Mechanistic characterization of vaginal microbiome-metabolome associations and metabolite-mediated host inflammation

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Project Summary/Abstract The vaginal microbiome is associated with important health outcomes, including bacterial vaginosis (BV), preterm birth, HIV risk, and cervical cancer, but mechanisms for these associations are unclear and current microbiome-directed therapies have low efficacy. Metabolome alterations including high-level production of amines like putrescine are a defining feature of BV and a major cause of symptoms, but underlying mechanisms and host responses to BV-associated metabolites including amines are poorly characterized. In preliminary data from a South African cohort with high BV prevalence, 60% of detectable metabolites in vaginal fluid significantly differ between optimal Lactobacillus-dominant bacterial communities and non-optimal non-Lactobacillus- dominant (NLD) communities. Strongly BV- and NLD-associated metabolites included putrescine and imidazole propionate (ImP), both of which are known to have adverse host effects in non-vaginal diseases but whose production and effects remain largely uncharacterized in the genital tract. These results suggest bacteria comprising NLD communities express enzymes that produce these metabolites. The study will (1) characterize metabolome and metagenome composition in additional cohorts to validate findings and identify candidate enzymes for putrescine and ImP production, (2) characterize the enzymes in cultured vaginal bacteria and assess effects of known pharmacologic inhibitors, and (3) assess effects of putrescine and ImP on metabolic and inflammatory host responses and test whether they can be blocked by known host pathway inhibitors. The results will elucidate vaginal metabolome-related pathophysiology and may directly identify candidate therapies. The PI is an Instructor in Medicine at Harvard Medical School and the Division of Infectious Diseases at Massachusetts General Hospital (MGH); in addition to the research plan this proposal includes a five-year career development plan. His career goal is to become an independent physician-scientist investigator studying mechanisms of vaginal microbiome- and metabolome-mediated disease through bacteriologic, biochemical, and immunologic approaches to identify novel therapies. The proposal builds on the PI’s prior experience studying vaginal microbiome dynamics and investigating the physiology of bacterial species within the microbiome. The current proposal significantly expands his scientific scope by investigating microbial determinants of vaginal metabolome composition, identifying host pathways those metabolites affect, and testing pathway inhibitors. He will pursue this research under the guidance of his primary mentor, Dr. Doug Kwon, at the Ragon Institute of MGH, MIT and Harvard and his co-mentor, Dr. Emily Balskus, at the Harvard University Department of Chemistry and Chemical Biology. He will pursue didactic coursework and receive training, guidance, and collaboration from a diverse team of experts. The proposed training provides the PI with a unique skillset and wealth of initial data to facilitate his transition to research independence.