The Recurrent Pregnancy Loss Unit, The Capital Region, Rigshospitalet and Hvidovre Hospital, Copenhagen University Hospitals, Copenhagen, Denmark.
Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Hum Reprod. 2022 Jun 30;37(7):1525-1543. doi: 10.1093/humrep/deac094.
How does hormonal contraceptive use and menstrual cycle phase affect the female microbiome across different body sites?
The menstrual cycle phase, but not hormonal contraceptive use, is associated with the vaginal and oral but not the gut microbiome composition in healthy young women.
Women with low vaginal levels of Lactobacillus crispatus are at increased risk of pre-term birth, fertility treatment failure, sexually transmitted infections and gynaecological cancers. Little is known about the effect of hormonal fluctuations on other body site's microbiomes as well as the interplay between them.
STUDY DESIGN, SIZE, DURATION: This study includes a cohort of 160 healthy young Danish women using three different contraceptive regimens: non-hormonal methods (n = 54), combined oral contraceptive (COC, n = 52) or levonorgestrel intrauterine system (LNG-IUS, n = 54). Samples were collected from four body sites during the menstrual cycle (menses, follicular and luteal phases) at Copenhagen University Hospital, Rigshospitalet, Denmark.
PARTICIPANTS/MATERIALS, SETTING, METHODS: The oral, vaginal, rectal and faecal microbiomes were characterized by shotgun sequencing. Microbial diversity and community distance measures were compared between study groups, menstrual phase timepoints and body sites. All participants answered an extensive questionnaire on current health, lifestyle and sex life. Confounding factors such as smoking, BMI and diet were analysed by PERMANOVA. Plasma oestradiol and progesterone levels are correlated with microbiome composition.
The use of COC and LNG-IUS was not associated with the microbiome composition or diversity. However, increased diversity in the vaginal microbiome was observed during menses, followed by a subsequent expansion of Lactobacillus spp. during the follicular and luteal phases which correlated with measured serum oestradiol levels (r = 0.11, P < 0.001). During menses, 89 women (58%) had a dysbiotic vaginal microbiome with <60% Lactobacillus spp. This declined to 49 (32%) in the follicular phase (P < 0.001) and 44 (29%) in the luteal phase (P < 0.001). During menses, bacterial richness and diversity in saliva reached its lowest point while no differences were observed in the faecal microbiome. The microbiome in different body sites was on average more similar within the same individual than between individuals, despite phase or hormonal treatment. Only the vagina presented a clear cluster structure with dominance of either L. crispatus, Lactobacillus iners, Gardnerella vaginalis or Prevotella spp.
The microbiome samples analysed in this study were submitted to the European Nucleotide Archive under project number PRJEB37731, samples ERS4421369-ERS4422941.
LIMITATIONS, REASONS FOR CAUTION: The cohort is homogenous which limits extrapolation of the effects of ethnicity and socio-economic status on the microbiome. We only present three defined timepoints across the menstrual phase and miss potential important day to day fluctuations.
The use of hormonal contraception did not significantly associate with the microbiome composition in the vagina, faeces, rectum or saliva in healthy young women. This is a welcome finding considering the widespread and prolonged use of these highly efficient contraceptive methods. The menstrual cycle is, however, a major confounding factor for the vaginal microbiome. As such, the time point in the menstrual cycle should be considered when analysing the microbiome of women of reproductive age, since stratifying by vaginal dysbiosis status during menstruation could be misleading. This is the first study to confirm by direct measurements of oestradiol, a correlation with the presence of L. crispatus, adding evidence of a possible hormonal mechanism for the maintenance of this desirable microbe.
STUDY FUNDING/COMPETING INTEREST(S): This work was partly funded by the Ferring Pharmaceuticals through a research collaboration with The Centre for Translational Microbiome Research (CTMR) at the Karolinska Institutet (L.W.H., E.F., G.E. and I.S.-K.). Ferring Pharmaceuticals also funded the infrastructure to obtain the clinical samples at Copenhagen University Hospital ([#MiHSN01], M.C.K., Z.B., and H.S.N.). This work was also supported by funding from Rigshospitalet's Research Funds ([#E-22614-01 and #E-22614-02] to M.C.K.) and Oda and Hans Svenningsen's Foundation ([#F-22614-08] to H.S.N.). M.C.K., L.W.H., E.F., Z.B., G.E., L.E., I.S.-K. and H.S.N., are partially funded by Ferring Pharmaceuticals, which also provided funds for the collection and processing of the samples analysed in this study. H.S.N.'s research is further supported by Freya Biosciences and the BioInnovation Institute. H.S.N. has received honoraria from Ferring Pharmaceuticals, Merck A/S, Astra-Zeneca, Cook Medical and Ibsa Nordic. A.N.A. reports no competing interests.
激素避孕的使用和月经周期阶段如何影响不同身体部位的女性微生物组？
在健康的年轻女性中，仅月经周期阶段，而不是激素避孕的使用，与阴道和口腔微生物组组成有关，但与肠道微生物组组成无关。
阴道中缺少乳杆菌的女性发生早产、生育治疗失败、性传播感染和妇科癌症的风险增加。关于激素波动对其他身体部位微生物组的影响，以及它们之间的相互作用，知之甚少。
研究设计、规模、持续时间：本研究纳入了来自丹麦哥本哈根大学医院里格医院的 160 名使用三种不同避孕方案的健康年轻女性：非激素方法（n=54）、复方口服避孕药（COC，n=52）或左炔诺孕酮宫内节育系统（LNG-IUS，n=54）。在月经周期（月经期、卵泡期和黄体期）的四个身体部位（阴道、口腔、直肠和粪便）采集样本。
参与者/材料、设置、方法：通过 shotgun 测序对口腔、阴道、直肠和粪便微生物组进行了特征描述。比较了研究组、月经周期时间点和身体部位之间的微生物多样性和群落距离测量值。所有参与者都回答了关于当前健康、生活方式和性生活的广泛问卷。通过 PERMANOVA 分析了吸烟、BMI 和饮食等混杂因素。血浆雌二醇和孕酮水平与微生物组组成相关。
COC 和 LNG-IUS 的使用与微生物组组成或多样性无关。然而，在月经期观察到阴道微生物组多样性增加，随后在卵泡期和黄体期期间观察到乳杆菌属的扩张，这与测量的血清雌二醇水平相关（r=0.11，P<0.001）。在月经期，89 名女性（58%）的阴道微生物组呈双歧杆菌减少，乳杆菌属<60%。这一比例在卵泡期下降至 49 名（32%）（P<0.001），黄体期下降至 44 名（29%）（P<0.001）。在月经期，唾液中的细菌丰富度和多样性达到最低点，而粪便微生物组没有差异。尽管存在阶段或激素治疗，不同身体部位的微生物组在个体内部平均比个体之间更相似。只有阴道呈现出明确的聚类结构，以乳杆菌crispatus、乳杆菌iners、加德纳菌阴道病或普雷沃氏菌属为主。
本研究分析的微生物组样本已提交给欧洲核苷酸档案库，项目编号 PRJEB37731，样本 ERS4421369-ERS4422941。
局限性、谨慎的原因：该队列是同质的，限制了种族和社会经济地位对微生物组的影响的推断。我们只呈现了月经周期的三个定义时间点，错过了潜在的重要日常波动。
在健康的年轻女性中，激素避孕的使用与阴道、粪便、直肠和唾液中的微生物组组成无关。考虑到这些高效避孕方法的广泛和长期使用，这是一个令人欣慰的发现。然而，月经周期是阴道微生物组的一个主要混杂因素。因此，在分析育龄妇女的微生物组时，应考虑月经周期的时间点，因为在月经期对阴道双歧杆菌减少进行分层可能会产生误导。本研究首次通过直接测量雌二醇证实了与乳杆菌crispatus 的相关性，为维持这种理想微生物的可能激素机制提供了证据。
研究资金/利益冲突：这项工作部分由 Ferring 制药公司通过与卡洛琳斯卡研究所（Karolinska Institutet）的转化微生物组研究中心（CTMR）的合作研究（L.W.H.、E.F.、G.E.和 I.S.-K.）资助。Ferring 制药公司还为哥本哈根大学医院的临床样本采集提供了基础设施（[#MiHSN01]，M.C.K.、Z.B.和 H.S.N.）。这项工作还得到了里格医院研究基金的支持（[#E-22614-01 和 #E-22614-02]至 M.C.K.）和 Oda 和 Hans Svenningsen 基金会的支持（[#F-22614-08 至 H.S.N.）。M.C.K.、L.W.H.、E.F.、Z.B.、G.E.、L.E.、I.S.-K.和 H.S.N.部分由 Ferring 制药公司资助，该公司还为分析本研究中采集的样本提供了资金。H.S.N.的研究还得到了 Freya Biosciences 和生物创新研究所的支持。H.S.N.收到了 Ferring 制药公司、默克公司、阿斯利康公司、库克医疗公司和 Ibsa Nordic 的酬金。A.N.A. 没有利益冲突的报告。
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