Menopausal hormone therapy, the gut microbiome, and estrogen-related outcomes in women with HIV

PROJECT SUMMARY / ABSTRACT The menopausal transition may pose significant risks for women with HIV (WWH) compared to those without HIV, including heightened symptoms and greater declines in cardiovascular health. Hormone therapy (HT) containing estrogen is indicated for treatment of menopausal symptoms (e.g., vasomotor symptoms), and also is protective for cardiovascular endpoints when used in women under 60 years old within 10 years of menopause in the general population, and potentially in WWH as well. The gut microbiome displays a bi- directional relationship with serum estrogens, playing a role in estrogen recycling and retention. However, despite compelling evidence for gut microbiome and estrogen interactions from our own research and others, it remains unknown whether the gut microbiome can bolster the efficacy of estrogen-based menopausal HT regarding menopause symptoms and cardiovascular benefits. This may be particularly important for WWH, who face lower estrogen levels, heightened menopause symptoms, and elevated cardiovascular risk compared to those without HIV. We propose to conduct an ancillary study of the gut microbiome in a randomized, double- blinded, placebo-controlled trial of estradiol in WWH. The “Menopausal Hormone Therapy for Women Living with HIV” (HoT) study is an ongoing trial in which 105 WWH aged 40-60 years in the late menopausal transition or early post-menopause are randomized to transdermal estradiol gel with or without oral progesterone (n=70) or placebo (n=35) for 12 weeks, with a primary outcome of change in vasomotor symptoms and other outcomes including cardiovascular markers. Using shotgun metagenomic sequencing of gut microbiome specimens collected at baseline (pre-treatment) and week 12, our specific aims are (1) to determine the effect of menopausal HT on the gut microbiome in WWH, and (2) to examine whether the gut microbiome modifies the effect of HT on serum estradiol, vasomotor symptoms, and cardiovascular-related markers including blood pressure and serum ICAM-1, VCAM-1, D-dimer, and fibrinogen. Our proposed study, nested within the first ever randomized, controlled trial of menopausal HT in WWH, will provide first-time evidence of the interaction of the gut microbiome with HT to improve its efficacy by reducing symptoms and cardiovascular risk, a significant burden among WWH. This clinically-relevant research may ultimately guide microbiome-targeted interventions to improve HT effectiveness in WWH and other populations of women.