PMID- 37149863
OWN - NLM
STAT- MEDLINE
DCOM- 20230605
LR  - 20230608
IS  - 2211-1247 (Electronic)
VI  - 42
IP  - 5
DP  - 2023 May 30
TI  - Vaginal epithelial dysfunction is mediated by the microbiome, metabolome, and 
      mTOR signaling.
PG  - 112474
LID - S2211-1247(23)00485-0 [pii]
LID - 10.1016/j.celrep.2023.112474 [doi]
LID - 112474
AB  - 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.
CI  - Copyright (c) 2023 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Berard, Alicia R
AU  - Berard AR
AD  - 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.
FAU - Brubaker, Douglas K
AU  - Brubaker DK
AD  - Weldon School of Biomedical Engineering and Regenstrief Center for Healthcare 
      Engineering, Purdue University, West Lafayette, IN 47907, USA.
FAU - Birse, Kenzie
AU  - Birse K
AD  - 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.
FAU - Lamont, Alana
AU  - Lamont A
AD  - Department of Obstetrics & Gynecology, University of Manitoba, Winnipeg, MB R3E 
      3P5, Canada.
FAU - Mackelprang, Romel D
AU  - Mackelprang RD
AD  - Department of Global Health, University of Washington, Seattle, WA 98105, USA.
FAU - Noel-Romas, Laura
AU  - Noel-Romas L
AD  - 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.
FAU - Perner, Michelle
AU  - Perner M
AD  - Medical Microbiology and Infectious Disease University of Manitoba, Winnipeg, MB 
      R3E 0J9, Canada.
FAU - Hou, Xuanlin
AU  - Hou X
AD  - Department of Global Health, University of Washington, Seattle, WA 98105, USA.
FAU - Irungu, Elizabeth
AU  - Irungu E
AD  - Partners in Health Research and Development, Kenya Medical Research Institute, 
      Mbagathi Road, Nairobi, Kenya.
FAU - Mugo, Nelly
AU  - Mugo N
AD  - 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.
FAU - Knodel, Samantha
AU  - Knodel S
AD  - 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.
FAU - Muwonge, Timothy R
AU  - Muwonge TR
AD  - Infectious Disease Institute, Makerere University, Makerere, Kampala, Uganda.
FAU - Katabira, Elly
AU  - Katabira E
AD  - Infectious Disease Institute, Makerere University, Makerere, Kampala, Uganda.
FAU - Hughes, Sean M
AU  - Hughes SM
AD  - Department of Obstetrics and Gynecology, University of Washington, Seattle, WA 
      98195, USA.
FAU - Levy, Claire
AU  - Levy C
AD  - Department of Obstetrics and Gynecology, University of Washington, Seattle, WA 
      98195, USA.
FAU - Calienes, Fernanda L
AU  - Calienes FL
AD  - Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
FAU - Lauffenburger, Douglas A
AU  - Lauffenburger DA
AD  - Department of Biological Engineering, MIT, Cambridge, MA 02142, USA.
FAU - Baeten, Jared M
AU  - Baeten JM
AD  - 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.
FAU - Celum, Connie
AU  - Celum C
AD  - 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.
FAU - Hladik, Florian
AU  - Hladik F
AD  - 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.
FAU - Lingappa, Jairam
AU  - Lingappa J
AD  - 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.
FAU - Burgener, Adam D
AU  - Burgener AD
AD  - 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. Electronic 
      address: adam.burgener@case.edu.
LA  - eng
GR  - R01 AI111738/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20230506
PL  - United States
TA  - Cell Rep
JT  - Cell reports
JID - 101573691
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
SB  - IM
MH  - Female
MH  - Humans
MH  - Proteomics
MH  - Vagina
MH  - *Vaginosis, Bacterial/microbiology
MH  - Lactobacillus/physiology
MH  - Metabolome
MH  - TOR Serine-Threonine Kinases
MH  - *Microbiota
MH  - Inflammation
PMC - PMC10242450
OTO - NOTNLM
OT  - BV
OT  - CP: Microbiology
OT  - bacterial vaginosis
OT  - epithelial barrier
OT  - imidazolepropionic acid
OT  - in vitro models
OT  - inflammation
OT  - mTOR signaling
OT  - metabolomics
OT  - proteomics
OT  - transcriptomics
OT  - vaginal dysbiosis
OT  - vaginal microbiome
COIS- Declaration of interests J.M.B. is an employee of Gilead Sciences, outside of the 
      submitted work.
EDAT- 2023/05/07 18:41
MHDA- 2023/06/05 06:42
PMCR- 2023/05/06
CRDT- 2023/05/07 12:36
PHST- 2022/09/29 00:00 [received]
PHST- 2023/03/15 00:00 [revised]
PHST- 2023/04/19 00:00 [accepted]
PHST- 2023/06/05 06:42 [medline]
PHST- 2023/05/07 18:41 [pubmed]
PHST- 2023/05/07 12:36 [entrez]
PHST- 2023/05/06 00:00 [pmc-release]
AID - S2211-1247(23)00485-0 [pii]
AID - 112474 [pii]
AID - 10.1016/j.celrep.2023.112474 [doi]
PST - ppublish
SO  - Cell Rep. 2023 May 30;42(5):112474. doi: 10.1016/j.celrep.2023.112474. Epub 2023 
      May 6.