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

Cell Reports (May 2023)

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

Journal volume & issue: Vol. 42, no. 5
p. 112474

Abstract

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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.

CP: Microbiology

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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