shapes BMD and skeletal mass acquisition. In Aim 1, we will determine the contribution of gut microbiota to post-natal skeletal mass acquisition and peak bone density. Here, we will leverage gnotobiotic and immunological approaches extending a proven transdisciplinary partnership to interrogate precisely controlled models of early-life intestinal microbial succession, to establish the role of the maternal microbiome in transmitting the effects of the pre-natal microbiome to offspring. In Aim 2 we will identify the role of gut bacterial activation of Th17 cells on post-natal skeletal development. Recent evidence has shown that the gut microbiome plays a causal role in bone disease, where we reported that the microbiome regulates the skeletal response to sex steroid deficiency. Our new preliminary data show that the microbiome also influences the skeletal response to PTH, where we show that GF mice and antibiotic treated conventional mice are resistant to the bone anabolic effects of PTH. Therefore, in Aim 3 we will identify the functional elements within the gut microbiome and within the host that are necessary for PTH to exert its modulatory effects on skeletal homeostasis. Understanding how the gut microbiome regulates skeletal mass acquisition and the skeletal effects of PTH would potentially enable trials of rational manipulation of the early life microbiota to remove microbial impediments to childhood skeletal mass acquisition, thereby facilitating optimal skeletal mass development within the American populace.