Menopause and hormonal influences on the gut microbiome for CVD risk in HIV

PROJECT SUMMARY/ABSTRACT Women with HIV face particularly higher risk of cardiovascular disease (CVD) than uninfected women, potentially related to lower levels of ovarian reserve and sex steroid hormones in women with HIV. Our preliminary findings in women with HIV suggest that menopause alters the gut microbiome and microbial translocation, which may contribute to CVD risk. Yet, no studies have investigated the association of menopause and sex hormones with gut microbiome composition and microbial translocation, nor considered the impact on CVD risk. This is particularly relevant in the context of HIV infection, where a dysbiotic gut microbiome and microbial translocation are thought to lead to persistent immune dysregulation and increased risk of CVD and other chronic diseases. Here, we explore the novel hypothesis that menopause and sex hormones influence CVD risk via modulation of the gut microbiota and microbial translocation, particularly in HIV infection. Leveraging ongoing gut microbiome and CVD projects in the Women's Interagency HIV Study (WIHS), this project will: 1) investigate longitudinal changes in the gut microbiome by menopausal status in women with and without HIV; 2) examine relationships of sex steroid hormones with the gut microbiome and soluble CD14 (sCD14), a biomarker of microbial translocation; and 3) examine the associations of menopause- and sex hormone-related gut microbiome/microbial translocation features and subclinical CVD. These aims will utilize pre-existing data, including comprehensive demographic and clinical data collected by the WIHS cohort, 16S rRNA gene sequencing and shotgun sequencing data from stool samples, serum sCD14, and carotid plaque and intima- media thickness data from B mode ultrasound. We additionally propose new measurement of 14 sex steroid hormones in serum, including adrenal precursors, androgens, and estrogens, using gold standard mass spectrometry assays, in 200 post-menopausal women. To facilitate my career development, I will also pursue training in the following areas: 1) HIV and CVD science; 2) Reproductive endocrinology; 3) Bioinformatic and statistical methods; 4) Clinical research operations; and 5) Grant development skills. The proposed study will uncover novel microbiome-related connections between menopause, sex hormones, and subclinical CVD in women with and without HIV. The training and research proposed in this award will directly set the stage for a larger study in the WIHS, to more comprehensively assess longitudinal changes in the gut microbiome, microbial translocation, and other cardiovascular risk biomarkers during the menopausal transition, and relate longitudinal trajectories and microbiome-biomarker interactions to HIV infection and CVD progression; as well as support future studies in other populations (e.g. men with HIV, non-HIV cohorts) and in clinical trials. Ultimately, this research may lead to new avenues of therapeutic intervention targeting the gut microbiome, to lower CVD risk in post-menopausal women with or without HIV.