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通讯作者:

石中华,E-mail:jesse_1982@163.com

中图分类号:R714.25

文献标识码:A

文章编号:1007-4368(2022)11-1632-05

DOI:10.7655/NYDXBNS20221122

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目录contents

    摘要

    肠道菌群是肠道内各类微生物共同构成的与人体存在共生关系的生态系统,这些微生物在人体肠道内参与了代谢、免疫和营养等多种功能,与人体的健康息息相关,与疾病的发生发展过程也有着千丝万缕的联系。妊娠期女性的肠道菌群构成发生了显著改变,肠道菌群失调也被认为在各妊娠相关疾病的发生发展过程中起重要作用。益生菌可改善肠道微环境,可作为妊娠相关疾病防治的新思路。本文就妊娠期糖尿病、子痫前期、早产、妊娠期肝内胆汁淤积症等常见妊娠相关疾病的孕妇肠道菌群改变及益生菌用于临床防治的有效性进行综述,以期为进一步进行肠道菌群影响孕妇健康的机制研究及益生菌用于临床疾病防治的更高质量研究提供依据。

    Abstract

    The gut flora is an ecosystem which is composed of various microorganisms in the intestine and has a symbiotic relationship with the human body. These microorganisms participate in various functions such as metabolism,immunity and nutrition in the human intestine,and are closely related to the health of the human body. They are also inextricably linked to the occurrence and development of diseases. The composition of the gut flora of pregnant women has undergone significant changes,and the dysbiosis of the gut flora is also considered important in the occurrence and development of pregnancy-related diseases. Probiotics can improve the intestinal microenvironment and can be used to prevent or treat these pregnancy-related diseases. This article reviews the changes in the gut flora of women with pregnancy - related diseases such as gestational diabetes mellitus,preeclampsia,premature delivery, intrahepatic cholestasis of pregnancy and the effectiveness of probiotics for clinical prevention and treatment. This review is also expected to provide a basis for further research on the mechanism of gut flora affecting the health of pregnant women and higher-quality research on probiotics.

  • 肠道菌群是肠道内由细菌、原生动物、真菌、病毒等微生物共同构成的与人体存在共生关系的生态系统,在健康人体肠道中,优势菌群主要为厚壁菌门、拟杆菌门、变形菌门和放线菌门,这些微生物在人体肠道内参与了代谢、免疫和营养等多种功能,与人体健康息息相关[1],与疾病的发生发展过程也有着千丝万缕的联系。而在妊娠期这一特殊时期,孕妇体内的各个系统都会发生一系列重构,发生这种变化是为了能更好地适应胎儿生长发育的需求[2],相应地,其肠道菌群的构成也发生了显著改变[3],现在普遍观点认为,肠道菌群失调是导致各类妊娠相关疾病发生的重要因素之一。

  • 1 妊娠期健康女性肠道菌群变化

  • 多项研究表明,妊娠期女性,即使没有合并任何并发症和相关内外科疾病,其肠道菌群也发生了显著改变。Koren等[3] 通过16S rRNA基因测序的方法,对妊娠期女性肠道菌群的变化进行了研究,结果显示,从孕早期到孕晚期,孕妇肠道菌群β⁃多样性随胎龄明显增加,α多样性降低,且菌群的组成也发生了明显变化,产丁酸的柔嫩梭菌属和优杆菌属的相对丰度有一定下降,放线菌门和变形菌门相对增加,研究者选用无菌小鼠,对其进行了孕晚期肠道菌群移植,发现可诱导炎症、胰岛素敏感性降低和体重过度增加。

  • 2 妊娠相关疾病与孕妇肠道菌群的相互关系

  • 2.1 妊娠期糖尿病(gestational diabetes mellitus, GDM)

  • Wang等[4] 研究发现与健康孕妇相比,GDM孕妇的肠道微生态系统存在明显紊乱,通过主成分分析,在分类操作单位(operational taxonomic unit, OTU)水平上确定了 18 个可鉴别 GDM 孕妇与健康孕妇的差异 OTU:在 GDM 组中富集的 OTU 主要属于毛螺菌科,而缺失的OTU主要分布在肠杆菌科和瘤胃球菌科,且这些肠道菌群的改变与人体氨基酸代谢及糖代谢途径中代谢产物含量的改变也存在关联,提示肠道菌群受孕妇血糖水平的影响可能是通过影响糖代谢及氨基酸代谢途径实现的。Liu等[5] 则认为,肠道菌群失调与脂质代谢之间也存在关联。另有研究表明,GDM孕妇肠道菌群的紊乱主要体现在拟杆菌属及链球菌属,且这些GDM孕妇自身肠道菌群的改变可能会垂直传播到下一代[6]。Ma等[7] 发现,虽然GDM的诊断时间在孕中期,但肠道菌群的差异在孕早期就有了,主要表现为GDM孕妇拟杆菌门和毛螺菌科丰度增高,其中毛螺菌科若异常增多,会提高短链脂肪酸(short⁃ chain fatty acids,SCFA)的利用率,导致宿主能量摄入过度[8]。而 Ferrocino 等[9] 对 GDM 孕妇妊娠中期和晚期肠道菌群的组成进行了动态监测,发现在门水平上,妊娠晚期较中期厚壁菌门增加,放线菌门和拟杆菌门减少;在属水平上,妊娠晚期拟杆菌、柯林斯菌和里肯菌明显减少,而布氏杆菌、丁酸杆菌、梭菌、粪球菌、粪杆菌、瘤胃球菌属显著增加。Chen等[10] 通过 DNA 微阵列技术在物种水平上对GDM孕妇肠道菌群的变化进行分析,发现了37个显著富集于GDM患者的物种,包括8种棒状杆菌、3种乳酸杆菌及部分布氏杆菌等,同时发现了104个富集于非GDM孕妇的物种,分属于芽孢杆菌、双歧杆菌、普雷沃菌等,进一步验证差异较大的菌群与GDM之间的关系,发现一些物种与 GDM患者的空腹血糖呈正相关,如阿尔塔米拉金色单胞菌、考氏科萨克氏菌,而厌氧消化链球菌与 GDM孕妇空腹血糖呈负相关。Crusell等[11] 对GDM 患者肠道菌群的结构改变与 2 型糖尿病患者的肠道菌群进行比对,发现了二者之间具有相似性, GDM 患者肠道双歧杆菌和乳酸杆菌数量减少,放线菌门丰度提高,这种变化可能是通过降低肿瘤坏死因子(tumor necrosis factor,TNF)⁃α 和白细胞介素 (interleukin,IL)⁃6 的表达来发挥效应。以上多项研究结果均表明,GDM孕妇存在肠道菌群失调,为了验证菌群失调和GDM的发生之间是否存在因果关系,Liu等[12] 通过将GDM孕妇和健康孕妇的孕中期肠道菌群移植到无菌小鼠体内,接受了GDM菌群移植的小鼠体内胰岛素水平与对照组无差异,但血糖水平明显增高。结合其他研究者对妊娠不同时期 GDM孕妇肠道菌群组成所发现的差异以及菌群移植的结果可发现,菌群失调的出现时间早于血糖的升高,菌群失调可能是GDM发生的原因。

  • 2.2 子痫前期(pre⁃eclampsia,PE)

  • Chen 等[13] 通过对 67 例 PE 孕妇及 85 例健康孕妇肠道菌群组成进行比较,发现存在显著差异:PE 组的α多样性显著降低,梭菌属、小杆菌属、韦荣氏球菌属、梭杆菌属明显富集,而毛螺菌属、阿克曼菌属、粪杆菌属明显减少,且这些菌群的改变与PE的临床表现相关,尤其是韦荣氏球菌和梭杆菌,与大多数PE孕妇临床指标的改变显著相关,包括一些肝功能指标、水肿水平,以及收缩压、舒张压、尿蛋白等。Wang等[14] 将PE孕妇与健康孕妇孕中期和孕晚期的肠道菌群分别进行了对比,发现在孕中期PE孕妇和健康孕妇肠道菌群组成没有明显差异,而在孕晚期则发生了较大变化,PE孕妇肠道内厚壁菌门含量明显低于对照组,而拟杆菌门和变形菌门则明显多于对照组。有研究通过对PE孕妇和健康孕妇孕晚期及产后的肠道菌群组成进行比对,在属水平上发现8种有明显差异的菌群,其中在PE孕妇体内数量增加的包括布劳特氏菌、瘤胃球菌、梭杆菌、嗜胆菌,数量减少的包括粪杆菌、吉米菌、小杆菌、艾克曼菌及甲烷短杆菌,这些菌群的改变与新生儿Apgar评分、新生儿出生体重及母血IL⁃6水平、脂多糖水平均相关,并且证实了孕晚期菌群的改变在产后 6 周内仍持续存在[15]。Chen等[13] 则将PE患者和健康孕妇体内的肠道微生物分别移植到小鼠体内,发现接受了 PE组肠道菌群移植的小鼠血压升高且在受孕后升高更明显,除此以外接受PE菌群移植的小鼠还在妊娠期表现出了如蛋白尿、胎盘胎儿重量减轻、胎盘炎症等一系列病理改变,由此可见,肠道菌群失调是引起 PE发生发展的重要机制之一,且菌群紊乱引起的胎盘炎症也是其中一个重要环节,在明确了这样的因果关系后,菌群移植或可成为PE预防和治疗的新思路。

  • 2.3 妊娠合并甲状腺功能减退

  • 既往许多研究证实肠道菌群在人体甲状腺功能的正常维持中起重要作用[16],而妊娠合并甲状腺功能减退是妊娠期最常见的甲状腺相关疾病[17]。 Wang 等[18] 对怀孕后发生甲状腺功能减退的孕妇与甲状腺功能正常孕妇的肠道菌群组成进行了对比,发现甲状腺功能减退孕妇肠道菌群中罗氏菌属、巴斯德氏菌目、毛罗菌属、普氏菌属及紫单胞菌科的丰度显著升高,而甲状腺功能正常孕妇梭菌属及布劳特氏菌属丰度较高。另外,自身免疫性甲状腺疾病 (autoimmune thyroid disease,AITD)是妊娠期甲减最主要的病因之一[19],而甲状腺过氧化物酶抗体(thy⁃ roid peroxidase antibody,TPOAb)是诊断 AITD 的最灵敏、最准确的生物学指标之一[20],国内一项研究对比了妊娠晚期甲减合并TPOAb 异常的孕妇与甲减但 TPOAb 正常的两组孕妇的肠道菌群组成的差异,发现TPOAb 阳性组孕妇肠道菌群β 多样性低于 TPOAb 阴性组,TPOAb 阳性组孕妇肠道菌群中双歧杆菌属的相对丰度明显增加,而毛螺菌属、嗜血杆菌属等的相对丰度较阴性组明显降低,提示孕期肠道菌群的改变可能引起AITD[21]。由此可见,微生物群的变化是影响妊娠合并甲状腺功能减退发生发展的因素之一。

  • 2.4 自发性早产与先兆早产

  • 微生物组与自发性早产的相关性经过多年研究,已经得到了广泛认可,但普遍认为与早产相关的微生物主要起源于生殖道[22],尽管如此,自发性早产仍无有效解决方法,因此,部分研究者将研究方向由生殖道微生物拓展到母体各部位的微生物,其中肠道菌群也是重要的一部分。Shiozaki等[23] 通过末端限制性片段长度多态性(terminal restriction fragment length polymorphism,T⁃RFLP)分析发现自发性早产孕妇较足月产孕妇,其肠道微生物群中的梭状芽孢杆菌亚群 Ⅷ、梭状芽孢杆菌群Ⅳ、梭状芽孢杆菌亚群a和类杆菌水平显著降低,而乳酸杆菌水平显著增高。国内一项研究将21例出现先兆早产症状的孕妇与健康孕妇的肠道菌群进行了比较,结果显示两组肠道菌群的结构分布并无明显差异,但病例组厚壁菌门丰度上升,变形菌门、放线菌门、拟杆菌门丰度下降,先兆早产孕妇毛螺旋菌属、丹毒丝菌科富集,而健康孕妇没有找到明显富集的特征菌属[24]。相较于GDM和PE等,母体肠道菌群与早产之间的研究相对较少,因此,未来需要更多研究证实孕期肠道菌群变化是否是分娩激活路径中的重要环节。

  • 2.5 妊娠期肝内胆汁淤积症(intrahepatic cholesta⁃ sis of pregnancy,ICP)

  • ICP 是妊娠期常见的肝脏疾病[25],其发生机制至今尚未完全明确。肠道菌群参与多个胆汁酸代谢的过程[26],因此了解肠道菌群的潜在变化也成为了理解ICP发生发展的有效途径之一。Li等[27] 通过比较ICP孕妇和健康孕妇的孕晚期肠道菌群组成发现,ICP孕妇肠道中布氏杆菌属、柠檬酸杆菌属、链球菌属及肠杆菌科、明串珠菌科的丰度显著高于健康孕妇,国内另一项研究则发现,在ICP孕妇中丰度显著降低的菌群如粪杆菌属、霍氏真杆菌属会产生短链脂肪酸,而在ICP孕妇中丰度显著增高的菌群如副杆菌属和嗜胆菌属则与胆汁酸代谢相关[28]。而Zhan等[29] 进一步研究了发生严重ICP的孕妇,发现其肠道菌群中大肠杆菌志贺菌属、奥尔森菌属和 Turicibacter 丰度明显增加,且这些严重 ICP 的孕妇体内不饱和脂肪酸的生物合成和丙酸代谢增强。综合上述研究结果,肠道菌群失调与胆汁酸代谢、脂质代谢等过程密切相关,在ICP的发生发展过程中起重要作用,但想要由此阐明ICP的发生机制还有待更深入的研究。

  • 2.6 产后抑郁

  • 早在20世纪末,美国神经学家迈克·格尔松教授就提出肠道菌群可经迷走神经系统、免疫系统等多种途径影响大脑功能,这一概念被称为“脑肠轴”。Aizawa 等[30] 通过研究发现,抑郁症患者相对健康人群,其肠道中乳酸杆菌、双歧杆菌含量明显减低。而国内1项研究分别对比了产后抑郁产妇与健康产妇在产后4周、8周和12周的粪便样本,在产后4周(抑郁症状表现较重时),相比健康产妇,产后抑郁产妇粪便样品中的α⁃变形菌、草酸杆菌丰度增高,其中α⁃变形菌的丰度直至产后12周仍持续高于健康对照组,而草酸杆菌的丰度则在产后8周、12周抑郁症状明显缓解时与健康产妇没有明显差异,由此推测草酸杆菌可能在抑郁情绪的出现与消失中起一定作用[31]

  • 3 益生菌防治妊娠相关疾病的研究进展

  • 鉴于肠道菌群紊乱与妊娠期相关疾病的发生发展都有着紧密关联,益生菌用于预防和治疗这些疾病也逐渐成为未来趋势,关于益生菌预防和治疗妊娠相关疾病的有效性,国内外也开展了大量研究。对于GDM,Taylor等[32] 通过对多项临床对照研究的结果进行分析,证实了补充益生菌有效改善了 GDM孕妇的胰岛素抵抗,但对空腹血糖或低密度脂蛋白胆固醇水平没有显著影响,因此在常规使用之前,还需要对特定细菌及特定用量进行进一步的高质量研究。Dolatkhah 等[33] 研究证实补充富含嗜酸乳杆菌 LA⁃5、双歧杆菌 MBB⁃12、嗜热链球菌⁃31 和保加利亚德氏纤毛乳杆菌LBY⁃27的益生菌制剂可改善GDM受试者的胰岛素抵抗。Zheng等[34] 通过一项基于16S rRNA的动物对照实验证实了补充鼠李糖乳杆菌(Lactobacillus rhamnosus GG,LGG)和动物双歧杆菌亚种可通过改善肠道菌群的生物多样性来明显改善大鼠的空腹血糖水平。LGG 还被证实对预防孕酮诱导的肝内胆汁淤积和肝损伤有效,未来有望用作为ICP的预防措施或辅助疗法[35]。而挪威的一项前瞻性队列研究发现,孕早期摄入益生菌降低了早产风险,孕晚期则降低了PE风险,摄入益生菌有望成为一项改善孕产结局的公共卫生策略[36]。对于甲状腺功能,已有研究表明益生菌在甲状腺疾病治疗中有一定效果,可作为辅助治疗的手段[37],但对于是否可用于妊娠期甲状腺功能减退还有待进一步明确。同样,益生菌用于产后抑郁防治的效果也得到了一定证实,Slykerman等[38] 就通过一项随机对照研究发现妊娠期补充LGG HN001可以有效降低产后抑郁的发生率。

  • 4 展望

  • 肠道菌群参与人体的各类代谢、免疫调节及炎症的发生等,在妊娠期各类相关疾病的发生发展过程中都起了重要作用,除上述几种妊娠相关疾病以外,其他如胎膜早破、妊娠剧吐等疾病是否与母体肠道菌群存在关联尚无定论,因此还需要更多研究来探索其中奥秘。益生菌用于妊娠相关疾病的防治存在巨大潜力,但目前研究对其有效性及安全性仍存在争议,不同疾病对应的特异性有效菌种、用量、干预时机等都没有明确定论,因此要想实现益生菌在临床的广泛应用还有很长一段路要走。未来研究还需要更深入更清晰地探索肠道菌群影响孕妇健康的作用机制,并以此为基础,展开对益生菌的更高质量研究,为妊娠相关疾病的有效防治开拓一条新道路。

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