Computational Microbiome Pharmacology Analysis Elucidates the Anti-Cancer Potential of Vaginal Microbes and Metabolites

Damilola Christianah Lawore¹Smrutiti Jena¹Alicia R Berard²Kenzie Birse²ALANA LAMONT³ROMEL D MACKRELPRANG⁴LAURA NOEL-ROMAS²Michelle Perner⁵Xuanlin Hou⁴Elizabeth M. Irungu⁶Nelly Rwamba Mugo^6,7Samantha Knodel²Timothy R Muwonge⁸ELLY KATABIRA⁸SEAN M HUGHES⁹CLAIRE LEVY¹⁰Fernanda L. Calienes¹⁰FLORIAN HLADIK^10,11,9Jairam Lingappa^11,12,4ADAM D BURGENER^13,2Leopold N Green¹⁴Douglas K Brubaker^15,2*

• ¹Purdue University, West Lafayette, United States
• ²Center for Global Health and Diseases, School of Medicine, Case Western Reserve University, Cleveland, Ohio, United States
• ³Department of Obstetrics and Gynecology, University of Manitoba,, Winnipeg, Canada
• ⁴Department of Global Health, School of Medicine, University of Washington, Seattle, Washington, United States
• ⁵Medical Microbiology and Infectious Disease, University of Manitoba,, Winnipeg, Canada
• ⁶Partners in Health Research and Development, Kenya Medical Research Institute,, Nairobi, Kenya
• ⁷Department of Global Health, School of Public Health, University of Washington, Seattle, Washington, United States
• ⁸Infectious Diseases Institute, College of Health Sciences, Makerere University, Kampala, Uganda
• ⁹Department of Obstetrics and Gynecology, University of Washington,, Seattle, United States
• ¹⁰Fred Hutchinson Cancer Center, Seattle, Washington, United States
• ¹¹Department of Medicine, School of Medicine, University of Washington, Seattle, Washington, United States
• ¹²Department of Pediatrics, University of Washington,, Seattle, United States
• ¹³Department of Medicine, Solna, Karolinska Institutet (KI), Solna, Stockholm, Sweden
• ¹⁴Weldon School of Biomedical Engineering, College of Engineering, Purdue University, West Lafayette, Indiana, United States
• ¹⁵The Blood Heart Lung Immunology Research Center, Case Western Reserve University, University Hospitals of Cleveland,, Cleveland, United States

The vaginal microbiome's role in risk, progression, and treatment of female cancers has been widely explored. Yet, there remains a need to develop methods to understand the interaction of microbiome factors with host cells and to characterize their potential therapeutic functions. To address this challenge, we developed a systems biology framework we term the Pharmacobiome for microbiome pharmacology analysis. The Pharmacobiome framework evaluates similarities between microbes, microbial byproducts, and known drugs based on their impact on host transcriptomic cellular signatures. Here, we apply our framework to characterization of the Anti-Gynecologic Cancer Vaginal Pharmacobiome. Using published vaginal microbiome multi-omics data from the Partners PrEP clinical trial, we constructed vaginal epithelial gene signatures associated with each profiled vaginal microbe and metabolite. We compared these microbiome-associated host gene signatures to post-drug perturbation host gene signatures related to 35 FDA-approved anti-cancer drugs from the Library of Integrated Network-based Cellular Signatures database to identify vaginal microbes and metabolites with high statistical and functional similarity to these drugs. We found that select lactobacilli particularly L. crispatus and their metabolites, such as taurine, can regulate host gene expression in ways similar to certain anti-cancer drugs. Additionally, we experimentally tested our model prediction that taurine, a metabolite produced by L. crispatus, kills cancerous breast and endometrial cancer cells. Our study shows that the Pharmacobiome is a robust framework for characterizing the anti-cancer therapeutic potential of vaginal microbiome factors with generalizability to other cancers, microbiomes, and diseases.