1887

Abstract

Evidence has linked exogenous and endogenous sex hormones with the human microbiome.

The longitudinal effects of oral contraceptives (OC) on the human gut microbiome have not previously been studied.

We sought to examine the longitudinal impact of OC use on the taxonomic composition and metabolic functions of the gut microbiota and endogenous sex steroid hormones after initiation of OC use.

We recruited ten healthy women who provided blood and stool samples prior to OC use, 1 month and 6 months after starting OC. We measured serum levels of sex hormones, including estradiol, progesterone, sex hormone-binding globulin (SHBG), and total testosterone. Shotgun metagenomic sequencing was performed on DNA extracted from faecal samples. Species and metabolic pathway abundances were determined using MetaPhlAn2 and HUMAnN2. Multivariate association with linear models was used to identify microbial species and metabolic pathways associated with OC use and endogenous levels of sex hormones.

The percentage variance of the microbial community explained by individual factors ranged from 9.9 % for age to 2.7 % for time since initiation of OC use. We observed no changes in the diversity or composition of the gut microbiome following OC initiation. However, the relative abundance of the biosynthesis pathways of peptidoglycan, amino acids (lysine, threonine, methionine, and tryptophan), and the NAD salvage pathway increased after OC initiation. In addition, serum levels of estradiol and SHBG were positively associated with a flavonoid-degrading bacterium. Similarly, microbes involving biosynthesis of -lysine, -threonine, and -methionine were significantly associated with lower estradiol, SHBG, and higher levels of total testosterone.

Our study provides the first piece of evidence supporting the association between exogenous and endogenous sex hormones and gut microbiome composition and function.

Funding
This study was supported by the:
  • National Institute of Diabetes and Digestive and Kidney Diseases (Award K23 DK099681)
    • Principle Award Recipient: HamedKhalili
  • This is an open-access article distributed under the terms of the Creative Commons Attribution License. This article was made open access via a Publish and Read agreement between the Microbiology Society and the corresponding author’s institution.
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/content/journal/jmm/10.1099/jmm.0.001512
2022-04-22
2024-04-18
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References

  1. Khalili H, Higuchi LM, Ananthakrishnan AN, Richter JM, Feskanich D et al. Oral contraceptives, reproductive factors and risk of inflammatory bowel disease. Gut 2013; 62:1153–1159 [View Article] [PubMed]
    [Google Scholar]
  2. Cornish JA, Tan E, Simillis C, Clark SK, Teare J et al. The risk of oral contraceptives in the etiology of inflammatory bowel disease: a meta-analysis. Am J Gastroenterol 2008; 103:2394–2400 [View Article] [PubMed]
    [Google Scholar]
  3. Orellana C, Saevarsdottir S, Klareskog L, Karlson EW, Alfredsson L et al. Oral contraceptives, breastfeeding and the risk of developing rheumatoid arthritis: results from the Swedish EIRA study. Ann Rheum Dis 2017; 76:1845–1852 [View Article] [PubMed]
    [Google Scholar]
  4. Sanchez-Guerrero J, Karlson EW, Liang MH, Hunter DJ, Speizer FE et al. Past use of oral contraceptives and the risk of developing systemic lupus erythematosus. Arthritis Rheum 1997; 40:804–808 [View Article] [PubMed]
    [Google Scholar]
  5. Khalili H, Granath F, Smedby KE, Ekbom A, Neovius M et al. Association between long-term oral contraceptive use and risk of crohn’s disease complications in a nationwide study. Gastroenterology 2016; 150:1561–1567 [View Article] [PubMed]
    [Google Scholar]
  6. Amini L, Kalhor M, Haghighi A, Seyedfatemi N, Hosseini F et al. Effect of oral contraceptive pills on rheumatoid arthritis disease activity in women: A randomized clinical trial. Med J Islam Repub Iran 2018; 32:61 [View Article] [PubMed]
    [Google Scholar]
  7. Khalili H. Risk of inflammatory bowel disease with oral contraceptives and menopausal hormone therapy: current evidence and future directions. Drug Saf 2016; 39:193–197 [View Article] [PubMed]
    [Google Scholar]
  8. Brusca MI, Rosa A, Albaina O, Moragues MD, Verdugo F et al. The impact of oral contraceptives on women’s periodontal health and the subgingival occurrence of aggressive periodontopathogens and Candida species. J Periodontol 2010; 81:1010–1018 [View Article] [PubMed]
    [Google Scholar]
  9. Devillard E, Burton JP, Hammond J-A, Lam D, Reid G et al. Novel insight into the vaginal microflora in postmenopausal women under hormone replacement therapy as analyzed by PCR-denaturing gradient gel electrophoresis. Eur J Obstet Gynecol Reprod Biol 2004; 117:76–81 [View Article] [PubMed]
    [Google Scholar]
  10. Heinemann C, Reid G. Vaginal microbial diversity among postmenopausal women with and without hormone replacement therapy. Can J Microbiol 2005; 51:777–781 [View Article] [PubMed]
    [Google Scholar]
  11. Galhardo CL, Soares JM Jr, Simões RS, Haidar MA, Rodrigues de Lima G et al. Estrogen effects on the vaginal pH, flora and cytology in late postmenopause after a long period without hormone therapy. Clin Exp Obstet Gynecol 2006; 33:85–89 [PubMed]
    [Google Scholar]
  12. Barrientos-Durán A, Fuentes-López A, de Salazar A, Plaza-Díaz J, García F et al. Reviewing the composition of vaginal microbiota: inclusion of nutrition and probiotic factors in the maintenance of eubiosis. Nutrients 2020; 12:E419 [View Article] [PubMed]
    [Google Scholar]
  13. Markle JGM, Frank DN, Mortin-Toth S, Robertson CE, Feazel LM et al. Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Science 2013; 339:1084–1088 [View Article] [PubMed]
    [Google Scholar]
  14. Shin J-H, Park Y-H, Sim M, Kim S-A, Joung H et al. Serum level of sex steroid hormone is associated with diversity and profiles of human gut microbiome. Res Microbiol 2019; 170:192–201 [View Article] [PubMed]
    [Google Scholar]
  15. Methé BA, Nelson KE, Pop M et al. A framework for human microbiome research. Nature 2012; 486:215–221 [View Article] [PubMed]
    [Google Scholar]
  16. Ananthakrishnan AN, Luo C, Yajnik V, Khalili H, Garber JJ et al. Gut microbiome function predicts response to anti-integrin biologic therapy in inflammatory bowel diseases. Cell Host Microbe 2017; 21:603–610 [View Article] [PubMed]
    [Google Scholar]
  17. McIver LJ, Abu-Ali G, Franzosa EA, Schwager R, Morgan XC et al. bioBakery: a meta’omic analysis environment. Bioinformatics 2018; 34:1235–1237 [View Article] [PubMed]
    [Google Scholar]
  18. Segata N, Waldron L, Ballarini A, Narasimhan V, Jousson O et al. Metagenomic microbial community profiling using unique clade-specific marker genes. Nat Methods 2012; 9:811–814 [View Article] [PubMed]
    [Google Scholar]
  19. Franzosa EA, McIver LJ, Rahnavard G, Thompson LR, Schirmer M et al. Species-level functional profiling of metagenomes and metatranscriptomes. Nat Methods 2018; 15:962–968 [View Article] [PubMed]
    [Google Scholar]
  20. Mallick H, Rahnavard A, McIver LJ, Ma S, Zhang Y et al. Multivariable association discovery in population-scale meta-omics studies. PLOS Comput Biol 2021; 17:e1009442 [View Article] [PubMed]
    [Google Scholar]
  21. Knights D, Silverberg MS, Weersma RK, Gevers D, Dijkstra G et al. Complex host genetics influence the microbiome in inflammatory bowel disease. Genome Med 2014; 6:107 [View Article] [PubMed]
    [Google Scholar]
  22. Morgan XC, Tickle TL, Sokol H, Gevers D, Devaney KL et al. Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment. Genome Biol 2012; 13:R79 [View Article] [PubMed]
    [Google Scholar]
  23. Tett A, Huang KD, Asnicar F, Fehlner-Peach H, Pasolli E et al. The Prevotella copri complex comprises four distinct clades underrepresented in westernized populations. Cell Host Microbe 2019; 26:666–679 [View Article] [PubMed]
    [Google Scholar]
  24. Wiegratz I, Kutschera E, Lee JH, Moore C, Mellinger U et al. Effect of four different oral contraceptives on various sex hormones and serum-binding globulins. Contraception 2003; 67:25–32 [View Article] [PubMed]
    [Google Scholar]
  25. Zhernakova A, Kurilshikov A, Bonder MJ, Tigchelaar EF, Schirmer M et al. Population-based metagenomics analysis reveals markers for gut microbiome composition and diversity. Science 2016; 352:565–569 [View Article] [PubMed]
    [Google Scholar]
  26. Mihajlovic J, Leutner M, Hausmann B, Kohl G, Schwarz J et al. Combined hormonal contraceptives are associated with minor changes in composition and diversity in gut microbiota of healthy women. Environ Microbiol 2021; 23:3037–3047 [View Article] [PubMed]
    [Google Scholar]
  27. Eyupoglu ND, Ergunay K, Acikgoz A, Akyon Y, Yilmaz E et al. Gut microbiota and oral contraceptive use in overweight and obese patients with polycystic ovary syndrome. J Clin Endocrinol Metab 2020; 105:dgaa600 [View Article] [PubMed]
    [Google Scholar]
  28. Jackson MA, Verdi S, Maxan M-E, Shin CM, Zierer J et al. Gut microbiota associations with common diseases and prescription medications in a population-based cohort. Nat Commun 2018; 9:2655 [View Article] [PubMed]
    [Google Scholar]
  29. Schneider H, Blaut M. Anaerobic degradation of flavonoids by Eubacterium ramulus. Arch Microbiol 2000; 173:71–75 [View Article] [PubMed]
    [Google Scholar]
  30. Braune A, Gütschow M, Engst W, Blaut M et al. Degradation of quercetin and luteolin by Eubacterium ramulus. Appl Environ Microbiol 2001; 67:5558–5567 [View Article] [PubMed]
    [Google Scholar]
  31. Kaliannan K, Robertson RC, Murphy K, Stanton C, Kang C et al. Estrogen-mediated gut microbiome alterations influence sexual dimorphism in metabolic syndrome in mice. Microbiome 2018; 6:205 [View Article] [PubMed]
    [Google Scholar]
  32. Benedek G, Zhang J, Nguyen H, Kent G, Seifert HA et al. Estrogen protection against EAE modulates the microbiota and mucosal-associated regulatory cells. J Neuroimmunol 2017; 310:51–59 [View Article] [PubMed]
    [Google Scholar]
  33. Acharya KD, Gao X, Bless EP, Chen J, Tetel MJ et al. Estradiol and high fat diet associate with changes in gut microbiota in female ob/ob mice. Sci Rep 2019; 9:20192 [View Article] [PubMed]
    [Google Scholar]
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