Copper intrauterine device increases vaginal concentrations of inflammatory anaerobes and depletes lactobacilli compared to hormonal options in a randomized trial.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
30 01 2023
30 01 2023
Historique:
received:
10
03
2022
accepted:
12
01
2023
entrez:
30
1
2023
pubmed:
31
1
2023
medline:
2
2
2023
Statut:
epublish
Résumé
Effective contraceptives are a global health imperative for reproductive-aged women. However, there remains a lack of rigorous data regarding the effects of contraceptive options on vaginal bacteria and inflammation. Among 218 women enrolled into a substudy of the ECHO Trial (NCT02550067), we evaluate the effect of injectable intramuscular depot medroxyprogesterone acetate (DMPA-IM), levonorgestrel implant (LNG), and a copper intrauterine device (Cu-IUD) on the vaginal environment after one and six consecutive months of use, using 16S rRNA gene sequencing and multiplex cytokine assays. Primary endpoints include incident BV occurrence, bacterial diversity, and bacterial and cytokine concentrations. Secondary endpoints are bacterial and cytokine concentrations associated with later HIV seroconversion. Participants randomized to Cu-IUD exhibit elevated bacterial diversity, increased cytokine concentrations, and decreased relative abundance of lactobacilli after one and six months of use, relative to enrollment and other contraceptive options. Total bacterial loads of women using Cu-IUD increase 5.5 fold after six months, predominantly driven by increases in the concentrations of several inflammatory anaerobes. Furthermore, growth of L. crispatus (MV-1A-US) is inhibited by Cu
Identifiants
pubmed: 36717556
doi: 10.1038/s41467-023-36002-4
pii: 10.1038/s41467-023-36002-4
pmc: PMC9886933
doi:
Substances chimiques
Medroxyprogesterone Acetate
C2QI4IOI2G
RNA, Ribosomal, 16S
0
Contraceptive Agents
0
Types de publication
Randomized Controlled Trial
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
499Subventions
Organisme : NIAID NIH HHS
ID : L40 AI147257
Pays : United States
Organisme : NICHD NIH HHS
ID : K99 HD106861
Pays : United States
Organisme : NICHD NIH HHS
ID : F32 HD102290
Pays : United States
Organisme : NICHD NIH HHS
ID : R01 HD089831
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2023. The Author(s).
Références
Sedgh, G. et al. Abortion incidence between 1990 and 2014: global, regional, and subregional levels and trends. Lancet 388, 258–267 (2016).
doi: 10.1016/S0140-6736(16)30380-4
Shah, I. H. & Ahman, E. Unsafe abortion differentials in 2008 by age and developing country region: high burden among young women. Reprod. Health Matters 20, 169–173 (2012).
doi: 10.1016/S0968-8080(12)39598-0
Balle, C. et al. Hormonal contraception alters vaginal microbiota and cytokines in South African adolescents in a randomized trial. Nat. Commun. 11, 5578 (2020).
doi: 10.1038/s41467-020-19382-9
Achilles, S. L. et al. Impact of contraceptive initiation on vaginal microbiota. Am. J. Obstet. Gynecol. 218, 622 e621–622 e610 (2018).
doi: 10.1016/j.ajog.2018.02.017
Crucitti, T. et al. Contraceptive rings promote vaginal lactobacilli in a high bacterial vaginosis prevalence population: a randomised, open-label longitudinal study in Rwandan women. PLoS ONE 13, e0201003 (2018).
doi: 10.1371/journal.pone.0201003
Miller, L. et al. Depomedroxyprogesterone-induced hypoestrogenism and changes in vaginal flora and epithelium. Obstet. Gynecol. 96, 431–439 (2000).
Brooks, J. P. et al. Changes in vaginal community state types reflect major shifts in the microbiome. Micro. Ecol. Health Dis. 28, 1303265 (2017).
Anahtar, M. N. et al. Cervicovaginal bacteria are a major modulator of host inflammatory responses in the female genital tract. Immunity 42, 965–976 (2015).
doi: 10.1016/j.immuni.2015.04.019
Borgdorff, H. et al. Lactobacillus-dominated cervicovaginal microbiota associated with reduced HIV/STI prevalence and genital HIV viral load in African women. ISME J. 8, 1781–1793 (2014).
doi: 10.1038/ismej.2014.26
Haddad, L. B. et al. Impact of etonogestrel implant use on T-cell and cytokine profiles in the female genital tract and blood. PLoS ONE 15, e0230473 (2020).
doi: 10.1371/journal.pone.0230473
Konstantinus, I. N. et al. Impact of hormonal contraceptives on cervical Th17 phenotype and function in adolescents: results from a randomized cross-over study comparing long-acting injectable norethisterone oenanthate (NET-EN), combined oral contraceptive pills, and combined contraceptive vaginal rings. Clin. Infect. Dis. https://doi.org/10.1093/cid/ciz1063 (2019).
doi: 10.1093/cid/ciz1063
Fettweis, J. M. et al. The vaginal microbiome and preterm birth. Nat. Med. 25, 1012–1021 (2019).
doi: 10.1038/s41591-019-0450-2
Fredricks, D. N., Fiedler, T. L. & Marrazzo, J. M. Molecular identification of bacteria associated with bacterial vaginosis. N. Engl. J. Med. 353, 1899–1911 (2005).
doi: 10.1056/NEJMoa043802
Myer, L. et al. Bacterial vaginosis and susceptibility to HIV infection in South African women: a nested case-control study. J. Infect. Dis. 192, 1372–1380 (2005).
doi: 10.1086/462427
Gosmann, C. et al. Lactobacillus-deficient cervicovaginal bacterial communities are associated with increased HIV acquisition in young South African women. Immunity 46, 29–37 (2017).
doi: 10.1016/j.immuni.2016.12.013
Spurbeck, R. R. & Arvidson, C. G. Lactobacilli at the front line of defense against vaginally acquired infections. Future Microbiol. 6, 567–582 (2011).
doi: 10.2217/fmb.11.36
Takada, K. et al. Lactobacillus crispatus accelerates re-epithelialization in vaginal epithelial cell line MS74. Am. J. Reprod. Immunol. 80, e13027 (2018).
doi: 10.1111/aji.13027
Rose, W. A. 2nd et al. Commensal bacteria modulate innate immune responses of vaginal epithelial cell multilayer cultures. PLoS ONE 7, e32728 (2012).
doi: 10.1371/journal.pone.0032728
Doerflinger, S. Y., Throop, A. L. & Herbst-Kralovetz, M. M. Bacteria in the vaginal microbiome alter the innate immune response and barrier properties of the human vaginal epithelia in a species-specific manner. J. Infect. Dis. 209, 1989–1999 (2014).
doi: 10.1093/infdis/jiu004
Petrova, M. I., Reid, G., Vaneechoutte, M. & Lebeer, S. Lactobacillus iners: friend or foe? Trends Microbiol. 25, 182–191 (2017).
doi: 10.1016/j.tim.2016.11.007
Ahmed, K. et al. HIV incidence among women using intramuscular depot medroxyprogesterone acetate, a copper intrauterine device, or a levonorgestrel implant for contraception: a randomised, multicentre, open-label trial. Lancet 394, 303–313 (2019).
doi: 10.1016/S0140-6736(19)31288-7
Organization, W. H. In Guidance Statement: Recommendations on Contraceptive Methods Used by Women at High Risk of HIV (WHO, 2019).
Van de Wijgert, J. H., Verwijs, M. C., Turner, A. N. & Morrison, C. S. Hormonal contraception decreases bacterial vaginosis but oral contraception may increase candidiasis: implications for HIV transmission. AIDS 27, 2141–2153 (2013).
doi: 10.1097/QAD.0b013e32836290b6
Pettifor, A. et al. Use of injectable progestin contraception and risk of STI among South African women. Contraception 80, 555–560 (2009).
doi: 10.1016/j.contraception.2009.06.007
Curry, A., Williams, T. & Penny, M. L. Pelvic inflammatory disease: diagnosis, management, and prevention. Am. Fam. Physician 100, 357–364 (2019).
Morrison, C. S., Turner, A. N. & Jones, L. B. Highly effective contraception and acquisition of HIV and other sexually transmitted infections. Best. Pr. Res. Clin. Obstet. Gynaecol. 23, 263–284 (2009).
doi: 10.1016/j.bpobgyn.2008.11.004
Kapiga, S. H., Lyamuya, E. F., Lwihula, G. K. & Hunter, D. J. The incidence of HIV infection among women using family planning methods in Dar es Salaam, Tanzania. AIDS 12, 75–84 (1998).
doi: 10.1097/00002030-199801000-00009
Mati, J. K., Hunter, D. J., Maggwa, B. N. & Tukei, P. M. Contraceptive use and the risk of HIV infection in Nairobi, Kenya. Int. J. Gynaecol. Obstet. 48, 61–67 (1995).
doi: 10.1016/0020-7292(94)02214-3
Lazzarin, A., Saracco, A., Musicco, M. & Nicolosi, A. Man-to-woman sexual transmission of the human immunodeficiency virus. Risk factors related to sexual behavior, man’s infectiousness, and woman’s susceptibility. Italian Study Group on HIV Heterosexual Transmission. Arch. Intern. Med. 151, 2411–2416 (1991).
doi: 10.1001/archinte.1991.00400120055009
Morrison, C. S. et al. Hormonal contraceptive use, cervical ectopy, and the acquisition of cervical infections. Sex. Transm. Dis. 31, 561–567 (2004).
doi: 10.1097/01.olq.0000137904.56037.70
Cottingham, J. & Hunter, D. Chlamydia trachomatis and oral contraceptive use: a quantitative review. Genitourin. Med. 68, 209–216 (1992).
Masson, L. et al. Genital inflammation and the risk of HIV acquisition in women. Clin. Infect. Dis. 61, 260–269 (2015).
doi: 10.1093/cid/civ298
Peebles, K. et al. Elevated risk of bacterial vaginosis among users of the copper intrauterine device: a prospective longitudinal cohort study. Clin. Infect. Dis. 73, 513–520 (2021).
Wiesenfeld, H. C., Hillier, S. L., Krohn, M. A., Landers, D. V. & Sweet, R. L. Bacterial vaginosis is a strong predictor of Neisseria gonorrhoeae and Chlamydia trachomatis infection. Clin. Infect. Dis. 36, 663–668 (2003).
doi: 10.1086/367658
Afolabi, B. B., Moses, O. E. & Oduyebo, O. O. Bacterial vaginosis and pregnancy outcome in Lagos, Nigeria. Open Forum Infect. Dis. 3, ofw030 (2016).
doi: 10.1093/ofid/ofw030
Dingens, A. S., Fairfortune, T. S., Reed, S. & Mitchell, C. Bacterial vaginosis and adverse outcomes among full-term infants: a cohort study. BMC Pregnancy Childbirth 16, 278 (2016).
doi: 10.1186/s12884-016-1073-y
Gupta, A., Singh, S., Chaudhary, R. & Nigam, S. Bacterial vaginosis in pregnancy (<28 weeks) and its effect on pregnancy outcome: a study from a western UP city. Indian J. Obstet. Gynecol. Res. 3, 90–94 (2016).
doi: 10.5958/2394-2754.2016.00021.7
Hay, P. E. et al. Abnormal bacterial colonisation of the genital tract and subsequent preterm delivery and late miscarriage. BMJ 308, 295–298 (1994).
doi: 10.1136/bmj.308.6924.295
Thorsen, P. et al. Bacterial vaginosis in early pregnancy is associated with low birth weight and small for gestational age, but not with spontaneous preterm birth: a population-based study on Danish women. J. Matern.-Fetal Neonatal Med. 19, 1–7 (2006).
doi: 10.1080/14767050500361604
Sazal, M., Stebliankin, V., Mathee, K., Yoo, C. & Narasimhan, G. Causal effects in microbiomes using interventional calculus. Sci. Rep. 11, 1–15 (2021).
doi: 10.1038/s41598-021-84905-3
Benjamini, Y. & Hochberg, Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. R. Stat. Soc.: Ser. B (Methodol.) 57, 289–300 (1995).
Benjamini, Y. & Yekutieli, D. The control of the false discovery rate in multiple testing under dependency. Ann. Stat. 29, 1165–1188 (2001).
doi: 10.1214/aos/1013699998
Arancibia, V., Pena, C., Allen, H. E. & Lagos, G. Characterization of copper in uterine fluids of patients who use the copper T-380A intrauterine device. Clin. Chim. Acta 332, 69–78 (2003).
doi: 10.1016/S0009-8981(03)00124-4
Dabee, S. et al. Defining characteristics of genital health in South African adolescent girls and young women at high risk for HIV infection. PLoS ONE 14, e0213975 (2019).
doi: 10.1371/journal.pone.0213975
McClelland, R. S. et al. Key vaginal bacteria associated with increased risk of HIV acquisition in African women: a nested case-control study. Lancet Infect. Dis. 18, 554–564 (2018).
doi: 10.1016/S1473-3099(18)30058-6
Wilks, S. A., Michels, H. T. & Keevil, C. W. Survival of Listeria monocytogenes Scott A on metal surfaces: implications for cross-contamination. Int. J. Food Microbiol. 111, 93–98 (2006).
doi: 10.1016/j.ijfoodmicro.2006.04.037
Robine, E., Boulange-Petermann, L. & Derangere, D. Assessing bactericidal properties of materials: the case of metallic surfaces in contact with air. J. Microbiol. Methods 49, 225–234 (2002).
doi: 10.1016/S0167-7012(01)00371-2
Wilks, S. A., Michels, H. & Keevil, C. W. The survival of Escherichia coli O157 on a range of metal surfaces. Int. J. Food Microbiol. 105, 445–454 (2005).
doi: 10.1016/j.ijfoodmicro.2005.04.021
Fowler, L., Engqvist, H. & Öhman-Mägi, C. Effect of copper ion concentration on bacteria and cells. Materials 12, 3798 (2019).
doi: 10.3390/ma12223798
Zevenhuizen, L. P., Dolfing, J., Eshuis, E. J. & Scholten-Koerselman, I. J. Inhibitory effects of copper on bacteria related to the free ion concentration. Microb. Ecol. 5, 139–146 (1979).
doi: 10.1007/BF02010505
Espirito Santo, C., Taudte, N., Nies, D. H. & Grass, G. Contribution of copper ion resistance to survival of Escherichia coli on metallic copper surfaces. Appl Environ. Microbiol. 74, 977–986 (2008).
doi: 10.1128/AEM.01938-07
Koch, K. A., Peña, M. M. O. & Thiele, D. J. Copper-binding motifs in catalysis, transport, detoxification and signaling. Chem. Biol. 4, 549–560 (1997).
doi: 10.1016/S1074-5521(97)90241-6
Martín, R. & Suárez, J. E. Biosynthesis and degradation of H
doi: 10.1128/AEM.01631-09
Achilles, S. L. et al. Zim CHIC: a cohort study of immune changes in the female genital tract associated with initiation and use of contraceptives. Am. J. Reprod. Immunol. 84, e13287 (2020).
doi: 10.1111/aji.13287
Bilardi, J. E. et al. The burden of bacterial vaginosis: women’s experience of the physical, emotional, sexual and social impact of living with recurrent bacterial vaginosis. PLoS ONE 8, e74378 (2013).
doi: 10.1371/journal.pone.0074378
Bunjun, R. et al. Initiating intramuscular depot medroxyprogesterone acetate (DMPA-IM) increases frequencies of Th17-like human immunodeficiency virus (HIV) target cells in the genital tract of women in South Africa: a randomized trial. Clin. Infect. Dis. 75, 2000–2011 (2022).
doi: 10.1093/cid/ciac284
Jaumdally, S. Z. et al. Lower genital tract cytokine profiles in South African women living with HIV: influence of mucosal sampling. Sci. Rep. 8, 12203 (2018).
doi: 10.1038/s41598-018-30663-8
Nugent, R. P., Krohn, M. A. & Hillier, S. L. Reliability of diagnosing bacterial vaginosis is improved by a standardized method of gram stain interpretation. J. Clin. Microbiol. 29, 297–301 (1991).
doi: 10.1128/jcm.29.2.297-301.1991
Durfee, T. et al. The complete genome sequence of Escherichia coli DH10B: insights into the biology of a laboratory workhorse. J. Bacteriol. 190, 2597–2606 (2008).
doi: 10.1128/JB.01695-07
Gohl, D. M. et al. Systematic improvement of amplicon marker gene methods for increased accuracy in microbiome studies. Nat. Biotechnol. 34, 942–949 (2016).
doi: 10.1038/nbt.3601
Fadrosh, D. W. et al. An improved dual-indexing approach for multiplexed 16S rRNA gene sequencing on the Illumina MiSeq platform. Microbiome 2, 6 (2014).
doi: 10.1186/2049-2618-2-6
Martin, M. Cutadapt removes adapter sequences from high-throughput sequencing reads. EMBnet. J. 17, 10–12 (2011).
doi: 10.14806/ej.17.1.200
Callahan, B. J. et al. DADA2: High-resolution sample inference from Illumina amplicon data. Nat. Methods 13, 581–583 (2016).
doi: 10.1038/nmeth.3869
Wang, Q., Garrity, G. M., Tiedje, J. M. & Cole, J. R. Naive Bayesian classifier for rapid assignment of rRNA sequences into the new bacterial taxonomy. Appl. Environ. Microbiol. 73, 5261–5267 (2007).
doi: 10.1128/AEM.00062-07
Quast, C. et al. The SILVA ribosomal RNA gene database project: improved data processing and web-based tools. Nucleic Acids Res. 41, D590–D596 (2013).
doi: 10.1093/nar/gks1219
McMurdie, P. J. & Holmes, S. phyloseq: an R package for reproducible interactive analysis and graphics of microbiome census data. PLoS ONE 8, e61217 (2013).
doi: 10.1371/journal.pone.0061217
Oksanen, J. et al. The vegan package. Community Ecol. Package 10, 631–637 (2007).
Maechler, M. “Finding groups in data”: cluster analysis extended Rousseeuw et al. R Package version 2.0. 6 (2019).
Tibshirani, R., Walther, G. & Hastie, T. Estimating the number of clusters in a data set via the gap statistic. J. R. Stat. Soc.: Ser. B (Stat. Methodol.) 63, 411–423 (2001).
doi: 10.1111/1467-9868.00293
Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).
doi: 10.1186/s13059-014-0550-8
Lin, H. & Peddada, S. D. Analysis of compositions of microbiomes with bias correction. Nat. Commun. 11, 3514 (2020).
doi: 10.1038/s41467-020-17041-7
Stephens, M. False discovery rates: a new deal. Biostatistics 18, 275–294 (2017).
Aitchison, J. The statistical analysis of compositional data. J. R. Stat. Soc.: Ser. B (Methodol.) 44, 139–160 (1982).
Spirtes, P. et al. Constructing Bayesian Network Models of Gene Expression Networks from Microarray Data (2000).
Wilson, C. B. & Weaver, W. M. Comparative susceptibility of group B streptococci and Staphylococcus aureus to killing by oxygen metabolites. J. Infect. Dis. 152, 323–329 (1985).
doi: 10.1093/infdis/152.2.323
Liu, C. M. et al. BactQuant: an enhanced broad-coverage bacterial quantitative real-time PCR assay. BMC Microbiol. 12, 56 (2012).
doi: 10.1186/1471-2180-12-56