Vaginal epithelial dysfunction is mediated by the microbiome, metabolome, and mTOR signaling
Alicia R. Berard,
Douglas K. Brubaker,
Kenzie Birse,
Alana Lamont,
Romel D. Mackelprang,
Laura Noël-Romas,
Michelle Perner,
Xuanlin Hou,
Elizabeth Irungu,
Nelly Mugo,
Samantha Knodel,
Timothy R. Muwonge,
Elly Katabira,
Sean M. Hughes,
Claire Levy,
Fernanda L. Calienes,
Douglas A. Lauffenburger,
Jared M. Baeten,
Connie Celum,
Florian Hladik,
Jairam Lingappa,
Adam D. Burgener
Affiliations
Alicia R. Berard
Department of Obstetrics & Gynecology, University of Manitoba, Winnipeg, MB R3E 3P5, Canada; Center for Global Health and Diseases, Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
Douglas K. Brubaker
Weldon School of Biomedical Engineering and Regenstrief Center for Healthcare Engineering, Purdue University, West Lafayette, IN 47907, USA
Kenzie Birse
Department of Obstetrics & Gynecology, University of Manitoba, Winnipeg, MB R3E 3P5, Canada; Center for Global Health and Diseases, Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
Alana Lamont
Department of Obstetrics & Gynecology, University of Manitoba, Winnipeg, MB R3E 3P5, Canada
Romel D. Mackelprang
Department of Global Health, University of Washington, Seattle, WA 98105, USA
Laura Noël-Romas
Department of Obstetrics & Gynecology, University of Manitoba, Winnipeg, MB R3E 3P5, Canada; Center for Global Health and Diseases, Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
Michelle Perner
Medical Microbiology and Infectious Disease University of Manitoba, Winnipeg, MB R3E 0J9, Canada
Xuanlin Hou
Department of Global Health, University of Washington, Seattle, WA 98105, USA
Elizabeth Irungu
Partners in Health Research and Development, Kenya Medical Research Institute, Mbagathi Road, Nairobi, Kenya
Nelly Mugo
Department of Global Health, University of Washington, Seattle, WA 98105, USA; Partners in Health Research and Development, Kenya Medical Research Institute, Mbagathi Road, Nairobi, Kenya
Samantha Knodel
Department of Obstetrics & Gynecology, University of Manitoba, Winnipeg, MB R3E 3P5, Canada; Center for Global Health and Diseases, Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
Timothy R. Muwonge
Infectious Disease Institute, Makerere University, Makerere, Kampala, Uganda
Elly Katabira
Infectious Disease Institute, Makerere University, Makerere, Kampala, Uganda
Sean M. Hughes
Department of Obstetrics and Gynecology, University of Washington, Seattle, WA 98195, USA
Claire Levy
Department of Obstetrics and Gynecology, University of Washington, Seattle, WA 98195, USA
Fernanda L. Calienes
Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
Douglas A. Lauffenburger
Department of Biological Engineering, MIT, Cambridge, MA 02142, USA
Jared M. Baeten
Department of Global Health, University of Washington, Seattle, WA 98105, USA; Department of Medicine, University of Washington, Seattle, WA 98195, USA; Department of Epidemiology, University of Washington, Seattle, WA 98195, USA; Gilead Sciences, Foster City, CA 94404, USA
Connie Celum
Department of Global Health, University of Washington, Seattle, WA 98105, USA; Department of Medicine, University of Washington, Seattle, WA 98195, USA; Department of Epidemiology, University of Washington, Seattle, WA 98195, USA
Florian Hladik
Department of Obstetrics and Gynecology, University of Washington, Seattle, WA 98195, USA; Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Department of Medicine, University of Washington, Seattle, WA 98195, USA
Jairam Lingappa
Department of Global Health, University of Washington, Seattle, WA 98105, USA; Department of Medicine, University of Washington, Seattle, WA 98195, USA; Department of Pediatrics, University of Washington, Seattle, WA 98195, USA
Adam D. Burgener
Department of Obstetrics & Gynecology, University of Manitoba, Winnipeg, MB R3E 3P5, Canada; Center for Global Health and Diseases, Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA; Department of Medicine Solna, Karolinska Institutet, Framstegsgatan, 171 64 Solna, Sweden; Corresponding author
Summary: Bacterial vaginosis (BV) is characterized by depletion of Lactobacillus and overgrowth of anaerobic and facultative bacteria, leading to increased mucosal inflammation, epithelial disruption, and poor reproductive health outcomes. However, the molecular mediators contributing to vaginal epithelial dysfunction are poorly understood. Here we utilize proteomic, transcriptomic, and metabolomic analyses to characterize biological features underlying BV in 405 African women and explore functional mechanisms in vitro. We identify five major vaginal microbiome groups: L. crispatus (21%), L. iners (18%), Lactobacillus (9%), Gardnerella (30%), and polymicrobial (22%). Using multi-omics we show that BV-associated epithelial disruption and mucosal inflammation link to the mammalian target of rapamycin (mTOR) pathway and associate with Gardnerella, M. mulieris, and specific metabolites including imidazole propionate. Experiments in vitro confirm that type strain G. vaginalis and M. mulieris supernatants and imidazole propionate directly affect epithelial barrier function and activation of mTOR pathways. These results find that the microbiome-mTOR axis is a central feature of epithelial dysfunction in BV.
