Emory Specialized Center of Research Excellence (SCORE) on Sex Differences

Emory University, Atlanta GA

Investigators

Linked publications, trials & patents

Abstract

PROJECT SUMMARY / ABSTRACT (Project 1: Bone) Osteoporosis is a serious condition that increases the risk of bone fractures. HIV infection and AIDS sequelae are risk factors for low bone mineral density (BMD). This can be exacerbated by antiretroviral therapy (ART), which causes intense bone loss within the first 6 -12 months of therapy. Consequently, fractures are more prevalent in people living with HIV infection (PLH). Estrogen deficiency after menopause is also associated with aggressive loss of BMD so, not surprisingly, postmenopausal Women living with HIV infection (WLH) have an even higher prevalence of low BMD and bone fracture than HIV(-) postmenopausal women do. These data suggest an additive collision between HIV/ART bone loss and postmenopausal-bone loss, creating an urgent need to design countermeasures to prevent fractures as >50% of PLH are over the age of 50, and many women living with HIV (WLH) experience early menopause transition. The mechanism/s that mediate these adverse responses are poorly defined, however. Mechanistically, there are several commonalities between HIV- and estrogen deficiency-bone loss. Both are associated with a significant decline in gut barrier integrity. A “leaky gut” can allow for an increased translocation of microbial factors from the gut lumen to sub-epithelial compartments where some microbial factors (including the Gram-negative bacterial coat protein lipopolysaccharide (LPS)) trigger pro-inflammatory responses which promote bone resorption through both direct and indirect effects on osteoclast differentiation. Factors from certain species of gut bacteria also promote differentiation of Th17 cells, a CD4 T-helper subset that is potently osteoclastogenic, due to the production of osteoclastogenic cytokines including the Th17 signature cytokine IL-17A. Studies in animals have further revealed that Th17 cells are required for estrogen deficiency bone loss. These data establish a putative link between the gut microbiome, and HIV-infection- and estrogen deficiency-bone loss. We hypothesize that the high rates of bone fracture in postmenopausal WLH, relative to HIV(-) women, are related to HIV- and estrogen deficiency-induced gut permeability, and the penetration of microbial antigens such as LPS driving local and systemic inflammation and leading to bone resorption and BMD loss. We further propose that WLH harboring Th17-inducing microbial species undergo even more intense bone loss due to the actions on osteoclastogenesis of Th17 cells and of IL-17A. These hypotheses will be investigated within the context of two Specific Aims. Aim 1 will leverage the SCORE cohort of WLH and controls to demonstrate the impact of gut barrier impairment, microbiota composition, Th17 T cells, and circulating IL-17A, with BMD and indices of bone turnover in pre- and post-menopausal WLH. Aim 2 will generate Human microbiota-associated mice (HMA), by using Fecal microbiota transplantation (FMT) of human microbiota samples from Aim 1, to demonstrate cause/effect relationships between bone loss and gut permeability and the presence of Th17-inducing bacterial species. Finally, we will test a precision probiotic therapy to blunt bone loss in the mice HMA model.