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通讯作者:

刁飞扬,E-mail:diaofeiyang@njmu.edu.cn

中图分类号:R714.25

文献标识码:A

文章编号:1007-4368(2022)07-1030-06

DOI:10.7655/NYDXBNS20220718

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目录contents

    摘要

    人体微生物群与宿主构成了相互制约、相互协调的微生态平衡,对人类健康而言不可或缺。各种原因导致的微生态失衡可能是人体多种疾病的重要致病因素。近年来,对女性生殖道、肠道微生物群与疾病的研究取得了突破性进展,提示其对妊娠期糖尿病、早产及先兆子痫等妊娠并发症的发生、发展和预后可能起重要作用。此外,母体生殖道、乳汁和肠道等部位的微生物群还可能影响新生儿代谢、免疫系统和神经系统的发育和功能。本文选择女性生殖道和肠道微生物群对妊娠并发症及子代发育影响的相关研究进行综述,以期为相关研究提供新视角、新思路。

    Abstract

    Objective:The human microbiota and the host constitute a mutually restricted and coordinated microecological balance, which is indispensable for human health. Microecological imbalance caused by various reasons may be an important pathogenic factor of many diseases in human body. In recent years,the research on female reproductive tract microbial community,intestinal flora and diseases has made a breakthrough,suggesting that they may play an important role in the occurrence,development and prognosis of obstetrics complications including preterm birth and gestational diabetes mellitus. In addition,it’s undeniable that the microbiota of the maternal reproductive tract,breast milk and intestinal tract may also influence the development and function of the neonate metabolism,immune system and nervous system. Here we review the studies on the impact of female reproductive tract flora and intestinal microbiota on pregnancy and offspring,in order to provide a new perspective and new ideas for future research.

  • 人体微生物群指存在于人体内外环境中所有微生物的集合,包括细菌、病毒、真菌和古细菌,数量是人体细胞的10倍,对维持人体健康具有重要意义[1]。过去对于微生物的研究囿于培养技术的局限性,一定程度低估了微生物对健康和疾病的影响。高通量测序技术,特别是16S rRNA扩增子测序技术的发展和成熟,极大地促进了人类对微生物群更全面与深入的了解[2]。2007年美国国立卫生院 (NIH)启动的人类微生物组计划(Human Microbiome Project,HMP),致力描绘了健康人体皮肤、口腔、鼻腔、肠道和泌尿生殖道等部位的微生物全景图[3]。 2013年启动的第二阶段(iHMP)则联合多组学聚焦微生物与人类重要疾病之间的关系,早产、糖尿病前期和炎症性肠病与微生物的研究数据为其他疾病的研究提供了有益的思考[4-6]

  • 健康状态下的子宫腔曾被认为是无菌的[7],而16S测序技术提供的证据则提示上生殖道存在微生物定植,且从阴道到盆腔呈现连续、逐渐扩展、乳杆菌所占比例逐渐下降的分布特征[8]。最新的动物实验发现阴道和子宫腔微生物群之间存在趋同性,阴道微生物群的扰动能引发宫腔微生物群相同的变化趋势,阴道定植乳杆菌可以降低宫腔促炎因子的表达水平[9]。肠道拥有丰富的微生物群落,参与营养代谢、免疫调节及抵御病原体等维持人体健康状态的重要机体功能。研究表明肠道微生物群的变化与肥胖、糖尿病和自闭症谱系障碍等疾病密切相关[10]。目前多项研究表明女性生殖道和肠道微生物群是孕期健康的重要影响因素,母体微生物群还可以通过影响胎儿和婴儿微生物群对子代生长发育起到重要作用。

  • 本文选择女性生殖道和肠道微生物群与妊娠并发症及子代发育的相关研究进行综述,以期为将来相关研究提供新视角、新思路。

  • 1 母体微生物群与妊娠并发症

  • 妊娠全过程伴随着内分泌、代谢和免疫等多方面的剧烈变化,对母体健康和胎儿正常发育影响深远,越来越多的证据提示微生物群在其中也发挥着不易觉察的重要作用。

  • 1.1 母体微生物群与妊娠期糖尿病

  • 妊娠期糖尿病(gestational diabetes mellitus, GDM)女性与健康妊娠期女性相比,肠道微生物的组成特征和孕期动态变化均存在显著差异。

  • 健康女性妊娠早期和中期肠道微生物群中厚壁菌门和类杆菌门占优势,妊娠晚期变形菌门和放线菌门的丰度显著升高。GDM女性的肠道微生物群α多样性降低,组成特征表现为厚壁菌门/类杆菌门比值升高、革兰氏阴性菌丰度增加,产短链脂肪酸(short⁃chain fatty acid,SCFA)和芳香族氨基酸的微生物丰度减少[11-12]

  • 健康女性肠道微生物群的多样性、丰度随着孕周增加呈现动态变化,妊娠早期与中期相比,布劳特氏菌属、罗氏菌属和嗜胆菌属丰度较低,类杆菌属和不动杆菌属丰度较高,且与随着妊娠进展胰岛素抵抗增加的趋势一致。然而GDM女性从妊娠早期到中期肠道微生物的动态变化明显减少,因此推测肠道菌群缺乏正常的动态变化可能是GDM的发病机制之一[12]

  • Crusell等[13] 发现校正孕前体重指数后,肠道菌群丰度在GDM组女性与血糖正常女性之间存在显著差异,前者柯林斯菌属、罗氏菌属和脱硫弧菌属丰度更高。如果GDM女性肠道内柯林斯菌在产后8个月仍维持较高丰度,将会增加其发展为2型糖尿病的风险。

  • GDM还是妊娠合并巨大儿的高危因素,研究表明巨大儿的胎盘微生物群中变形杆菌、类杆菌、厚壁菌和放线菌的丰度均高于出生体重正常的新生儿[14],提示母体微生物群在妊娠期糖尿病和巨大儿发病机制中的可能作用。

  • 1.2 母体微生物群与早产

  • 早产常见的病因是泌尿生殖道、口腔和肠道等部位的致病菌,通过血液传播、直接迁移等途径感染胎膜、胎盘和子宫腔[15]。母体生殖道和肠道微生物群失去健康稳态也是早产的重要发病机制之一。

  • 健康妊娠女性孕期的阴道微生物群α多样性和丰度低于非孕期,乳杆菌占优势并保持稳定[15-16]。 Fettweis等[4] 发现自发性早产女性的阴道微生物群多样性增加,卷曲乳杆菌丰度显著降低,细菌性阴道病相关细菌1型、普雷沃菌、斯尼斯氏菌和细菌性阴道病相关细菌TM7⁃H1丰度增加,此4类微生物或可成为预测早产的标志物。

  • Aagaard等[17] 对320例胎盘进行16S rRNA测序发现,胎盘中含有与早产有关的非致病性共生微生物群,包括厚壁菌门、软壁菌门、变形菌门、类杆菌门和梭杆菌门,其丰度低但代谢功能活跃。但de Goffau等[18] 认为正常情况下人类胎盘不存在微生物群,部分标本是在分娩或手术过程中受到污染,与早产或先兆子痫没有明显关联。因此胎盘是否存在微生物定植、胎盘部位微生物的来源仍是研究的热点,曾有学者发现小鼠口腔微生物经由血源性途径传播到胎盘定植,可以引起宫内感染而导致早产[19]

  • 肠道微生物群与早产关系的研究最早见于2011年挪威的一项前瞻性母婴队列研究。该研究发现口服益生菌酸奶的女性,自发性早产的发生率显著降低,孕周延长[20]。研究表明早产女性肠道微生物群的α多样性较足月分娩女性降低,双歧杆菌、链球菌以及梭状芽孢杆菌丰度减少。双歧杆菌的抗炎特性能抑制脂多糖诱导的核转录因子⁃κB激活及白细胞介素(interleukin,IL)⁃8和环氧化酶⁃2的产生,所以双歧杆菌减少可能会增加感染导致的早产的易感性[21-22]。口服双歧杆菌是否可以预防早产值得进一步研究。

  • 1.3 母体微生物群与子痫前期

  • 子痫前期(preeclampsia,PE)是一种严重影响母婴健康的妊娠并发症,病因包括子宫螺旋小动脉重铸不足、炎症免疫过度激活和血管内皮细胞受损等。既往研究显示,高血压患者的肠道微生物失调导致短链脂肪酸合成减少,而短链脂肪酸可以直接扩张血管或与G蛋白偶联受体结合调节血压,提示肠道微生物异常可能增加女性发生PE的风险[23]

  • 研究显示,PE女性肠道微生物群的α多样性较血压正常女性显著降低,特别是梭杆菌和小类杆菌等厌氧菌丰度显著升高。为小鼠分别定植PE女性和血压正常女性粪菌,发现定植PE女性粪菌组小鼠妊娠后血压、尿蛋白明显升高,胎盘组织形态异常。实验观察到PE女性粪菌定植组小鼠出现肠道免疫失调,调节性T细胞(Treg)/辅助性T⁃17细胞 (Th17)减少;肠道屏障功能受损,导致肠道内脂多糖水平上升,血浆内毒素和氧化三甲胺水平升高,肠道细菌移位到胎盘,提示了“肠道—胎盘”轴的存在可能[24-25]

  • 2 母体微生物群与子代发育

  • 既往研究提示母体肠道和生殖道微生物群不但在妊娠并发症发病机制中扮演着重要角色,母体微生物组还可以垂直传递给子代,是子代代谢、免疫和神经系统早期发育过程中的重要影响因素之一。了解生命早期微生物的获得和演替对子代疾病的预防和治疗具有重要意义。

  • 2.1 子代母源微生物群的获得

  • 2.1.1 母胎界面微生物群

  • 母胎界面是否无菌仍然未取得共识,胎儿获得第一批微生物群的确切时间存在争议。2014年Aagaard等[17] 的研究结果首次挑战胎盘无菌的传统观念;但随后一项研究使用定量PCR和Illumina测序方法比较了污染对照和胎盘样本,表明两组样本间16S rRNA拷贝数低且难以区分,PERMANOVA分析也未显示两组微生物群落不同[1826]。也有研究者认为人类羊水、羊膜和脐带血中的确存在微生物群,羊水含有链球菌属和核梭杆菌,脐带血中包含肠球菌、链球菌、葡萄球菌和丙酸杆菌,推测其可能为母体口腔来源[27-28]

  • 2.1.2 分娩时和婴儿期

  • 分娩时婴儿获得性微生物群来源于母亲的不同身体部位。一项意大利的母婴队列研究显示,婴儿肠道中50.7%的微生物是分娩时分别从母亲的肠道(22.1%)、阴道(16.3%)、口腔(7.2%)和皮肤 (5.0%)获得的,主要为放线杆菌和类杆菌[29]

  • 分娩时婴儿获得性微生物群来源还受出生方式的影响。经阴道分娩的婴儿的皮肤、口腔、鼻腔和肠道微生物群与母亲阴道微生物群相似,富含乳杆菌;而剖宫产婴儿全部身体部位的微生物群与母亲皮肤和环境微生物相似,包括葡萄球菌、链球菌和丙酸杆菌[30]。不同分娩方式造成的婴儿肠道微生物群差异可以持续到4岁,但随着年龄的增长其差异逐渐减小[31]。也有研究认为其影响到出生后6周即告消退[32]

  • 母乳喂养是婴儿期获得母体微生物群的一条重要通路,约25%~30%的婴儿微生物群来自母乳[33]。每800mL母乳中含有高达1×107 个细菌细胞,包括葡萄球菌、链球菌、双歧杆菌和乳杆菌。除了垂直传播外,母体肠道内的双歧杆菌和乳杆菌可以经由母乳进入胎儿肠道,因此母乳喂养的婴儿体内双歧杆菌和乳杆菌更加丰富,短链脂肪酸更多,肠道pH值更低,是婴儿抵御病原菌的重要保护机制之一[33-34]

  • 2.1.3 其他可能影响因素

  • 越来越多的证据表明,剖宫产、早产和其他高危情况预防性使用抗生素会影响婴儿早期微生物群。同为足月顺产,产程中接受预防性抗生素治疗的婴儿肠道微生物群较未使用抗生素者α多样性降低。出生后抗生素的使用可能破坏新生儿微生物群的脆弱生态,持续使用会增加2型糖尿病和炎症性肠病等疾病的罹患风险[1634]。有研究显示早产儿肠道细菌种类较足月儿减少10倍,兼性厌氧菌增加,免疫系统成熟时间延迟,这些差异是由胎龄、抗生素使用和母乳微生物等多种因素共同作用导致的[35]

  • 人类辅助生殖技术(assisted reproductive tech⁃ nology,ART)中复杂的药物使用是否影响母体微生物群和子代发育也有零星报道。对接受ART治疗的继发不孕女性,在月经前3d和应用控制性卵巢刺激药物后采集阴道分泌物,结果显示两组阴道微生物群α、β多样性、在门和属水平上物种相对丰度无明显差异,作者认为促排卵药物对阴道微生物群无明显影响[36]。Lu等[37] 对ART助孕和自然受孕出生的新生儿肠道微生物群进行比较,发现ART组新生儿胎粪的α多样性显著低于自然受孕组,丰度依次为变形菌门、厚壁菌门,自然受孕组则与之相反。ART组类杆菌丰度低于自然妊娠组,且其丰度与胚胎移植后黄体支持使用阴道栓剂呈正相关,与使用促性腺激素释放激素拮抗剂促排卵方案、扳机日高雌二醇水平呈负相关。无论何种受孕方式,肠道微生物群多样性降低和类杆菌相对丰度的下降都与出生后42d内婴儿体重的快速增长相关。该研究提示ART技术通过微生物群对母婴健康的影响值得进一步研究。

  • 2.2 母体微生物群与子代发育

  • 2.2.1 母体微生物群与子代代谢功能

  • 虽然代谢性疾病的宫内起源已经引起广泛的重视,但对母体肠道微生物调控胚胎阶段能量代谢的机制知之甚少。Kimura等[38] 研究表明孕鼠肠道微生物群可以通过SCFA激活其胚胎的SCFA受体GPR41和GPR43,从而促进交感神经元、肠内分泌细胞和胰腺β细胞分化,调控胚胎的能量代谢。与无特定病原菌小鼠子代相比,无菌小鼠子代血浆内SCFA、胃肠激素肽YY和胰高血糖素样肽⁃1水平显著降低,皮下白色脂肪组织、肝脏重量增加,血糖、甘油三酯和总胆固醇水平显著升高,提示母体正常肠道微生物的缺失使得子代对代谢综合征具有更高的易感性。

  • Wang等[39] 发现GDM母体和新生儿的肠道微生物群变化趋势相同,即与GDM相关的微生物变化具有代际一致性,其α多样性低于妊娠期血糖正常孕妇及其新生儿。此外,GDM组新生儿肠道微生物群的均匀度、丰富度显著降低,提示获得母体微生物群的代谢功能受损。还有研究者发现,相较于健康对照组,GDM组新生儿胎粪代谢物中甘油磷酰胆碱、甘胆酸和鼠李糖丰度显著降低,核黄素和牛磺酸丰度增加,这5种代谢物在GDM母体血清与胎粪中变化趋势一致。其中甘油磷酰胆碱与脂质代谢有关,而甘胆酸与脂质的消化和吸收有关,这一结果表明GDM母体可能通过微生物及其代谢物影响新生儿体内微生物分布和功能,进而导致子代的代谢功能异常,对新生儿的营养吸收产生不利影响,甚至影响子代后期生长发育[40]

  • 2.2.2 母体微生物群与子代免疫系统发育

  • 获得性母源微生物群对子代免疫系统的发育具有重要作用。人类新生儿的先天免疫系统趋向Th2型,但肠道微生物失调可导致免疫系统趋向Th1为主的促炎状态,分泌IL⁃12和干扰素(interferon, IFN)⁃γ,扰乱正常的免疫调节系统,导致炎症性肠病、过敏和自身免疫性疾病等长期问题[34]。动物实验证明,在分娩过程中胎鼠获得的母源微生物群促进其肠道上皮细胞激活,获得免疫耐受,这一过程对先天性免疫识别及胎鼠肠道微生物维持稳态至关重要[41]。GDM母亲的新生儿微生物群与母体具有共同的缺陷,其胎粪中疱疹病毒、水痘病毒、腺病毒和乳头瘤病毒丰度高于对照组,提示肠道微生物异常可增加新生儿接触病毒后的易感性[39]

  • 母乳不仅为婴儿提供必要的营养,也是婴儿与母体微生物交流的重要途径,母乳中的微生物可以改善婴幼儿营养物质的代谢和吸收,促进免疫系统、肠道屏障和肠-脑轴的发育[16]。这一过程可能是通过免疫球蛋白(Ig)A、乳铁蛋白、溶菌酶、抗菌肽和低聚糖等介导的。益生菌有利于有益微生物生存,越来越多的婴儿配方奶中添加益生菌,但仍缺乏支持其有效性的数据[34]

  • 2.2.3 母体微生物群与子代神经系统发育

  • 既往研究发现微生物群可以调控大脑发育和行为。抗生素清扫小鼠及无菌小鼠的大脑发育和神经行为均异于正常小鼠,且部分异常不能在成年后通过治疗纠正,说明孕鼠微生物环境对胎鼠的大脑和神经发育至关重要。研究显示与无特定病原体小鼠相比,抗生素清扫小鼠及无菌小鼠的胎鼠大脑中与轴突发生相关的基因表达降低、皮质轴突数量和长度减少。孕早期和中期母鼠肠道微生物群的缺乏与子代触觉反应障碍有关。抗生素清扫母鼠在定植梭状芽胞杆菌后胎鼠大脑中代谢物氧化三甲胺和咪唑丙酸水平升高,可减轻轴突发生缺陷并改善后代触觉感觉行为,提示母体微生物群可通过其代谢物促进胎儿丘脑皮质轴突的发生[42]

  • Sangdoo等[43] 研究还发现母体肠道菌群与子代自闭症谱系障碍有关。小肠中含有分节丝状菌的母鼠注射聚肌胞苷酸poly(I∶C)可激活肠道中的CD4 + T细胞和CD103 + CD11b + CD11c + 树突状细胞,通过分泌炎性细胞因子IL⁃1β、IL⁃6和IL⁃23刺激Th17产生IL⁃17a,母鼠血浆中IL⁃17a水平异常升高可引起胎儿与母体免疫激活相关的行为和神经发育异常。

  • 3 小结与展望

  • 人体微生物群的研究日益受到关注和热议,但女性生殖道、肠道微生物群失调与妊娠并发症和子代发育之间因果关系尚待确立,母婴垂直传播早期微生物群的确切来源、时间、影响和传播方式仍待阐明。发现可对妊娠期糖尿病、早产和子痫前期等妊娠并发症进行早期诊断的微生物群标志物,进而通过调控母体微生物群降低妊娠并发症的发病率、促进子代健康发育,仍存在众多未知和巨大挑战。对这些问题的深入研究和解答将为母婴健康服务者提供新策略和新方案。

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