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Principal Investigator: SETH MICHAEL BLOOM
Organization: MASSACHUSETTS GENERAL HOSPITAL
Fiscal Year: 2024
Award: $182,304
Funding agency: National Institute of Allergy and Infectious Diseases
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.
Terms: <1,4-Butanediamine><1,4-Diaminobutane><1,5-Pentanediamine><AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Address><Affect><Africa South of the Sahara><African><African Females><African Women><Amines><Anabolism><Anatomic Sites><Anatomic structures><Anatomy><Bacteria><Bacterial Physiology><Bacterial Vaginitis><Bacterial Vaginosis><Bacteriology><Bio-Informatics><Biochemical><Biogenic Amines><Bioinformatics><Biological Markers><Biology><Body Tissues><Cadaverine><Cancers><Cell Growth in Number><Cell Multiplication><Cell Proliferation><Cellular Metabolic Process><Cellular Proliferation><Cervical Cancer><Cervix Cancer><Chemicals><Chemistry><Clinical><Clinical Markers><Collaborations><Communicable Diseases><Communities><Data><Development Plans><Disease><Disorder><Disproportionate number of females><Disproportionate number of women><Disproportionately affects females><Disproportionately affects women><Disproportionately impacts females><Disproportionately impacts women><Disproportionately in females><Disproportionately in women><Dysfunction><Environment><Enzymatic Biochemistry><Enzyme Antagonist><Enzyme Gene><Enzyme Inhibitor><Enzyme Inhibitor Agent><Enzyme Inhibitor Drugs><Enzymes><Enzymology><Functional Metagenomics><Functional disorder><General Hospitals><Genomics><Goals><HIV><HIV risk><Health><Human Immunodeficiency Viruses><IF-5A><Imidazole><Immune response><Immunochemical Immunologic><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><Immunology><Immunomodulation><In Vitro><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Inflammation><Inflammatory><Inflammatory Response><Investigators><Knowledge><LAV-HTLV-III><Lactobacillus><Link><Lymphadenopathy-Associated Virus><Malignant Cervical Neoplasm><Malignant Cervical Tumor><Malignant Neoplasm of the Cervix><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Cervix><Malignant Tumor of the Cervix Uteri><Malignant Uterine Cervix Neoplasm><Malignant Uterine Cervix Tumor><Malignant neoplasm of cervix uteri><Massachusetts><Measures><Mediating><Mediator><Medicine><Mentors><Metabolic><Metagenomics><Methods><Microbial Biofilms><Mucosa><Mucosal Inflammation><Mucosal Tissue><Mucositis><Mucous Membrane><Nonspecific Vaginitis><Olfaction><Outcome><Pathogenesis><Pathogenicity><Pathway interactions><Pentamethylenediamine><Physicians><Physiopathology><Population><Premature Birth><Prematurely delivering><Preterm Birth><Prevalence><Production><Propionates><Putrescine><Reproducibility><Research><Research Personnel><Researchers><Role><Scientist><Site><Smell><Smell Perception><Source><South African><Sub-Saharan Africa><Subsaharan Africa><Symptoms><Testing><Tetramethylenediamine><Therapeutic><Tissues><Training><Universities><Uterine Cervix Cancer><Vagina><Vaginal Diseases><Vaginal Disorder><Validation><Virus-HIV><Woman><amine><bacterial community><bio-markers><biofilm><biologic marker><biomarker><biosynthesis><candidate biomarker><candidate identification><candidate marker><career><career development><cell metabolism><cellular metabaolism><cohort><cytokine><diagnostic criteria><eIF-4D><eIF-5A><eIF5A protein><enzyme activity><eukaryotic initiation factor-4D><experience><experiment><experimental research><experimental study><experiments><female bias><female preponderance><genital tract><high level production><high scale production><high volume manufacturing><high volume production><host response><immune modulation><immune regulation><immune system response><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><in vivo><inhibitor><innovate><innovation><innovative><instructor><interest><malignancy><medical college><medical schools><metabolism measurement><metabolome><metabolomics><metabonome><metabonomics><metagenome><metatranscriptomics><microbial><microbial consortia><microbial flora><microbiome><microbiome community composition><microbiome composition><microbiome species composition><microbiome structure><microbiota><microflora><multiomics><multiple omics><multispecies consortia><neoplasm/cancer><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutics><new therapy><new therapy approaches><new treatment approach><new treatment strategy><next generation therapeutics><non-specific vaginitis><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutics><novel therapy><novel therapy approach><odor perception><olfactory perception><panomics><pathophysiology><pathway><pharmacologic><potential biological marker><potential biomarker><premature childbirth><premature delivery><preterm delivery><prevent><preventing><reproductive outcome><reproductive tract><school of medicine><skills><social role><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><translation factor><vagina disorder><vagina microbiota><vaginal biome><vaginal flora><vaginal fluid><vaginal microbial community><vaginal microbiome><vaginal microbiota><vaginal microflora><validations><women's preponderance>