儿童肠道菌群生理功能及相关疾病的研究进展

1、肠道菌群生理功能及相关儿童疾病的研究进展肠道是体内细菌定植的主要场所，胃肠道栖息的细菌大约重1000g，大约30个属，400500多种，总体数量在1014以上，比人体细胞的10倍还多；肠道定植的细菌具有数量巨大、多样化、复杂性和动态性的特点，肠道菌群（intestinal microflora）是目前人体微生态学研究关注的核心。随着认识的深入和分子生物学技术的应用，证实肠道菌群对儿童重要的生理功能诸如免疫、代谢、营养等的发育成熟过程起着决定性的作用，与感染性疾病、肠道慢性炎症性疾病、过敏性疾病、自身免疫性疾病及代谢性疾病等密切相关。本文对近年来儿童肠道菌群生理功能及相关儿童疾病的研究新进展进行

2、综述。1肠道菌群的生理功能 肠道微生态承载着人类后天获得基因，参与人类正常生理和疾病病理过程，与人体健康密不可分。研究表明肠道菌群能防御感染与增强肠道屏障功能，对外来致病菌及条件致病菌的入侵具有较强的生物拮抗作用；肠道菌群可合成维生素并促进营养素吸收，刺激宿主免疫器官及其功能的发育；肠道菌群所生成的氨、硫化氢、胺、毒素等代谢产物是有害的，也促使机体完善免疫机制以清除之。近年来在肠道菌群对机体代谢和免疫作用方面特别引起关注。1.1 肠道菌群与营养代谢功能肠道菌群在食物的消化吸收方面发挥着重要作用。来自欧洲分子生物学实验室的科学家发现肠道菌群有三种不同的优势族群类型，其中Bacteroides（拟

3、杆菌属）擅长分解碳水化合物，而Prevotella（普雷沃菌属）则倾向于分解肠道黏液，和Ruminococcus（瘤胃球菌属）会帮助细胞吸收糖类1，都是有助于食物的消化吸收。大量证据表明肠道菌群能竞争性消耗致病菌的营养素，促进钙、镁和铁等无机盐的吸收，参与了机体多种等维生素的合成；更重要是参与蛋白质、肽和氨基酸的代谢并具有改善脂质代谢的作用：肠道菌群可利用特有的酶类 (如半乳糖苷酶等)分解未被上消化道水解吸收的营养物质，生成乙酸、丙酸和酪酸等短链脂肪酸(SCFA)，后者既能作为能量底物被机体利用（如酪酸提供结肠上皮能量，乙酸和丙酸可随门静脉到达肝脏和外周器官，成为糖原和脂肪合成的底物），也能调

4、控人体抗组氨酸脱乙酰酶基因表达发挥抗癌作用，对G蛋白耦合受体基因表达发挥作用进而调控外周代谢器官脂肪合成2。在研究肥胖及其相关代谢性疾病的过程中发现肥胖、糖尿病或者非酒精性脂肪肝的动物或成人身上都伴随着肠道菌群数量或组成的变化。动物模型实验表明肠道拟杆菌属增加会增加积聚和肥胖，婴儿期肠道较高的脆弱拟杆菌和葡萄球菌的减少与学龄期较高体重指数有关3。Kalliomaki等4为了明确早期的肠道菌群是否与儿童肥胖相关，通过对25名超重的7岁儿童进行前瞻性研究，发现与体质量正常的同龄儿童相比，肠道双歧杆菌减少，肠球菌增多。Furet等5分析了肥胖者行减肥手术前后粪便菌群变化，结果发现普拉梭菌术前含量较低

5、，且与炎症物质呈负相关，术后该细菌保持增长趋势，与宿主摄入食物无关。Larsen等6通过荧光定量PCR检测2型糖尿病患者肠道菌群发现厚壁菌属、梭菌属明显减少，有更丰富的变形菌，且该菌属与血糖水平成正相关，表明肠道菌群可能参与糖尿病的形成。肠道菌群可能通过影响能量吸收、脂肪代谢以及细菌内毒素等途径引发肥胖和代谢紊乱。随着生活条件的改变，人类生活习惯和饮食结构也随之改变，长期高脂饮食导致能量过剩引起肥胖；高脂饮食可能与肠道菌群相互作用导致炎症：高脂饮食改变了肠道菌群的结构，肠内双歧杆菌减少，肠道通透性增加，肠上皮细胞合成乳糜颗粒增多，促进脂多糖吸收和运转到靶组，引起游离脂肪酸水平升高及炎症因子表达

6、，导致糖尿病等代谢紊乱性疾病增多。Cani等7发现肠道双歧杆菌数量明显增多的大鼠，其内脏、附睾和皮下脂肪含量都有明显减少，与肥胖和糖尿病发病呈正相关的血浆促胰岛素多肽的水平也显著降低；双歧杆菌还能够促使肠道前体细胞向分泌细胞分化，使得血浆中的胰高血糖素样肽1和胰高血糖素样肽2水平明显升高。肥胖患者肠道菌群结构和发酵产物改变，引起一系列代谢过程变化，导致胰岛素抵抗；结肠细菌发酵膳食纤维释放SCFA，进一步提高机体能量摄取，调控外周代谢器官的脂肪合成；肠道菌群结构改变通过固有免疫机制导致肠粘膜屏障损伤和非酒精性脂肪肝等21。1.2肠道菌群与免疫功能 肠道菌群与肠粘膜构成了人体最重要的外周免疫器官。

7、维持肠道细菌与肠上皮稳态的免疫机制：粘膜层、肠上皮抗菌多肽、浆细胞分泌的分泌性免疫球蛋白（sIgA）。SIgA是免疫系统发育的一个重要因素，SIgA表达对肠道菌群与宿主体内平衡的建立以及对胃肠道菌群的免疫耐受有重要作用8。肠道正常菌群和食物传播的病原微生物都是通过改变新生儿期Th2细胞的活性来增强SIgA介导肠表面屏障和促进口服耐受，从而在日后形成细胞因子新的平衡9。树突状细胞是一种极其重要的免疫细胞，Latvala等10研究发现鼠李糖乳杆菌、双歧杆菌、嗜热链球菌等均可刺激树突状细胞表达CD86和HEHLA-DR，促进其成熟，但不同细菌促进其分泌细胞因子不同。肠道菌群也调控着NK细胞、嗜酸性细

8、胞、Treg细胞等T细胞亚群分化成熟11-13：肠道的革兰氏(+)菌群是诱导IL-17分化成熟的刺激剂，丝状片段菌(SFB)是诱导IL-17分化成熟的主要菌种，能增强小肠对病原菌鼠类柠檬酸杆菌的拮抗；梭菌属是诱导结肠粘膜表达Foxp3+ Treg细胞分化的功能菌群，改善结肠粘膜炎症和IgE介导的过敏应答；婴儿双歧杆菌能通过刺激树突细胞促进Treg细胞分化增殖。肠道细菌的代谢产物同样参与免疫系统的调节：Vinolo等14证实短链脂肪酸（SCFA）可影响白细胞向炎症迁移和破坏病原微生物的能力，这种作用通过细胞因子 (TNF-, IL-2, IL-6, IL-10)、花生酸类和细胞趋化因子的生成来实

9、现。 已有证据表明肠道菌群促进出生后肠道黏膜免疫系统和全身免疫系统的发育成熟，与日后发生过敏、肥胖和糖尿病等免疫相关性疾病有关。Olszak等15 研究者发现新生无菌鼠肠粘膜下层和肺组织蓄积大量NK细胞，提高了组织炎性应答，提高了IBD和过敏症的易感性，而植入肠道菌群，通过诱导CXCL16表达，抑制NK细胞在肠粘膜和肺组织蓄积，结论是初生早期的微生物暴露可限制NK细胞在肠粘膜和肺组织蓄积，调控宿主对IBD和过敏症的易感性。肠道菌群与宿主免疫系统的相互作用既可以导致B细胞的损害而增加1型糖尿病的风险，也可以通过细菌的脂多糖等引起代谢性炎症16。2.菌群紊乱相关的儿童疾病肠道菌群与健康密切相关，菌

10、群与人体之间保持动态平衡能有效防止肠道内细菌及内毒素易位；当正常的微生物群落受机体及外环境影响，微生态平衡遭到破坏可使人体致病。腹泻病和慢性便秘是儿童常见消化道疾病，其与肠道菌群紊乱的关系及益生菌治疗的有效性已广为所知。坏死性小肠结肠炎以早产儿多见，早年的研究认为肠道到正常菌群定植延迟是发病因素之一；最近的研究发现新生早产猪经过抗生素处理NEC发生率显著增加，提示抗生素使用与NEC有关17，而荟萃分析显示给予胎龄小于34周体重低于1500 g的早产儿生后10天内肠内益生菌7天以上可减少30%的NEC发病率并减少死亡18。幽门螺杆菌(HP)感染可引起食管返流、胃炎、消化道溃疡等疾病，也可导致营养

11、不良和生长发育迟缓，在年龄稍大儿童中较为常见，而发展中国家感染率更高；经典的三联根治疗法虽可控制HP感染，也打破了肠道菌群的动态平衡；研究证实益生菌尽管在增加儿童HP的根除率方面有争议，但可纠正菌群失衡并减轻药物治疗的副作用19。 炎症性肠病（IBD）是一组原因不明的慢性非特异性胃肠道炎症性疾病，包括克罗恩并和溃疡性结肠炎，其发病原因尚不明确。Hviid等20进行的前瞻性队列研究结果表明抗生素应用是导致儿童IBD发生的非常重要的环境因素。Sokol等21证实IBD患者肠道菌群中厚壁菌和拟杆菌的比例减少而变形菌比例增高。另有研究表明克罗恩的儿童肠道菌群存在双歧杆菌和乳酸杆菌的降低22。 肠易激综

12、合征（IBS）指的是一组包括腹痛、腹胀、排便习惯改变和大便性状异常、粘液便等表现的临床综合症，持续存在或反复发作，是最常见的一种功能性肠道疾病；尽管IBS发病机制尚不清楚，肠道微生态失衡在腹泻型和便秘型都是有关的：与健康人比较患者肠道菌群主要以乳酸菌属、链球菌属、瘤胃球菌属和韦荣氏球菌属占优势23；Saulnier等人24采用基因芯片检测22例学龄期和青春期前的IBS儿童，与正常儿童相比IBS儿童拥有大量的变形菌，其中有经常腹痛的还拥有一种特殊的菌种:Alistipes。婴儿肠绞痛（Infantile Colic）也可以看做功能性肠道疾病，表现为婴儿阵发性烦躁不安，极度痛苦喊叫，腹膨胀，排气多

13、，一般于生后24周发病，大多到34个月痊愈。还没有学者对引起婴儿肠绞痛的原因作出肯定的回答，可以确定与婴儿消化道发育不完整有关。Savino等25研究了50例纯母乳喂养的肠绞痛婴儿，而给予罗伊氏乳杆菌干预后哭闹时间明显缩短，同时粪便中乳酸杆菌显著增加而大肠杆菌及氨类均有减少。乳糜泻（coeliac disease），又称麦胶性肠病，在 HYPERLINK app:bk:%E5%8C%97%E7%BE%8E 北美、 HYPERLINK app:bk:%E5%8C%97%E6%AC%A7 北欧、澳大利亚发病率较高，国内很少见。发病高峰年龄主要是儿童与青年，在婴幼儿主要表现为生长迟缓、体重下降、 H

14、YPERLINK app:bk:%E5%91%95%E5%90%90 呕吐、 HYPERLINK app:bk:%E8%85%B9%E6%B3%BB 腹泻、 HYPERLINK app:bk:%E8%85%B9%E7%97%9B 腹痛、 HYPERLINK app:bk:%E8%85%B9%E8%83%80 腹胀及易激惹。现认为发病是 HYPERLINK app:bk:%E9%81%97%E4%BC%A0 遗传、 HYPERLINK app:bk:%E5%85%8D%E7%96%AB 免疫和麦胶饮食相互作用的结果，患者对含麦胶（俗称面筋）的麦粉食物异常敏感，是一种Th1介导的免疫紊乱疾病。Pa

15、lma等26研究有遗传风险的婴儿发现肠道有大量的脆弱拟杆菌和葡萄球菌，而双歧杆菌spp及长双歧杆菌等数量较少。 肥胖和糖尿病等相关代谢性疾病的发病率在全球范围呈直线上升趋势，遗传、环境、行为和心理社会因素已被证明与此类疾病的形成有重要作用。最新研究证明存在于肠道的微生物是构成肥胖的重要环境因素。母乳中含有丰富的双歧杆菌，母乳喂养的婴儿日后发生超重和肥胖的机率减少，母乳喂养的时间与超重的发生率成负相关；而母亲孕期BMI、胎儿生长方式以及婴儿期使用抗生素等均与随后童年时期的肥胖症风险有关26。肥胖和糖尿病患儿肠道菌群均有异常：最近一项研究证实哈萨克女性肥胖儿童肠道菌群 Bacteroidetes

16、减少，而拟杆菌门/厚壁门菌比例下降26；糖尿病患者肠道菌群中厚壁菌属、梭菌属明显减少，变形菌更加丰富6。对138 例3周到一岁婴儿的前瞻性研究显示早期肠道富集脆弱拟杆菌而葡萄球菌较低与学龄前期的肥胖症风险有相关3。Luoto等29发现孕期妇女添加乳酸杆菌和双歧杆菌可以减少妊娠糖尿病和降低高体重婴儿的出生风险。过敏性疾病是当今世界重大卫生学问题，儿童常见疾病有湿疹、特异性皮炎、哮喘等，“卫生学说”是解释过敏性疾病上升的重要机制，大多数学者认同与“生活方式西方化”致肠道菌群减少有关，0-1岁应用抗生素与儿童期哮喘、过敏性鼻炎、结膜炎及湿疹等过敏症发生率增加显著高度相关30。流行病学资料显示过敏患儿

17、较之非过敏儿童有较高水平的梭状芽孢杆菌，而双歧杆菌等相应减少31；Bisgaard 32的课题组研究证实婴儿期的肠道细菌多样性降低与生后6年内变应性致敏、过敏性鼻炎和外周嗜酸细胞增高有关；Pelucchi等33人对怀孕期妇女或婴儿生后早期给与益生菌，结果婴儿期的特异性皮炎的发生率明显降低。自闭症（Autism）也称孤独症，是一种广泛性发展障碍，社会交流障碍是自闭症患儿面临的最大问题。Finegold等34采用焦磷酸测序法对33例自闭症患儿的肠道菌群进行观察，发现严重自闭症患儿拟杆菌门、放线菌门明显增高，而粪便中呈现较高水平的脱磷孤菌属（Desulfovibrio）和普通拟杆菌（Bacteroi

18、des vulgatus），后者的特殊变化是否发病的原因抑或是疾病的结果尚不能判定，但肠菌异常所致代谢紊乱可能是发病机制之一。囊性纤维化 (Cystic fibrosis)是遗传疾病，以肺部和消化系统所受的影响最为严重，白种人多见，非洲人和亚裔人则较少患病。有学者发现囊性纤维化患儿生命早期的肠道菌群也有异常，而给予益生菌干预可以减少肠道的炎症和延迟呼吸道损伤修复，认为肠道菌群紊乱与本病有关联，具体机制仍需研究35。综上所述，肠道作为机体最大的免疫器官和微生态体系，直接影响机体的正常生长发育、患病率及远期健康，保持其功能的正常发挥至关重要。儿童肠道菌群具有动态、脆弱的特点，早期菌群与机体免疫系统

19、和代谢发育有密切相关；肠道菌群失调可诱发多种疾病，多种疾病又可导致肠道菌群失调，互为因果；以肠道细菌为靶点研究儿童相关疾病将有良好的前景。参考文献：Arumugam M, Raes J, Pelletier E, et al. HYPERLINK /pubmed/21508958 Enterotypes of the human gut microbiome.Nature，2011，473(7346):174-80. HYPERLINK /pubmed?term=Tremaroli%20V%5BAuthor%5D&cauthor=true&cauthor_uid=22972297 Tremar

20、oli V, HYPERLINK /pubmed?term=B%C3%A4ckhed%20F%5BAuthor%5D&cauthor=true&cauthor_uid=22972297 Bckhed F. Functional interactions between the gut microbiota and host metabolism. HYPERLINK /pubmed?term=Tremaroli%20V%2C%20Backhed%20F.%20%20Nature%20%202012%3B489%3A242-249 l # o Nature. Nature, 2012, 489(

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