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      Deciphering the complex interplay between microbiota, HPV, inflammation and cancer through cervicovaginal metabolic profiling

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          Abstract

          Background

          Dysbiotic vaginal microbiota have been implicated as contributors to persistent HPV-mediated cervical carcinogenesis and genital inflammation with mechanisms unknown. Given that cancer is a metabolic disease, metabolic profiling of the cervicovaginal microenvironment has the potential to reveal the functional interplay between the host and microbes in HPV persistence and progression to cancer.

          Methods

          Our study design included HPV-negative/positive controls, women with low-grade and high-grade cervical dysplasia, or cervical cancer ( n = 78). Metabolic fingerprints were profiled using liquid chromatography-mass spectrometry. Vaginal microbiota and genital inflammation were analysed using 16S rRNA gene sequencing and immunoassays, respectively. We used an integrative bioinformatic pipeline to reveal host and microbe contributions to the metabolome and to comprehensively assess the link between HPV, microbiota, inflammation and cervical disease.

          Findings

          Metabolic analysis yielded 475 metabolites with known identities. Unique metabolic fingerprints discriminated patient groups from healthy controls. Three-hydroxybutyrate, eicosenoate, and oleate/vaccenate discriminated (with excellent capacity) between cancer patients versus the healthy participants. Sphingolipids, plasmalogens, and linoleate positively correlated with genital inflammation. Non- Lactobacillus dominant communities, particularly in high-grade dysplasia, perturbed amino acid and nucleotide metabolisms. Adenosine and cytosine correlated positively with Lactobacillus abundance and negatively with genital inflammation. Glycochenodeoxycholate and carnitine metabolisms connected non- Lactobacillus dominance to genital inflammation.

          Interpretation

          Cervicovaginal metabolic profiles were driven by cancer followed by genital inflammation, HPV infection, and vaginal microbiota. This study provides evidence for metabolite-driven complex host-microbe interactions as hallmarks of cervical cancer with future translational potential.

          Fund

          Flinn Foundation (#1974), Banner Foundation Obstetrics/Gynecology, and NIH NCI (P30-CA023074).

          Graphical abstract

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          Most cited references55

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          The meaning and use of the area under a receiver operating characteristic (ROC) curve.

          J A Hanley, B J McNeil, Marnix van Holsbeeck (1982)
          A representation and interpretation of the area under a receiver operating characteristic (ROC) curve obtained by the "rating" method, or by mathematical predictions based on patient characteristics, is presented. It is shown that in such a setting the area represents the probability that a randomly chosen diseased subject is (correctly) rated or ranked with greater suspicion than a randomly chosen non-diseased subject. Moreover, this probability of a correct ranking is the same quantity that is estimated by the already well-studied nonparametric Wilcoxon statistic. These two relationships are exploited to (a) provide rapid closed-form expressions for the approximate magnitude of the sampling variability, i.e., standard error that one uses to accompany the area under a smoothed ROC curve, (b) guide in determining the size of the sample required to provide a sufficiently reliable estimate of this area, and (c) determine how large sample sizes should be to ensure that one can statistically detect differences in the accuracy of diagnostic techniques.
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            Cervical intraepithelial neoplasia disease progression is associated with increased vaginal microbiome diversity

            A. N. Mitra, D. MacIntyre, Y Lee … (2015)
            Persistent infection with oncogenic Human Papillomavirus (HPV) is necessary for cervical carcinogenesis. Although evidence suggests that the vaginal microbiome plays a functional role in the persistence or regression of HPV infections, this has yet to be described in women with cervical intra-epithelial neoplasia (CIN). We hypothesised that increasing microbiome diversity is associated with increasing CIN severity. llumina MiSeq sequencing of 16S rRNA gene amplicons was used to characterise the vaginal microbiota of women with low-grade squamous intra-epithelial lesions (LSIL; n = 52), high-grade (HSIL; n = 92), invasive cervical cancer (ICC; n = 5) and healthy controls (n = 20). Hierarchical clustering analysis revealed an increased prevalence of microbiomes characterised by high-diversity and low levels of Lactobacillus spp. (community state type-CST IV) with increasing disease severity, irrespective of HPV status (Normal = 2/20,10%; LSIL = 11/52,21%; HSIL = 25/92,27%; ICC = 2/5,40%). Increasing disease severity was associated with decreasing relative abundance of Lactobacillus spp. The vaginal microbiome in HSIL was characterised by higher levels of Sneathia sanguinegens (P < 0.01), Anaerococcus tetradius (P < 0.05) and Peptostreptococcus anaerobius (P < 0.05) and lower levels of Lactobacillus jensenii (P < 0.01) compared to LSIL. Our results suggest advancing CIN disease severity is associated with increasing vaginal microbiota diversity and may be involved in regulating viral persistence and disease progression.
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              Vaginal pH and Microbicidal Lactic Acid When Lactobacilli Dominate the Microbiota

              Deirdre E. O’Hanlon, Thomas R Moench, Richard Cone (2013)
              Lactic acid at sufficiently acidic pH is a potent microbicide, and lactic acid produced by vaginal lactobacilli may help protect against reproductive tract infections. However, previous observations likely underestimated healthy vaginal acidity and total lactate concentration since they failed to exclude women without a lactobacillus-dominated vaginal microbiota, and also did not account for the high carbon dioxide, low oxygen environment of the vagina. Fifty-six women with low (0-3) Nugent scores (indicating a lactobacillus-dominated vaginal microbiota) and no symptoms of reproductive tract disease or infection, provided a total of 64 cervicovaginal fluid samples using a collection method that avoided the need for sample dilution and rigorously minimized aerobic exposure. The pH of samples was measured by microelectrode immediately after collection and under a physiological vaginal concentration of CO2. Commercial enzymatic assays of total lactate and total acetate concentrations were validated for use in CVF, and compared to the more usual HPLC method. The average pH of the CVF samples was 3.5 ± 0.3 (mean ± SD), range 2.8-4.2, and the average total lactate was 1.0% ± 0.2% w/v; this is a five-fold higher average hydrogen ion concentration (lower pH) and a fivefold higher total lactate concentration than in the prior literature. The microbicidal form of lactic acid (protonated lactic acid) was therefore eleven-fold more concentrated, and a markedly more potent microbicide, than indicated by prior research. This suggests that when lactobacilli dominate the vaginal microbiota, women have significantly more lactic acid-mediated protection against infections than currently believed. Our results invite further evaluations of the prophylactic and therapeutic actions of vaginal lactic acid, whether provided in situ by endogenous lactobacilli, by probiotic lactobacilli, or by products that reinforce vaginal lactic acid.
              Article 0 comments Cited 186 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Melissa M. Herbst-Kralovetz
                Journal
                Journal ID (nlm-ta): EBioMedicine
                Journal ID (iso-abbrev): EBioMedicine
                Title: EBioMedicine
                Publisher: Elsevier
                ISSN (Electronic): 2352-3964
                Publication date PMC-release: 24 April 2019
                Publication date Collection: June 2019
                Publication date (Electronic): 24 April 2019
                Volume: 44
                Pages: 675-690
                Affiliations
                [a ]Department of Obstetrics and Gynecology, College of Medicine-Phoenix, University of Arizona, Phoenix, AZ 85004, USA
                [b ]Department of Basic Medical Sciences, College of Medicine-Phoenix, University of Arizona, Phoenix, AZ, 85004, USA
                [c ]UA Cancer Center, University of Arizona, Tucson/Phoenix, AZ 85004, USA
                [d ]US Oncology, Phoenix, AZ 85016, USA
                [e ]Maricopa Integrated Health Systems, Phoenix, AZ 85008, USA
                [f ]Dignity Health St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA
                Author notes
                [* ]Corresponding author at: Department of Basic Medical Sciences, College of Medicine-Phoenix, University of Arizona, Phoenix, AZ 85004, USA. mherbst1@ 123456email.arizona.edu
                Article
                Publisher ID: S2352-3964(19)30267-1
                DOI: 10.1016/j.ebiom.2019.04.028
                PMC ID: 6604110
                PubMed ID: 31027917
                SO-VID: b54a2e57-550c-4e2b-85eb-82cf974ee055
                Copyright © © 2019 The Authors
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 26 February 2019
                Date revision received : 12 April 2019
                Date accepted : 12 April 2019
                Categories
                Subject: Research paper

                Keywords: lactobacillus abundance,lipids and nucleotides,amino acid degradation,cervical dysplasia and cancer,vaginal dysbiosis,host-microbe interactions,genital inflammation
                Data availability:
                Keywords: lactobacillus abundance, lipids and nucleotides, amino acid degradation, cervical dysplasia and cancer, vaginal dysbiosis, host-microbe interactions, genital inflammation

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