Abstract
Bacterial vaginosis (BV), a common syndrome characterized by Lactobacillus-deficient vaginal microbiota, is associated with adverse health outcomes. BV often recurs after standard antibiotic therapy in part because antibiotics promote microbiota dominance by Lactobacillus iners instead of Lactobacillus crispatus, which has more beneficial health associations. Strategies to promote L. crispatus and inhibit L. iners are thus needed. We show that oleic acid (OA) and similar long-chain fatty acids simultaneously inhibit L. iners and enhance L. crispatus growth. These phenotypes require OA-inducible genes conserved in L. crispatus and related lactobacilli, including an oleate hydratase (ohyA) and putative fatty acid efflux pump (farE). FarE me- diates OA resistance, while OhyA is robustly active in the vaginal microbiota and enhances bacterial fitness by biochemically sequestering OA in a derivative form only ohyA-harboring organisms can exploit. OA pro- motes L. crispatus dominance more effectively than antibiotics in an in vitro BV model, suggesting a metab- olite-based treatment approach.
Document Type
Article
Publication Date
2024
Digital Object Identifier (DOI)
https://doi.org/10.1016/j.cell.2024.07.029
Funding Information
We dedicate this manuscript to the memory of Dr. Charles O. Rock, who made significant contributions to the field of bacterial lipid biology and to the work described here. Additionally, we thank FRESH study participants and staff, the UKZN HIV Pathogenesis Programme laboratory staff, E. Glassey and A.G. Schmidt (Ragon Institute) for assistance with protein expression and pu- rification, R.T. Walton and J. Chen (MIT) for genetics guidance, K. Miller (St. Jude’s Children’s Research Hospital) for technical assistance on enzyme char- acterization, C.N. Tzouanas and S. Goldman (MIT) for scientific discussion and manuscript review, R. Majovski (Broad Institute) for manuscript review, and the Vaginal Microbiome Research Consortium for valuable feedback and discus- sion. M.Z. and M.W.T. were supported by the National Science Foundation Graduate Research Fellowship under grant no. 1745302; S.M.B. by the NIH grant no. 1K08AI171166; C.D.R. by the NIH grant no. 4R00AI166116; F.A.H. by the Schmidt Science Fellowship; P.C.B., M.Z., and M.W.T. by the NIH NIAID grant no. 5U19AI42780; C.O.R. in part by the American Lebanese Syrian Asso- ciated Charities (ALSAC) and St. Jude Children’s Research Hospital; and D.S.K., S.M.B., and M.Z. by grants from the Bill & Melinda Gates Foundation. EC1000 and pORI28 were gifts from Todd Klaenhammer and Jan Kok (respec- tively, Addgene plasmid #71852 and Addgene plasmid #71595; http://n2t.net/ addgene:71595; RRID:Addgene_71595). pTRK892 and pTRK669 were gifts from Rodolphe Barrangou and Todd Klaenhammer (respectively, Addgene plasmid #71803; http://n2t.net/addgene:71803; RRID:Addgene_71803 and Addgene plasmid #71313; http://n2t.net/addgene:71313; and RRID:Addg- ene_71313). Bulk RNA sequencing samples were processed and data were generated by the Infectious Disease and Microbiome Program’s Microbial Omics Core at the Broad Institute of MIT and Harvard. Electron microscopy im- aging, consultation, and services were performed in the HMS Electron Micro- scopy Facility. DNA sequencing of plasmids constructed for the comple- mented S. aureus strains was performed by St. Jude Children’s Research Hospital’s Hartwell Center for Biotechnology.
Repository Citation
Blainey, Paul C.; Bloom, Seth M.; and Kwon, Douglas S., "Vaginal Lactobacillus fatty acid response mechanisms reveal a metabolite-targeted strategy for bacterial vaginosis treatment" (2024). Markey Cancer Center Faculty Publications. 265.
https://uknowledge.uky.edu/markey_facpub/265
Notes/Citation Information
© 2024 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).