Vaginal Lactobacillus fatty acid response mechanisms reveal a metabolite-targeted strategy for bacterial vaginosis treatment

Meilin Zhu; Matthew W Frank; Christopher D Radka; Sarah Jeanfavre; Jiawu Xu; Megan W Tse; Julian Avila Pacheco; Jae Sun Kim; Kerry Pierce; Amy Deik; Fatima Aysha Hussain; Joseph Elsherbini; Salina Hussain; Nondumiso Xulu; Nasreen Khan; Vanessa Pillay; Caroline M Mitchell; Krista L Dong; Thumbi Ndung'u; Clary B Clish; Charles O Rock; Paul C Blainey; Seth M Bloom; Douglas S Kwon

doi:10.1016/j.cell.2024.07.029

Vaginal Lactobacillus fatty acid response mechanisms reveal a metabolite-targeted strategy for bacterial vaginosis treatment

Cell. 2024 Sep 19;187(19):5413-5430.e29. doi: 10.1016/j.cell.2024.07.029. Epub 2024 Aug 19.

Authors

Meilin Zhu¹, Matthew W Frank², Christopher D Radka³, Sarah Jeanfavre⁴, Jiawu Xu⁵, Megan W Tse⁶, Julian Avila Pacheco⁴, Jae Sun Kim⁵, Kerry Pierce⁴, Amy Deik⁴, Fatima Aysha Hussain⁷, Joseph Elsherbini⁵, Salina Hussain⁵, Nondumiso Xulu⁸, Nasreen Khan⁸, Vanessa Pillay⁹, Caroline M Mitchell¹⁰, Krista L Dong¹¹, Thumbi Ndung'u¹², Clary B Clish⁴, Charles O Rock², Paul C Blainey¹³, Seth M Bloom¹⁴, Douglas S Kwon¹⁵

Affiliations

¹ Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA.
² Department of Host-Microbe Interactions, St. Jude Children's Research Hospital, Memphis, TN, USA.
³ Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, KY, USA.
⁴ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁵ Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA.
⁶ Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁷ Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA.
⁸ HIV Pathogenesis Programme, The Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa.
⁹ Health Systems Trust, Durban, South Africa.
¹⁰ Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA; Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, USA.
¹¹ Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA; Health Systems Trust, Durban, South Africa; Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA, USA.
¹² Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; HIV Pathogenesis Programme, The Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa; Africa Health Research Institute, Durban, South Africa; Max Planck Institute for Infection Biology, Berlin, Germany; Division of Infection and Immunity, University College London, London, UK.
¹³ Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology, Cambridge, MA, USA. Electronic address: [email protected].
¹⁴ Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA; Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA, USA. Electronic address: [email protected].
¹⁵ Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA; Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA, USA. Electronic address: [email protected].

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 mediates 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 promotes L. crispatus dominance more effectively than antibiotics in an in vitro BV model, suggesting a metabolite-based treatment approach.

Keywords: Lactobacillus; bacterial vaginosis; female genital tract; metabolism; vaginal microbiome; women’s health.

MeSH terms

Anti-Bacterial Agents / pharmacology
Anti-Bacterial Agents / therapeutic use
Bacterial Proteins / metabolism
Fatty Acids* / metabolism
Female
Humans
Lactobacillus crispatus / metabolism
Lactobacillus* / metabolism
Microbiota / drug effects
Oleic Acid / metabolism
Vagina* / microbiology
Vaginosis, Bacterial* / drug therapy
Vaginosis, Bacterial* / microbiology

Substances

Fatty Acids
Oleic Acid
Anti-Bacterial Agents
Bacterial Proteins

Abstract

MeSH terms

Substances

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