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【协和医学杂志】口腔菌群与儿童生长发育

发布时间:2025-06-06 11:33:08  浏览量:4

专家论坛

1212口腔菌群作为人体第二大多样化微生物群,其生态失衡可通过“口腔-全身轴”参与多种病理过程。在成人人群中,不同部位的动脉粥样硬化斑块中存在牙龈卟啉单胞菌、放线聚集杆菌等[1],而龋源性微生物群的异常增殖则可破坏口腔黏膜屏障的通透性,进而介导条件致病菌在呼吸道定植,与肺炎链球菌感染及气道高反应性显著相关[2]。儿童时期是生命早期发育的关键窗口期,在这一时期口腔菌群的定植与演替具有高度可塑性,其特征对儿童神经发育、免疫成熟等关键生理过程具有决定性影响[3],早期口腔菌群定植的破坏和健康口腔菌群建立受阻可能对儿童全身生长发育产生不利影响。因此,深入了解口腔菌群在儿童生长发育中的作用,对儿童的健康成长意义深远。在“健康中国2030”战略框架下,“主动健康”模式正逐步从理论转化为实践。该模式强调以预防为导向、数据为驱动的健康管理策略,其核心在于通过多组学生物标志物监测(如唾液微生物组检测)实现疾病风险的前瞻性预警[4]。针对儿童群体,基于口腔菌群的主动健康干预已展现出一定的应用潜力,本文就口腔菌群对儿童生长发育的影响展开综述,并列举了相关主动健康策略,旨在为儿童健康管理提供理论依据和实践指导。

1

儿童早期口腔菌群的定植与演替

在0~6岁儿童早期,口腔菌群的组成会发生显著变化,并且受遗传因素、产妇健康状况、分娩方式、喂养习惯、抗生素使用等多种因素影响[5-6]。婴儿在出生时及出生后数小时内,其口腔通过产道、母乳喂养、与父母及医护人员的接触以及呼吸接触到大量微生物。随着婴儿的成长,口腔菌群的多样性和丰富度逐渐增加。Dzidic等[7]采用高通量测序技术对90名儿童7岁前唾液样本中的微生物组成进行研究发现,在牙齿萌出前,口腔黏膜表面是细菌定植的主要部位,链球菌、韦荣菌属和乳杆菌属较为常见,其中链球菌因其能够黏附在上皮细胞且是母乳中的主要菌群之一,丰度较高。而牙齿萌出为口腔菌群提供新的粘附位点,变形链球菌在这一阶段加速定植[8]与此同时,与年龄增长相关的口腔菌群 α 多样性稳步增加,个体唾液样本中微生物的丰富度和物种分布均匀性随时间推移而增加[9]。牙齿萌出后,牙菌斑菌群形成具有独特结构和功能的口腔群落。在对有龋齿和无龋齿的学龄前儿童进行测序比较时发现,无论龋齿状态如何,唾液和斑块样本之间的微生物组成均存在显著差异。在属水平上,儿童唾液中含量最高的两个属是链球菌属和韦荣菌属,而在斑块中含量最高的属是韦荣菌属、链球菌属、放线菌属、硒单胞菌属和钩状菌属[10]。牙周主要致病菌牙龈卟啉单胞菌最早可以通过母婴垂直传播进入儿童口腔,在牙齿萌出后比例增加[11]。

2

口腔菌群对儿童成长发育的影响

2.1

骨骼

儿童期是骨骼发育的关键时期,口腔菌群可通过代谢、免疫及内分泌途径参与骨骼发育的调控。龋病相关微生物(如变形链球菌、乳杆菌)通过代谢碳水化合物产酸,破坏牙釉质,导致咀嚼效率降低,进而影响营养物质的吸收,干扰骨骼发育所需的钙、磷代谢以及维生素D稳态[12-14]。临床研究表明,重度龋齿患儿血清中的维生素D、钙和白蛋白浓度显著低于健康儿童[15-16]

此外,牙周致病菌(如牙龈卟啉单胞菌)可通过激活宿主免疫反应,诱导肿瘤坏死因子-α(TNF-α)、白细胞介素(IL)-1β等促炎因子的系统性释放,形成全身慢性低度炎症环境。

在牙龈卟啉单胞菌诱导的实验性牙周炎模型中,血清中促炎细胞因子水平显著升高[17],可通过血液循环作用于骨骼微环境,一方面通过核因子κB(NF-κB)受体激活剂(RANK)/RANK配体(RANKL)信号轴促进破骨细胞分化;另一方面通过Wnt/β-catenin信号通路抑制成骨细胞矿化功能,最终导致骨形成-吸收失衡[18]值得注意的是,口腔菌群还可干扰内分泌系统,导致生长激素水平降低,进而影响骨骼发育。在无菌饲养的果蝇模型中,特定菌株的植物乳杆菌可恢复其正常生长,促进生长激素产生,但具体分子通路仍需进一步探究[19-20]

2.2

神经系统

近年研究表明,口腔菌群与神经系统的发育和功能密切相关,尤其在自闭症谱系障碍(ASD)、注意缺陷多动障碍(ADHD)、癫痫及神经退行性疾病等的病理进程中发挥关键调节作用[21-24]ASD是以社交沟通障碍和受限、重复的行为为特征的神经发育障碍[25]。Qiao等[26-27]通过16S rRNA基因测序技术比较了ASD患儿与健康儿童的口腔菌群特征,发现前者的口腔菌群多样性显著降低,尤其是附着在牙菌斑上的微生物组成与健康儿童存在显著差异。ASD源口腔菌群移植小鼠模型实验表明,其口腔及肠道菌群组成发生显著改变,并表现出典型的自闭症样行为(如社交回避、焦虑和重复的行为),同时伴随神经信号传导异常[28]此外,ASD患儿口腔菌群组成的特定变化与其症状严重程度呈显著相关性[29]。值得注意的是,ASD相关口腔菌群失衡还将增加帕金森病和阿尔茨海默病的发生风险[30-32],这提示对口腔菌群动态变化进行监测,或可作为神经发育障碍早期筛查的潜在生物标志物,具有重要的转化医学价值。ADHD作为高发性神经行为障碍,全球儿童患病率约为7.6%[33-34]。近年研究发现,ADHD患者的口腔菌群显著失衡,其中牙龈卟啉单胞菌可通过Toll样受体4(TLR4)/NF-κB通路,诱导促炎因子释放、补体激活及脑内炎症反应,从而增加ADHD的发病风险[35-37]。此外,口腔菌群还可通过调节脑-肠轴的色氨酸代谢途径,减少5-羟色胺(5-HT)合成,加剧ADHD患者的冲动行为[38-39]。干预性研究表明,复合益生菌制剂可能通过独立于肠道菌群调控的机制,降低ADHD的患病风险[40-41],这提示口腔菌群在ADHD发病过程中发挥潜在作用。然而,口腔菌群对ADHD的直接作用机制及其临床转化价值仍需通过多组学分析及随机对照试验深入验证。癫痫是一种以反复、无诱因的癫痫发作为特征的慢性神经系统疾病[42]。基于16S rRNA测序的病例对照研究显示,癫痫患儿的口腔菌群中厚壁菌门/拟杆菌门比值显著下降,放线菌门水平升高[21]。癫痫患儿口腔菌群多样性较健康对照组显著增加,且二者多个菌属的丰度存在显著差异,该团队进一步采用随机森林分析,构建了基于口腔菌群特征的癫痫诊断模型,该模型在测试队列中表现出较高的诊断准确性[43]。因此,口腔菌群的变化可能与癫痫的发生密切相关。此外,口腔致病菌可能通过影响β-淀粉样蛋白(Aβ)相关病理机制加速神经退行性病变进程,以唐氏综合征患者为例,其淀粉样前体蛋白(APP)编码基因过表达,而牙龈卟啉单胞菌的牙龈蛋白酶可切割APP产生Aβ1-42片段,从而导致海马区淀粉样斑块密度增加[44]。同时,其代谢产物脂多糖(LPS)通过破坏血脑屏障,促进外周巨噬细胞源性Aβ在脑内沉积,并激活小胶质细胞的TLR4/NF-κB通路,从而导致神经炎症[45-47]。未来仍需进一步探索口腔菌群在神经系统发育早期的具体作用机制,以及如何通过调控口腔菌群来预防神经系统发育异常。

2.3

消化系统

消化系统的正常发育是儿童健康成长的基础,而口腔作为消化系统的解剖学起始部位,其微生物组通过口腔-肠轴对远端肠道稳态进行系统性调控[48]。研究表明,口腔菌群可通过吞咽途径进入消化道,其中牙周致病菌(如牙龈卟啉单胞菌、放线聚集杆菌和变形链球菌)能够耐受胃酸环境并在肠道定植,进而引发肠道菌群失衡,破坏肠黏膜屏障完整性[49-50]。动物实验证实,经口灌胃给予C57BL/6小鼠牙龈卟啉单胞菌(1×109CFU/只)后,该菌可于3 h定植于回肠,16 h迁移至结肠,显著改变肠道菌群结构[51]此外,牙龈卟啉单胞菌经口服后,可使肠系膜淋巴细胞中的辅助性T细胞17(Th17)比例增加,从而影响肠道免疫系统[52]。牙周炎源唾液移植模型小鼠肠道中卟啉单胞菌科及梭杆菌门显著富集,伴随促炎因子(IL-1β、IL-6)及趋化因子(集落刺激因子1)mRNA表达上调,以及紧密连接蛋白组成改变,使肠道炎症反应增强和黏膜通透性增加[49,53-54]。肠黏膜受损增加了抗原暴露,间接激活免疫细胞并上调全身炎症因子的表达。值得注意的是,唾液链球菌作为口腔早期定植菌,在肠道微生态中也扮演重要角色,其可下调小肠上皮细胞NF-κB信号通路,参与调节肠道炎症反应和维持肠道稳态[55-56]。此外,在170例乳牙牙髓感染样本中分离出活性幽门螺杆菌,这提示口腔-胃菌群传播可能是抗生素治疗后胃病复发的重要机制[57]

2.4

心血管系统

口腔致病菌可通过多种途径影响心血管疾病的发生和发展。例如,牙周致病菌伴放线聚集杆菌释放的白细胞毒素A(LtxA)能够通过诱导丝切蛋白去磷酸化及肌动蛋白解聚,直接导致白细胞死亡[52]。此外,LtxA还可破坏中性粒细胞的酶功能,引起过度瓜氨酸化,并释放异常蛋白质,激活自身免疫反应,促进动脉粥样硬化的发生[58]。牙周致病菌释放的促炎因子进入血液循环后,可能损伤血管内皮功能,影响血管通透性、凝血功能及免疫反应,从而增加动脉粥样硬化的发生风险[59-60]除牙周致病菌外,龋齿的主要致病菌(变形链球菌)能够侵入人脐静脉内皮细胞,显著增加感染性心内膜炎的发生风险,特别是患有先天性心脏病或既往有感染性心内膜炎病史的儿童[61]。值得注意的是,高血压患者的口腔菌群组成与健康对照组存在显著差异[62],口腔菌群的生态失衡(疾病所致)或破坏(使用抗菌漱口水或抗生素)可能抑制硝酸盐-亚硝酸盐-一氧化氮途径,减少一氧化氮生成,从而对血压调节产生负面影响[63]

2.5

免疫系统

研究表明,宫内菌群与母体口腔菌群相似,在怀孕期间,宫内菌群会刺激胎儿免疫系统并增强新生儿对母体菌群的免疫耐受性,从而促进产后母体菌群成功定植[64]。口腔菌群通过竞争性抑制和代谢产物(细菌素、过氧化氢)分泌可有效防止病原体的定植,并与唾液中的抗菌成分(溶菌酶、乳铁蛋白)协同作用,共同构成宿主免疫防御的第一道防线[65]。若口腔菌群失衡,则会破坏宿主的免疫稳态,并激活全身炎症反应[66]。有研究对7岁之前出现过敏症状的儿童唾液样本进行基因测序分析,发现患有过敏性疾病(特别是哮喘)的儿童7岁时唾液中菌群的多样性较低,组成差异较大,这可能是由于婴儿期免疫系统受损导致的。此外,溶血性兼性双球菌在过敏儿童中的丰度增加,加氏乳杆菌和卷曲乳杆菌在健康儿童中的丰度增加,这些差异可能影响早期免疫系统的成熟[67]。值得注意的是,微生物代谢产物(如短链脂肪酸)在免疫调节中发挥重要作用,可能影响T细胞分化,促进调节性T细胞增殖,并诱导其分泌IL-10,从而抑制其他效应淋巴细胞的活性[68-69]

2.6

其他

越来越多的研究表明,儿童口腔菌群与呼吸系统、内分泌系统的功能发育密切相关,例如,口腔菌群可通过呼吸道吸入,引发呼吸道感染[70];儿童下丘脑-垂体-肾上腺皮质轴的激活与口腔致龋菌群的计数较高存在相关[71];儿童口腔菌群中厚壁菌门与拟杆菌门的比例与体重增加密切相关[72]。

3

主动健康干预策略

3.1

益生菌

益生菌被定义为“当摄入足够量时,能够为宿主带来健康益处的活性微生物”[73],其作用机制包括抑制有害菌群生长并维持宿主菌群稳态。研究表明,生命早期(尤其是出生后1000 d内)的菌群定植对生长发育至关重要,因此该阶段是益生菌及益生元干预的关键窗口,可优化菌群结构并促进生长发育[73]2019年,Sarmento等[74]通过使用益生菌强化奶酪发现,其可显著影响儿童口腔菌群的组成。2022年,Janiani等[75]指出,短期摄入益生菌牛奶可降低儿童唾液中变形链球菌的水平,但其长期效果并不显著。同年,Staszczyk 等[76]通过持续短期食用益生菌的相关研究发现,其可能延缓儿童龋齿的发生。而Guamán等[77]研究表明,特异性益生菌及其代谢物可减少儿童胃肠道疾病的发生,提高免疫力,并降低其过敏和呼吸道感染的发生率。这提示益生菌在促进口腔健康方面的潜在益处,然而其长期影响仍需通过进一步研究加以明确。

3.2

木糖醇

木糖醇是一种五碳糖醇,能够有效抑制变形链球菌的生长。其作用机制包括增加唾液中的淀粉酶、碳酸酐酶和乳过氧化物酶的活性,从而拮抗葡萄糖的糖酵解。研究表明,经常使用木糖醇与变形链球菌数量减少密切相关,且可能降低牙菌斑的黏附[78]。一项针对128名儿童的临床研究调查了每日固定剂量的木糖醇对唾液中变异链球菌和可见牙菌斑数量的影响,结果表明,木糖醇可以减少儿童唾液中牙菌斑和酸的产生,并干扰口腔菌群的组成[79]。与其他糖类不同,木糖醇无法被变形链球菌加工以获取能量,反而会启动徒劳的能量循环,破坏细菌的正常代谢过程[80]

3.3

漱口水

漱口水作为抗菌剂和抗牙菌斑剂,是口腔护理中一种有效且安全的输送系统。其主要作用是抑制细菌粘附、定植并最终影响细菌生长。绿茶提取物漱口水是一种无毒且安全的漱口水,尤其适合儿童使用。研究表明,绿茶提取物漱口水能显著减少儿童唾液中变形链球菌的数量,并在预防龋齿方面表现出良好的效果[81]。

4

小结与展望

本文系统阐述了口腔菌群在儿童生长发育中的多维调控作用,揭示了其通过代谢、免疫及跨器官通讯网络影响骨骼、神经系统、消化系统、心血管系统、免疫系统等发育的具体机制。现有研究表明,生命早期口腔菌群的定植与演替具有高度可塑性,其失衡可能导致全身性炎症、营养吸收障碍及神经发育异常。因此,在儿童早期预防口腔菌群失衡至关重要。目前,使用益生菌、木糖醇等的主动健康策略已展现出一定的干预潜力,但仍需通过长期临床研究验证其安全性与有效性。未来研究需关注以下方向:

1

深入解析口腔菌群与宿主互作的关键信号通路(如RANKL/OPG、TLR/NF-κB),明确特定菌株的作用机制。

2

开发多组学整合分析技术,动态监测儿童口腔菌群与生长发育指标的关联。

3

探索口腔菌群与肠道、脑等远端器官的协同作用,构建“口腔-全身轴”调控网络。

4

推进个性化干预策略的临床转化,结合人工智能与生物标志物筛查,实现儿童健康风险的早期预警。

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作者贡献

叶蓉蓉、杜函泽负责文献收集整理和论文撰写;陈适、李道伟负责论文修订;潘慧负责论文设计和指导。

作者简介

吉林大学白求恩口腔医学院

叶蓉蓉

吉林大学白求恩口腔医学院2022级硕士研究生。主要研究方向:口腔颌面部组织损伤修复机制研究。

通信作者

吉林大学口腔医院

李道伟

吉林大学口腔医院,主任医师,博士生导师。中国妇幼健康研究会生长发育与代谢专业委员会常委,中华口腔医学会口腔生物医学专业委员会委员。主要研究方向:骨及关节损伤修复,聚焦于探索炎症、衰老调控骨关节重塑机制。

北京协和医院

潘慧

内分泌科主任医师,教授,博士生导师。担任中华医学会行为医学分会行为医学专业委员会主任委员等职务。研究方向:内分泌与代谢性疾病。

会议通知

2010年创刊,国家卫生健康委主管、中国医学科学院北京协和医院主办的综合性医学期刊,已被评为“中国科技核心期刊”“中国科学引文数据库(CSCD)来源期刊”和“中文核心期刊要目总览(北大中文核心)期刊”,被 Scopus 和 DOAJ 数据库收录,入选“中国科技期刊卓越行动计划”项目。

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