Objective Characterise the vaginal metabolome of cervical HPVinfected and uninfected women.Design Cross-sectional.Sample Thirty-nine participants, 13 categorised as HPV-negative and 26 as HPV-positive (any genotype; HPV + ), 14 of whom were positive with at least one high-risk HPV strain (hrHPV).Method Self-collected mid-vaginal swabs were profiled for bacterial composition by 16S rRNA gene amplicon sequencing, metabolites by both gas and liquid chromatography mass spectrometry, and 37 types of HPV DNA. Main outcome measures Metabolite abundances.Results Vaginal microbiota clustered into Community State Type (CST) I (Lactobacillus crispatus-dominated), CST III (Lactobacillus iners-dominated), and CST IV (low-Lactobacillus, 'molecular-BV'). HPV + women had higher biogenic amine and phospholipid concentrations compared with HPVwomen after adjustment for CST and cigarette smoking. Metabolomic profiles of HPV + and HPV À women differed in strata of CST. In CST III, there were higher concentrations of biogenic amines and glycogen-related metabolites in HPV + women than in HPVwomen. In CST IV, there were lower concentrations of glutathione, glycogen, and phospholipid-related metabolites in HPV + participants than in HPVparticipants. Across all CSTs, women with hrHPV strains had lower concentrations of amino acids, lipids, and peptides compared with women who had only low-risk HPV (lrHPV). ConclusionsThe vaginal metabolome of HPV + women differed from HPV À women in terms of several metabolites, including biogenic amines, glutathione, and lipid-related metabolites. If the temporal relation between increased levels of reduced glutathione and oxidised glutathione and HPV incidence/persistence is confirmed in future studies, anti-oxidant therapies may be considered as a non-surgical HPV control intervention. Keywords 16S rRNA gene amplicon sequencing, human papillomavirus, vaginal metabolome, vaginal microbiota. Tweetable abstract Metabolomics study: Vaginal microenvironment of HPV + women may be informative for nonsurgical interventions. Please cite this paper as: Borgogna JC, Shardell MD, Santori EK, Nelson TM, Rath JM, Glover ED, Ravel J, Gravitt PE, Yeoman CJ, Brotman RM. The vaginal metabolome and microbiota of cervical HPV-positive and HPV-negative women: a cross-sectional analysis.

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