AbstractImmunological adaptions during pregnancy play a crucial role in healthy fetal development. Aberrant immune modifications however contribute to adverse pregnancy outcomes, which may be driven by maternal factors such as previous pregnancies and BMI. This secondary analysis of the MicrobeMom2 RCT investigates the changes to maternal inflammatory biomarkers derived from serum and stimulated peripheral blood mononuclear cells (PBMCs) during pregnancy, and the effects of previous pregnancies (parity) and BMI on maternal immune responses.

摘要怀孕期间的免疫适应在胎儿健康发育中起着至关重要的作用。然而，异常的免疫修饰会导致不良的妊娠结局，这可能是由母体因素（如先前的妊娠和BMI）驱动的。这项对微生物2随机对照试验的二次分析调查了妊娠期间血清和刺激的外周血单核细胞（PBMC）衍生的母体炎症生物标志物的变化，以及先前妊娠（胎次）和BMI对母体免疫反应的影响。

Changes in immune and metabolic biomarkers from early (11–15 weeks’ gestation) to late (28–32 weeks’ gestation) pregnancy were compared using paired t-tests. Participants were then split by parity (nulliparous, parous) and BMI (BMI < 25, BMI > = 25), and the relationship between parity and BMI with immune biomarker levels was examined using independent t-tests, paired t-tests, ANCOVA, and linear regression.

使用配对t检验比较了从妊娠早期（妊娠11-15周）到妊娠晚期（妊娠28-32周）的免疫和代谢生物标志物的变化。然后将参与者按胎次（未生育，出生）和BMI（BMI<25，BMI>==25）进行分组，并使用独立t检验，配对t检验，ANCOVA和线性回归检查胎次和BMI与免疫生物标志物水平之间的关系。

Equivalent non-parametric tests were used for skewed data. Recruited women (n = 72) were on average 31.17 (SD ± 4.53) years of age and 25.11 (SD ± 3.82) BMI (kg/m2). Of these, 51 (70.8%) had a previous term pregnancy. Throughout gestation, PBMC cytokines displayed contrasting trends to serum, with a dampening of immune responses noted in PBMCs, and enhanced production of cytokines observed in the serum.

等效的非参数检验用于偏斜数据。招募的女性（n=72）平均年龄为31.17（SD±4.53）岁，BMI（kg/m2）为25.11（SD±3.82）。。在整个妊娠期间，PBMC细胞因子显示出与血清相反的趋势，PBMC中注意到的免疫反应减弱，并且在血清中观察到细胞因子的产生增强。

Significant decreases in PBMC derived TNF-α, IL-10 and IFN-γ were seen from early to late pregnancy. Serum C3, IL-17A, IL-6, TNF-α, CD163, GDF-15 and leptin increased throughout gestation. First pregnancy was associated with higher levels of leptin in late pregnancy, while parous women showed significant decreases in PBMC derived TNF-α, IL10, and IFN-γ with gestation.

从妊娠早期到晚期，PBMC衍生的TNF-α，IL-10和IFN-γ显着降低。在整个妊娠期间，血清C3，IL-17A，IL-6，TNF-α，CD163，GDF-15和瘦素升高。首次妊娠与妊娠晚期瘦素水平较高有关，而妊娠期女性PBMC衍生的TNF-α，IL10和IFN-γ显着降低。

Differences in levels of C3, IL-17A, TNF-α, GDF-15 and leptin we.

C3，IL-17A，TNF-α，GDF-15和瘦素水平的差异。

IntroductionThe maternal immune system is faced with a unique complexity during pregnancy given that it must support the growth of a semi-allogenic fetus whilst also providing defence against infection1. This challenging task is facilitated by a series of essential immunological adaptations that occur from implantation to delivery2.

引言母亲的免疫系统在怀孕期间面临着独特的复杂性，因为它必须支持半同种异体胎儿的生长，同时还可以抵抗感染1。从植入到分娩发生的一系列基本免疫适应促进了这项具有挑战性的任务2。

Loss of immunological balance however can result in adverse pregnancy outcomes such as pre-eclampsia, pre-term birth and miscarriage3. Further study of both the normal maternal immune response and the factors which impact it is required to fully understand the driving factors of these immune imbalances.Cytokine levels throughout pregnancy have been previously explored in the plasma and serum4,5,6,7,8,9.

然而，免疫平衡的丧失可能导致不良妊娠结局，如先兆子痫，早产和流产3。需要进一步研究正常的母体免疫反应及其影响因素，以充分了解这些免疫失衡的驱动因素。先前已经在血浆和血清中探索了整个怀孕期间的细胞因子水平4,5,6,7,8,9。

While many of these studies agree that pregnancy is a time of immunological change, there are contrasting reports of cytokine secretion patterns, likely due to differences in timing and methodology3. Cellular activity in the periphery has also been examined, which provides insight into the ability of cells to respond to infection1,10,11,12.

虽然许多这些研究都同意怀孕是一个免疫学改变的时期，但有关于细胞因子分泌模式的对比报道，可能是由于时间和方法的差异3。还检查了外周的细胞活性，这提供了对细胞对感染作出反应的能力的见解1,10,11,12。

However, patterns of cellular cytokine expression have also contrasted between studies, and few have reported immune component levels from both serum and peripheral blood mononuclear cells (PBMCs) in the same cohort9.Discrepancies between studies may also be attributed to maternal factors. Some research has suggested that parity or body mass index (BMI) impacts immune activity.

。一些研究表明，胎次或体重指数（BMI）会影响免疫活动。

Pre-eclampsia, an inflammatory complication of pregnancy, has been shown to have increased prevalence in nulliparous women13,14. It is postulated that this is due to tolerability of the maternal immune system to paternal antigens in previous pregnancies15. Another risk factor for pre-eclampsia is high maternal BMI, which is believed.

子痫前期是妊娠的一种炎症并发症，已被证明在未产妇中患病率增加13,14。据推测，这是由于母体免疫系统对先前妊娠中父亲抗原的耐受性15。据信，先兆子痫的另一个危险因素是母亲的高BMI。

Data availability

数据可用性

The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request.

本研究中使用和分析的数据集可根据合理要求从通讯作者处获得。

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Download referencesAcknowledgementsWe would like to thank the women who kindly participated in the study.FundingThis publication has emanated from research supported in part by a peer reviewed research grant from Science Foundation Ireland (SFI) under Grant No. 12/RC/2273 and 16/SP/3827 which included a research grant from PrecisionBiotics Group Ltd.Author informationAuthor notesThese authors jointly supervised this work:.

下载参考文献致谢我们要感谢热情参与这项研究的女性。资助本出版物来源于爱尔兰科学基金会（SFI）根据第12/RC/2273和16/SP/3827号资助的同行评审研究资助部分支持的研究，其中包括PrecisionBiotics Group Ltd.的研究资助。作者信息作者注意到这些作者共同监督了这项工作：。

Sarah L. Doyle and Fionnuala M. McAuliffe.Authors and AffiliationsUCD Perinatal Research Centre, School of Medicine, University College Dublin, National Maternity Hospital, Dublin 2, IrelandGrace Mealy, Sarah Louise Killeen, Cara Yelverton & Fionnuala M. McAuliffeDepartment of Clinical Medicine, Trinity College Institute of Neuroscience, School of Medicine, Trinity College Dublin, Dublin 2, IrelandKiva Brennan & Sarah L.

Sarah L.Doyle和Fionnuala M.McAuliffe。作者和附属机构，如都柏林大学医学院围产期研究中心，都柏林国家妇产医院，都柏林2，IrelandGrace Mealy，Sarah Louise Killeen，Cara Yelverton＆Fionnuala M.McAuliffe三一学院神经科学学院临床医学系，都柏林三一学院医学院，都柏林2，IrelandKiva Brennan＆Sarah L。

DoyleDepartment of Clinical Chemistry, St Vincent’s University Hospital, Dublin, IrelandMark KilbaneThe National Institute for Bioprocessing, Research, and Training (NIBRT), Dublin, IrelandRadka SaldovaUCD School of Medicine, College of Health and Agricultural Science (CHAS), University College Dublin (UCD), Dublin, IrelandRadka SaldovaPrecisionBiotics Group Ltd (Novozymes), Cork Airport Business Park, Kinsale Road, Cork, IrelandDavid GroegerSchool of Microbiology, University College Cork, Cork, IrelandDouwe VanSinderenAPC Microbiome Ireland, University College Cork, Cork, IrelandDouwe VanSinderen & Paul D.

都柏林圣文森特大学医院DoyleDepartment of Clinical Chemistry，都柏林，IrelandRadka-SaldovaUCD医学院，卫生与农业科学学院（CHAS），都柏林大学学院（UCD），都柏林，IrelandRadka-SaldovaPrecisionBiotics Group Ltd（Novozymes），科克机场商业园，科克金赛路，科克，IrelandDavid GroegerSchool of Microbiology，科克大学学院，科克，IrelandDouwe-VanSinderenAPC Microbiome Ireland，科克大学学院Douwe VanSinderen和Paul D。

CotterMoorepark, Teagasc Food Research Centre, Fermoy, Cork, IrelandPaul D. CotterAuthorsGrace MealyView author publicationsYou can also search for this author in.

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PubMed Google ScholarContributionsConceptualization: FMcA, SD, KB, GM. Methodology: FMcA, SD, KB, GM, DvS. Software: GM. Validation: n/a. Formal analysis: FMcA, SD, KB, GM. Investigation: KB, GM, MK. Resources: FMcA, SD. Data Curation: GM, FMcA, KB, SD, SLK. Writing—Original Draft: GM, KB, FMcA, SD.

PubMed谷歌学术贡献概念：FMcA，SD，KB，GM。方法：FMcA，SD，KB，GM，DvS。软件：GM。验证：n/a。正式分析：FMcA，SD，KB，GM。调查：KB，GM，MK。资源：FMcA，SD。数据管理：GM，FMcA，KB，SD，SLK。撰写初稿：GM，KB，FMcA，SD。

Writing—Review & Editing: All authors. Visualization: GM, SLK, KB, SD, FMcA. Supervision: FMcA, SD. Project administration: GM, FMcA. Funding acquisition: PC, DVS, RS, DG, FMcA.Corresponding authorCorrespondence to.

写作评论和编辑：所有作者。可视化：GM，SLK，KB，SD，FMcA。监督：FMcA，SD。项目管理：总经理，FMcA。资金获取：PC、DVS、RS、DG、FMcA。对应作者对应。

Fionnuala M. McAuliffe.Ethics declarations

菲昂努阿拉·M·麦考利夫。道德宣言

Competing interests

相互竞争的利益

DG is an employee of PrecisionBiotics Group Ltd. PDC is a co-founder and CTO of SeqBiome Ltd., a microbiome analysis company. The remaining authors report no conflicts of interest.

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Reprints and permissionsAbout this articleCite this articleMealy, G., Brennan, K., Killeen, S.L. et al. Impact of previous pregnancy and BMI on cellular and serum immune activity from early to late pregnancy.

转载和许可本文引用本文Mealy，G.，Brennan，K.，Killeen，S.L。等人。先前怀孕和BMI对妊娠早期至晚期细胞和血清免疫活性的影响。

Sci Rep 14, 16055 (2024). https://doi.org/10.1038/s41598-024-66651-4Download citationReceived: 26 January 2024Accepted: 03 July 2024Published: 11 July 2024DOI: https://doi.org/10.1038/s41598-024-66651-4Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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Adaptive immunityAntimicrobial responsesBiomarkersCytokinesImmunologyInflammationInnate immunityLymphocytes

适应性免疫和微生物反应生物标志物细胞因子免疫炎症免疫淋巴细胞

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