Abstract

Objective

Evidence supports an inverse association between vitamin D and bacterial vaginosis (BV) during pregnancy. Furthermore, both the vaginal microbiome and vitamin D status correlate with pregnancy outcome. Women of African ancestry are more likely to experience BV, to be vitamin D deficient, and to have certain pregnancy complications. We investigated the association between vitamin D status and the vaginal microbiome.

Study design

Subjects were assigned to a treatment (4400 IU) or a control group (400 IU vitamin D daily), sampled three times during pregnancy, and vaginal 16S rRNA gene taxonomic profiles and plasma 25-hydroxyvitamin D [25(OH)D] concentrations were examined.

Result

Gestational age and ethnicity were significantly associated with the microbiome. Megasphaera correlated negatively (p = 0.0187) with 25(OH)D among women of African ancestry. Among controls, women of European ancestry exhibited a positive correlation between plasma 25(OH)D and L. crispatus abundance.

Conclusion

Certain vaginal bacteria are associated with plasma 25(OH)D concentration.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

  1. 1.

    Tabatabaei N, Eren AM, Barreiro LB, Yotova V, Dumaine A, Allard C et al. Vaginal microbiome in early pregnancy and subsequent risk of spontaneous preterm birth: a case-control study. BJOG. 2018. https://doi.org/10.1111/1471-0528.15299.

  2. 2.

    Callahan BJ, DiGiulio DB, Goltsman DSA, Sun CL, Costello EK, Jeganathan P, et al. Replication and refinement of a vaginal microbial signature of preterm birth in two racially distinct cohorts of US women. Proc Natl Acad Sci USA. 2017;114:9966–71.

  3. 3.

    Amegah AK, Klevor MK, Wagner CL. Maternal vitamin D insufficiency and risk of adverse pregnancy and birth outcomes: a systematic review and meta-analysis of longitudinal studies. PLoS ONE. 2017;12:e0173605.

  4. 4.

    Tabatabaei N, Auger N, Herba CM, Wei S, Allard C, Fink GD, et al. Maternal vitamin D insufficiency early in pregnancy is associated with increased risk of preterm birth in ethnic minority women in Canada. J Nutr. 2017;147:1145–51.

  5. 5.

    Zhao X, Fang R, Yu R, Chen D, Zhao J, Xiao J. Maternal vitamin D status in the late second trimester and the risk of severe preeclampsia in southeastern China. Nutrients. 2017;9. https://doi.org/10.3390/nu9020138.

  6. 6.

    Wen J, Hong Q, Zhu L, Xu P, Fu Z, Cui X, et al. Association of maternal serum 25-hydroxyvitamin D concentrations in second and third trimester with risk of gestational diabetes and other pregnancy outcomes. Int J Obes (Lond). 2017;41:489–96.

  7. 7.

    Toko EN, Sumba OP, Daud II, Ogolla S, Majiwa M, Krisher JT et al. Maternal vitamin D status and adverse birth outcomes in children from rural Western Kenya. Nutrients. 2016;8. https://doi.org/10.3390/nu8120794.

  8. 8.

    Kiely ME, Zhang JY, Kinsella M, Khashan AS, Kenny LC. Vitamin D status is associated with uteroplacental dysfunction indicated by pre-eclampsia and small-for-gestational-age birth in a large prospective pregnancy cohort in Ireland with low vitamin D status. Am J Clin Nutr. 2016;104:354–61.

  9. 9.

    Miliku K, Vinkhuyzen A, Blanken LM, McGrath JJ, Eyles DW, Burne TH, et al. Maternal vitamin D concentrations during pregnancy, fetal growth patterns, and risks of adverse birth outcomes. Am J Clin Nutr. 2016;103:1514–22.

  10. 10.

    Wagner CL, Hollis BW, Kotsa K, Fakhoury H, Karras SN. Vitamin D administration during pregnancy as prevention for pregnancy, neonatal and postnatal complications. Rev Endocr Metab Disord. 2017;18:307–22.

  11. 11.

    Weinert LS, Silveiro SP. Maternal-fetal impact of vitamin D deficiency: a critical review. Matern Child Health J. 2015;19:94–101.

  12. 12.

    Tamblyn JA, Hewison M, Wagner CL, Bulmer JN, Kilby MD. Immunological role of vitamin D at the maternal-fetal interface. J Endocrinol. 2015;224:R107–121.

  13. 13.

    Bodnar LM, Krohn MA, Simhan HN. Maternal vitamin D deficiency is associated with bacterial vaginosis in the first trimester of pregnancy. J Nutr. 2009;139:1157–61.

  14. 14.

    Dunlop AL, Taylor RN, Tangpricha V, Fortunato S, Menon R. Maternal vitamin D, folate, and polyunsaturated fatty acid status and bacterial vaginosis during pregnancy. Infect Dis Obstet Gynecol. 2011;2011:216217.

  15. 15.

    Hensel KJ, Randis TM, Gelber SE, Ratner AJ. Pregnancy-specific association of vitamin D deficiency and bacterial vaginosis. Am J Obstet Gynecol. 2011;204:41.e1–9.

  16. 16.

    Turner AN, Carr Reese P, Fields KS, Anderson J, Ervin M, Davis JA, et al. A blinded, randomized controlled trial of high-dose vitamin D supplementation to reduce recurrence of bacterial vaginosis. Am J Obstet Gynecol. 2014;211:479.e1–479.e13.

  17. 17.

    Taheri M, Baheiraei A, Foroushani AR, Nikmanesh B, Modarres M. Treatment of vitamin D deficiency is an effective method in the elimination of asymptomatic bacterial vaginosis: a placebo-controlled randomized clinical trial. Indian J Med Res. 2015;141:799–806.

  18. 18.

    O’Callaghan KM, Kiely ME. Ethnic disparities in the dietary requirement for vitamin D during pregnancy: considerations for nutrition policy and research. Proc Nutr Soc. 2018;77:164–73.

  19. 19.

    Fettweis JM, Brooks JP, Serrano MG, Sheth NU, Girerd PH, Edwards DJ, et al. Differences in vaginal microbiome in African American women versus women of European ancestry. Microbiol Read Engl. 2014;160:2272–82.

  20. 20.

    Oliver EA, Klebanoff M, Yossef-Salameh L, Oza-Frank R, Moosavinasab S, Reagan P, et al. Preterm birth and gestational length in four race-nativity groups, including Somali Americans. Obstet Gynecol. 2018;131:281–9.

  21. 21.

    Hamilton BE, Martin JA, Osterman MJK, Curtin SC, Matthews TJ. Births: Final Data for 2014. Natl Vital Stat Rep. 2015;64:1–64.

  22. 22.

    Seto TL, Tabangin ME, Langdon G, Mangeot C, Dawodu A, Steinhoff M, et al. Racial disparities in cord blood vitamin D levels and its association with small-for-gestational-age infants. J Perinatol. 2016;36:623–8.

  23. 23.

    Wagner CL, Baggerly C, McDonnell S, Baggerly KA, French CB, Baggerly L, et al. Post-hoc analysis of vitamin D status and reduced risk of preterm birth in two vitamin D pregnancy cohorts compared with South Carolina March of Dimes 2009–11 rates. J Steroid Biochem Mol Biol. 2016;155:245–51.

  24. 24.

    Abercrombie M, Shary J, Ebeling M, Hollis B, Wagner C. Analysis of the NICHD vitamin D pregnancy cohort on a per-protocol vs. intent-to-treat basis: the effect of adherence on trial results. J Nutr Food Sci. 2018;8:696.

  25. 25.

    Nugent RP, Krohn MA, Hillier SL. Reliability of diagnosing bacterial vaginosis is improved by a standardized method of gram stain interpretation. J Clin Microbiol. 1991;29:297–301.

  26. 26.

    Hollis BW, Wagner CL. Vitamin D supplementation during pregnancy: improvements in birth outcomes and complications through direct genomic alteration. Mol Cell Endocrinol. 2017;453:113–30.

  27. 27.

    ACOG Committee on Practice Bulletins--Gynecology. ACOG Practice Bulletin. Clinical management guidelines for obstetrician-gynecologists, Number 72, May 2006: Vaginitis. Obstet Gynecol. 2006;107:1195–206.

  28. 28.

    Fadrosh DW, Ma B, Gajer P, Sengamalay N, Ott S, Brotman RM, et al. An improved dual-indexing approach for multiplexed 16 S rRNA gene sequencing on the Illumina MiSeq platform. Microbiome. 2014;2:6.

  29. 29.

    Kozich JJ, Westcott SL, Baxter NT, Highlander SK, Schloss PD. Development of a dual-index sequencing strategy and curation pipeline for analyzing amplicon sequence data on the MiSeq Illumina sequencing platform. Appl Environ Microbiol. 2013;79:5112–20.

  30. 30.

    Bartram AK, Lynch MDJ, Stearns JC, Moreno-Hagelsieb G, Neufeld JD. Generation of multimillion-sequence 16 S rRNA gene libraries from complex microbial communities by assembling paired-end Illumina reads. Appl Environ Microbiol. 2011;77:3846–52.

  31. 31.

    Parikh HI, Koparde VN, Bradley SP, Buck GA, Sheth NU. MeFiT: merging and filtering tool for illumina paired-end reads for 16 S rRNA amplicon sequencing. BMC Bioinformatics. 2016;17:491.

  32. 32.

    Fettweis JM, Serrano MG, Sheth NU, Mayer CM, Glascock AL, Brooks JP, et al. Species-level classification of the vaginal microbiome. BMC Genomics. 2012;13(Suppl 8):S17.

  33. 33.

    Edgar RC. Search and clustering orders of magnitude faster than BLAST. Bioinformatics. 2010;26:2460–1.

  34. 34.

    Brooks JP, Buck GA, Chen G, Diao L, Edwards DJ, Fettweis JM, et al. Changes in vaginal community state types reflect major shifts in the microbiome. Microb Ecol Health Dis. 2017;28:1303265.

  35. 35.

    Gniadecki R, Gajkowska B, Hansen M. 1,25-dihydroxyvitamin D3 stimulates the assembly of adherens junctions in keratinocytes: involvement of protein kinase C. Endocrinology. 1997;138:2241–8.

  36. 36.

    Lee A, Lee MR, Lee H-H, Kim Y-S, Kim J-M, Enkhbold T, et al. Vitamin D proliferates vaginal epithelium through RhoA expression in postmenopausal atrophic vagina tissue. Mol Cells. 2017;40:677–84.

  37. 37.

    Rad P, Tadayon M, Abbaspour M, Latifi SM, Rashidi I, Delaviz H. The effect of vitamin D on vaginal atrophy in postmenopausal women. Iran J Nurs Midwifery Res. 2015;20:211–5.

  38. 38.

    Yildirim B, Kaleli B, Düzcan E, Topuz O. The effects of postmenopausal Vitamin D treatment on vaginal atrophy. Maturitas. 2004;49:334–7.

  39. 39.

    Forde JE, Dale TC. Glycogen synthase kinase 3: a key regulator of cellular fate. Cell Mol Life Sci. 2007;64:1930–44.

  40. 40.

    Maestro B, Campión J, Dávila N, Calle C. Stimulation by 1,25-dihydroxyvitamin D3 of insulin receptor expression and insulin responsiveness for glucose transport in U-937 human promonocytic cells. Endocr J. 2000;47:383–91.

  41. 41.

    Maestro B, Molero S, Bajo S, Dávila N, Calle C. Transcriptional activation of the human insulin receptor gene by 1,25-dihydroxyvitamin D(3). Cell Biochem Funct. 2002;20:227–32.

  42. 42.

    Parker L, Levinger I, Mousa A, Howlett K, de Courten B. Plasma 25-hydroxyvitamin D is related to protein signaling involved in glucose homeostasis in a tissue-specific manner. Nutrients. 2016;8. https://doi.org/10.3390/nu8100631.

  43. 43.

    Mirmonsef P, Hotton AL, Gilbert D, Burgad D, Landay A, Weber KM, et al. Free glycogen in vaginal fluids is associated with Lactobacillus colonization and low vaginal pH. PLoS ONE. 2014;9:e102467.

  44. 44.

    Wang T-T, Nestel FP, Bourdeau V, Nagai Y, Wang Q, Liao J, et al. Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J Immunol. 2004;173:2909–12.

  45. 45.

    Hertting O, Holm Å, Lüthje P, Brauner H, Dyrdak R, Jonasson AF, et al. Vitamin D induction of the human antimicrobial Peptide cathelicidin in the urinary bladder. PLoS ONE. 2010;5:e15580.

  46. 46.

    McMahon L, Schwartz K, Yilmaz O, Brown E, Ryan LK, Diamond G. Vitamin D-mediated induction of innate immunity in gingival epithelial cells. Infect Immun. 2011;79:2250–6.

  47. 47.

    Brockman-Schneider RA, Pickles RJ, Gern JE. Effects of vitamin D on airway epithelial cell morphology and rhinovirus replication. PLoS ONE. 2014;9:e86755.

  48. 48.

    Zheng Y, Niyonsaba F, Ushio H, Nagaoka I, Ikeda S, Okumura K, et al. Cathelicidin LL-37 induces the generation of reactive oxygen species and release of human alpha-defensins from neutrophils. Br J Dermatol. 2007;157:1124–31.

  49. 49.

    Romero R, Hassan SS, Gajer P, Tarca AL, Fadrosh DW, Nikita L, et al. The composition and stability of the vaginal microbiota of normal pregnant women is different from that of non-pregnant women. Microbiome. 2014;2:4.

  50. 50.

    Stout MJ, Zhou Y, Wylie KM, Tarr PI, Macones GA, Tuuli MG. Early pregnancy vaginal microbiome trends and preterm birth. Am J Obstet Gynecol. 2017;217:356.e1–18.

  51. 51.

    DiGiulio DB, Callahan BJ, McMurdie PJ, Costello EK, Lyell DJ, Robaczewska A, et al. Temporal and spatial variation of the human microbiota during pregnancy. Proc Natl Acad Sci USA. 2015;112:11060–5.

  52. 52.

    Fredricks DN, Fiedler TL, Thomas KK, Oakley BB, Marrazzo JM. Targeted PCR for detection of vaginal bacteria associated with bacterial vaginosis. J Clin Microbiol. 2007;45:3270–6.

  53. 53.

    Kusters JG, Reuland EA, Bouter S, Koenig P, Dorigo-Zetsma JW. A multiplex real-time PCR assay for routine diagnosis of bacterial vaginosis. Eur J Clin Microbiol Infect Dis. 2015;34:1779–85.

  54. 54.

    Nelson DB, Hanlon A, Nachamkin I, Haggerty C, Mastrogiannis DS, Liu C, et al. Early pregnancy changes in bacterial vaginosis-associated bacteria and preterm delivery. Paediatr Perinat Epidemiol. 2014;28:88–96.

  55. 55.

    Zozaya-Hinchliffe M, Martin DH, Ferris MJ. Prevalence and abundance of uncultivated Megasphaera-like bacteria in the human vaginal environment. Appl Environ Microbiol. 2008;74:1656–9.

  56. 56.

    Lennard K, Dabee S, Barnabas SL, Havyarimana E, Blakney A, Jaumdally SZ et al. Microbial composition predicts genital tract inflammation and persistent bacterial vaginosis in South African adolescent females. Infect Immun. 2018;86. https://doi.org/10.1128/IAI.00410-17.

  57. 57.

    McClelland RS, Lingappa JR, Srinivasan S, Kinuthia J, John-Stewart GC, Jaoko W, et al. Evaluation of the association between the concentrations of key vaginal bacteria and the increased risk of HIV acquisition in African women from five cohorts: a nested case-control study. Lancet Infect Dis. 2018;18:554–64.

  58. 58.

    Gajer P, Brotman RM, Bai G, Sakamoto J, Schütte UME, Zhong X, et al. Temporal dynamics of the human vaginal microbiota. Sci Transl Med. 2012;4:132ra52.

  59. 59.

    Verstraelen H, Verhelst R, Claeys G, De Backer E, Temmerman M, Vaneechoutte M. Longitudinal analysis of the vaginal microflora in pregnancy suggests that L. crispatus promotes the stability of the normal vaginal microflora and that L. gasseri and/or L. iners are more conducive to the occurrence of abnormal vaginal microflora. BMC Microbiol. 2009;9:116.

  60. 60.

    Hollis BW, Johnson D, Hulsey TC, Ebeling M, Wagner CL. Vitamin D supplementation during pregnancy: double-blind, randomized clinical trial of safety and effectiveness. J Bone Miner Res. 2011;26:2341–57.

  61. 61.

    Wickham H. ggplot2 - elegant graphics for data analysis. Springer. http://www.springer.com/us/book/9780387981413 (accessed 13 Jul 2016).

Download references

Acknowledgements

This work was funded in part from a grant from the W. K. Kellogg Foundation and by the South Carolina Clinical & Translational Research (SCTR) Institute, with an academic home at the Medical University of South Carolina, NIH/NCAT Grant number UL1 TR000062. This work was also supported by National Institutes of Health [grant U54 DE023786 “A Multi-‘omic Analysis of the Vaginal Microbiome during Pregnancy”]. All sequencing and analysis of sequence data were performed in the Genomics Core of the Nucleic Acids Research Facilities at VCU.

Author information

Author notes

  1. These authors contributed equally: G.A. Buck, C.L. Wagner

Affiliations

  1. Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA, USA

    • Kimberly K. Jefferson
    • , Hardik I. Parikh
    • , Erin M. Garcia
    • , Myrna G. Serrano
    • , Jennifer M. Fettweis
    •  & Gregory A. Buck
  2. Center for the Study of Biological Complexity, Virginia Commonwealth University, Richmond, VA, USA

    • Hardik I. Parikh
    • , David J. Edwards
    •  & Jerome F. Strauss III
  3. Department of Statistical Sciences and Operations Research, Virginia Commonwealth University, Richmond, VA, USA

    • David J. Edwards
  4. Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham, UK

    • Martin Hewison
  5. Division of Neonatology, Shawn Jenkins Children’s Hospital, Medical University of South Carolina Children’s Hospital, Charleston, SC, USA

    • Judith R. Shary
    • , Bruce W. Hollis
    •  & Carol L. Wagner
  6. Department of Obstetrics and Gynecology, Johns Hopkins University, Baltimore, MD, USA

    • Anna M. Powell
  7. Department of Obstetrics and Gynecology, Virginia Commonwealth University, Richmond, VA, USA

    • Jennifer M. Fettweis
    •  & Jerome F. Strauss III

Authors

  1. Search for Kimberly K. Jefferson in:

  2. Search for Hardik I. Parikh in:

  3. Search for Erin M. Garcia in:

  4. Search for David J. Edwards in:

  5. Search for Myrna G. Serrano in:

  6. Search for Martin Hewison in:

  7. Search for Judith R. Shary in:

  8. Search for Anna M. Powell in:

  9. Search for Bruce W. Hollis in:

  10. Search for Jennifer M. Fettweis in:

  11. Search for Jerome F. Strauss III in:

  12. Search for Gregory A. Buck in:

  13. Search for Carol L. Wagner in:

Conflict of interest

The authors declare that they have no conflict of interest.

Corresponding authors

Correspondence to Gregory A. Buck or Carol L. Wagner.

Supplementary information

About this article

Publication history

Received

Revised

Accepted

Published

DOI

https://doi.org/10.1038/s41372-019-0343-8