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文章信息
- 张雪梅, 袁振亚, 乔嘉凯, 王秀颖, 迪力拜尔·帕尔哈提, 温洪宇
- ZHANG Xue-Mei, YUAN Zhen-Ya, QIAO Jia-Kai, WANG Xiu-Ying, Dilibaier Paerhati, WEN Hong-Yu
- 肠道菌群与抗生素相关性腹泻的关系
- Relationship between intestinal flora and antibiotic-associated diarrhea
- 微生物学通报, 2019, 46(9): 2386-2393
- Microbiology China, 2019, 46(9): 2386-2393
- DOI: 10.13344/j.microbiol.china.180791
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文章历史
- 收稿日期: 2018-10-14
- 接受日期: 2019-01-22
- 网络首发日期: 2019-02-28
肠道菌群是指分布在人体肠道的微生物菌群,它们与人体肠道系统共同构成了肠道微生态,对维持人体肠道正常功能发挥了至关重要的作用[1]。临床上,抗生素能够有效对抗细菌感染和防止病原菌扩散,但随着青霉素等广谱抗菌药物的大量使用,部分细菌会对β-内酰胺类抗生素产生耐药性[2],这可能是由于这些细菌所含青霉素结合蛋白结构的改变、数量的增多、与抗生素亲和力的下降等原因造成的[3]。同时,抗生素对人体内的正常肠道菌群也具有一定负面作用,能够降低肠道微生态的多样性和稳定性,破坏肠道微生态的结构及功能,增加部分疾病发生的风险[4]。
抗生素相关性腹泻(Antibiotic-associated diarrhea,AAD)是由于长期大量使用广谱抗菌药物造成的最常见的药物副作用之一[5]。AAD的发病机制复杂,按照是否由特定的病原菌引起可分为非感染性腹泻和感染性腹泻。非感染性腹泻是由抗菌药物的毒副作用影响肠道消化吸收功能引起的[6],而感染性腹泻通常是由一些特殊的致病菌或条件致病菌引起的[7-8]。临床上使用益生菌或者微生态制剂则是预防和治疗感染性AAD的主要方法之一,可以保护宿主免受病原菌的侵袭,促进宿主的消化吸收和药物代谢等[1, 9]。我们就不同肠道菌群与AAD的关系作一综述,为临床上更精准地预防、诊断和治疗AAD提供参考。
1 肠道菌群与抗生素相关性腹泻的相关性肠道微生物菌群在人类婴儿出生后便会经历巨大的变化,其多样性的改变可能受到众多因素的影响。随着高通量测序技术的发展,越来越多的证据表明肠道菌群的变化与抗生素治疗有关[10]。例如:Dethlefsen等[11]通过在不同时间段对3名健康人肠道菌群的16S rRNA基因进行高通量测序,最终鉴定了3 300−5 700类肠道菌群,发现环丙沙星降低了肠道菌群的丰富度、多样性和均匀度;停止用药后,大部分肠道菌在4周内恢复到处理前的正常水平,但仍有几类肠道菌6个月后也未能恢复正常。进一步的深度测序研究[12]发现,在两个疗程的环丙沙星治疗过程中,抗生素对人体肠道微生物菌群具有快速且非常显著的影响,可以在3−4 d内导致其多样性大幅减少。尽管在结束治疗2 d后,肠道菌群的多样性明显恢复,但与治疗前相比,43类肠道菌数量显著减少,11类肠道菌数量显著增加。同时,Claesson等的研究发现相对于118个未接受抗生素的个体,接受抗生素治疗的43个人的肠道微生物菌群中含有相对比例较大的拟杆菌[13]。此外,通过高通量测序和定量PCR等方法,一项对9名接受抗生素治疗的婴儿肠道微生物菌群的研究发现,相对于健康对照组,抗生素治疗婴儿的肠道中变形菌的比例显著增加,而放线菌的比例显著减少[14]。
抗生素诱导的肠道菌群变化可能导致特定病原菌感染,如艰难梭菌感染(Clostridium difficile infection,CDI)等,从而产生AAD等症状[15]。Knecht等[16]通过测序技术研究了人类肠道微生物组的改变对DNA (总肠道菌群)和rRNA (肠道菌群潜在活性)水平的影响;他们研究发现,与未处理组相比,对于抗生素处理后未出现CDI的患者,不同类型的抗生素处理使肠道菌群在DNA水平上显示显著差异,但在RNA水平上的差异却不明显;而对于抗生素处理后出现的CDI患者,其肠道中部分细菌(不限于艰难梭菌)的数量出现明显变化,并伴随腹泻等临床症状。由此说明,抗生素治疗会改变肠道菌群的种类和潜在活性。此外,Shahinas等[17]通过低容量灌肠进行粪便微生物组移植替代抗生素治疗CDI,并使用16S rRNA基因的深度测序比较了来自CDI患者的移植前后粪便标本的微生物多样性,初步研究发现CDI的临床治愈与肠道菌群多样性和丰富度的增加有关。综上,肠道菌群的变化与抗生素相关性腹泻具有一定的相关性。
2 有害菌能够导致抗生素相关性腹泻 2.1 致病菌与抗生素相关性腹泻不同的致病菌造成AAD的机制不尽相同,下面将对几种主要致病菌的致病机制作进一步综述。
2.1.1 艰难梭菌(Clostridium difficile,CD)艰难梭菌是一种专性厌氧革兰阳性芽孢杆菌,是AAD的主要病原体,它能够产生3种不同的蛋白质毒素:艰难梭菌毒素A (C. difficile toxins A,TcdA)、艰难梭菌毒素B (C. difficile toxins B,TcdB)以及艰难梭菌转移酶毒素(C. difficile transferase toxin,CDT)[18]。TcdA具有肠毒素和弱细胞毒性作用,可以增加肠上皮细胞(Intestinal epithelial cells,IECs)通透性,致使肠上皮屏障功能改变;TcdB为细胞毒素,可以直接损伤肠壁细胞,使肠道黏膜细胞发生凋亡,引起炎症[18]。在分子水平上,TcdA和TcdB分别由位于致病性基因座(A locus of pathogenicity,PaLoc)中的不同基因编码,TcdB的基因结构较TcdA更为简单,且与TcdA之间具有一定的同源性[19]。CDT是一种肌动蛋白-ADP-核糖基化毒素,可以引起肌动蛋白的解聚,使IECs形成与微管相关的突起,增强细菌的黏附性[20]。产生CDT菌株的PaLoc存在非功能性残余,其3ʹ端只含有部分TcdA基因片段,而5ʹ端TcdB基因完全缺失,因此该菌株不产生TcdA和TcdB,但临床上依然可能引起AAD[21-22]。
2.1.2 产气荚膜梭菌(Clostridium perfringens)根据产生的主要毒素不同,产气荚膜梭菌可以分为A−E五种不同类型的菌株,每种类型的菌株分别与不同的疾病相关[23]。其中,编码产气荚膜梭菌肠毒素(C. perfringens enterotoxin,CPE)的A型菌株是食源性和非食源性胃肠道感染的主要病原体,大约有15%的AAD由其导致[24]。CPE是一种在芽孢形成过程中产生并在母细胞裂解后释放的成孔毒素,具有C-末端结合结构域和N-末端毒性结构域,通过与IECs中的紧密连接蛋白Claudin受体结合,募集宿主蛋白寡聚化成大约450 kD的CPE六聚体(CPE hexamer,CH)-1,在膜上形成活性孔。随后CPE能够进入基底外侧膜,造成更多的CH-1活性孔,并进一步寡聚化成大约600 kD的CH-2,造成紧密连接(Tight junctions,TJs)的损伤[25]。同时CH-1活性孔可以直接改变质膜通透性,使大量钙离子流入,介导细胞死亡,从而破坏肠绒毛的完整性,导致肠道损伤和电解质失调,引起腹泻等临床症状[23, 26]。
2.1.3 金黄色葡萄球菌(Staphylococcus aureus)金黄色葡萄球菌引起AAD的主要病原体是耐甲氧西林金黄色葡萄球菌和肠产毒性耐药金黄色葡萄球菌[27-28]。金黄色葡萄球菌能够产生大约20多种葡萄球菌肠毒素(Staphylococcal enterotoxins,SEs),引起各类胃肠道疾病[29]。SEs是一类由附属遗传元件(质粒、原噬菌体等)编码的大约25 kD的耐热性蛋白[29]。其中,SEA和SED在AAD分离株中较为常见,部分AAD分离株还编码其他SEs (包括SEB、SEC和SEE等),这些毒素破坏了肠道上皮细胞的正常结构,形成黄绿色假膜,引起肠道急性渗出性炎症,出现霍乱样腹泻,严重的会进一步引起肺炎和菌血症,甚至死亡[30-32]。此外,AAD分离株还产生一种白细胞毒素(Leukotoxin ED,LukED),能够通过与趋化因子受体CCR5、CXCR1和CXCR2相互作用,对免疫细胞产生细胞毒性,但在AAD中的作用机制还尚不明确[33]。
2.1.4 念珠菌(Candida)引起念珠菌感染的病原体主要是热带念珠菌、白色念珠菌和克柔念珠菌,其中白色念珠菌还对万古霉素和大红霉素有极大的耐药性[34-35]。临床上,联合应用广谱抗菌药破坏了肠道微生态的稳态,使肠道内其他细菌的生长繁殖处于抑制状态,肠道内定居的念珠菌过度繁殖,容易导致由念珠菌感染引起的AAD[36]。同时,念珠菌可以通过分泌天冬氨酸蛋白酶与其他细菌竞争黏附于肠道黏膜表面,并且侵入组织,抑制乳糖酶活性,导致乳糖不耐受,引起一定程度的腹泻[36]。此外,AAD患者肠道内白色念珠菌的过度增殖会导致体内钠、钾和空腹血糖水平的升高,影响内环境的稳态[35]。
2.1.5 产酸克雷伯菌(Klebsiella oxytoca)产酸克雷伯菌引起的AAD常与应用β-内酰胺类、喹诺酮类和氨基糖苷类等抗生素治疗有关,是抗菌药物相关出血性肠炎(Antibiotic-associated hemorrhagic colitis,AAHC)的主要病原体[37]。产酸克雷伯菌可以产生一种非蛋白质类的小分子毒素,对IECs造成细胞毒性,导致IECs的死亡。抗菌药物的使用改变了肠道内环境稳态,导致产酸克雷伯菌在肠道过度繁殖,细胞毒素聚集,使肠黏膜严重损伤,引起AAHC[38]。但对于非出血性AAD,临床研究表明产酸克雷伯菌不是主要的致病因子[39]。
2.1.6 铜绿假单胞菌(Pseudomonas aeruginosa)铜绿假单胞菌通常不认为与AAD有关。然而,Kim等[40]在7例AAD患者粪便中分离出的7种铜绿假单胞菌都对先前给予的抗生素产生抗药性,其中,两名患者在停用抗生素且不接受特异性治疗后停止腹泻,另外五名患者停用抗生素后仍然持续腹泻,但在成功接受抗假单胞菌药物的治疗后腹泻停止,这表明部分AAD可能是由铜绿假单胞菌引起的。
2.1.7 无害梭菌(Clostridium innocuum)最新的一项研究[41]发现在无害梭菌感染的小鼠回肠环中出现了组织损伤、坏死和水肿等症状。同时,由无害梭菌引起的AAD在临床表现为腹泻或更为严重的伪膜性结肠炎,这表明无害梭菌可能作为AAD的病原体发挥潜在作用。
2.2 条件致病菌与抗生素相关性腹泻条件致病菌是指一类长期寄生于人和动物的肠道、口腔、上呼吸道和生殖道等内,正常情况下不致病,参与调节宿主正常的生理功能,但在一定条件下能够引起不良反应的微生物。长期应用广谱抗生素会使机体免疫功能紊乱或菌群失调,导致条件致病菌的内源性感染,引发AAD等症状。
2.2.1 脆弱拟杆菌(Bacteroides fragilis)脆弱拟杆菌是一种大量存在于人和动物肠道的革兰氏阴性专性厌氧菌,为肠道常见菌群之一,分为产肠毒素型(Enterotoxigenic B. fragilis,ETBF)和非产肠毒素型。研究[42]表明,非产肠毒素型脆弱拟杆菌菌株ZY-312可以增加大鼠结肠内特定共生菌群的丰度,参与特定共生菌群介导的IECs增殖和分化,使IECs再生,恢复IECs的屏障功能,改善AAD症状。而ETBF会分泌脆弱拟杆菌肠毒素(Bacteroides fragilis enterotoxin,BFT)到菌体细胞外,BFT具有很强的蛋白水解酶活性和组织细胞毒性,纳克级别的BFT就可以改变人类结IECs系细胞HT-29的细胞骨架结构,使之发生形态学改变[43]。临床上,ETBF是可能导致儿童急性腹泻的病原体之一,使用美罗培南等抗生素治疗可能会使ETBF产生耐药性,而甲硝唑的使用仍然对治疗ETBF引起的腹泻有显著效果[44-45]。
2.2.2 酪酸梭菌(Clostridium butyricum)酪酸梭菌是一种严格厌氧的芽孢杆菌,常见于人和动物的肠道中[46]。非产毒型酪酸梭菌菌株在亚洲被广泛当作益生菌使用,临床上用于AAD的预防和治疗[46-47]。而最近研究发现,从一名老年AAD患者粪便中分离出的一种新的致病性酪酸梭菌(NOR33234)基因组中存在编码肠毒素的基因序列,可能产生与肉毒杆菌毒素相似的毒素蛋白,引起AAD等症状[48]。此外,部分致病性酪酸梭菌还与婴儿的肉毒杆菌中毒或早产儿的坏死性小肠结肠炎有关[46]。
2.2.3 大肠杆菌(Escherichia coli)大肠杆菌是人和动物肠道中的一种常见杆状细菌,少数大肠杆菌可以产生特殊的毒力因子,引起肠道感染,导致腹泻。在广泛使用抗生素的地区,部分小儿腹泻患者粪便中分离出的肠致病性大肠杆菌(Enteropathogenic E. coli,EPEC)和肠集聚性大肠杆菌(Enteroaggregative E. coli,EAEC)会出现产超广谱β-内酰胺酶(Extended-spectrum β-lactamase,ESBL)的表型,对庆大霉素等抗生素的敏感性显著降低,这可能与其获得了CTX-M-15耐药基因有关[49]。
3 益生菌用于预防和治疗抗生素相关性腹泻益生菌是一类能改善宿主肠道微生态平衡、发挥有益作用的活性有益微生物的总称。目前研究及应用较多的是乳杆菌属、双歧杆菌属、酵母菌属等。下面将对益生菌预防和治疗AAD的作用机制作进一步综述。
3.1 改善宿主的免疫功能和免疫水平益生菌能够通过IECs与肠道免疫系统相互作用,对宿主的免疫系统产生重要的影响。Fong等[50]发现,鼠李糖乳杆菌GG (Lactobacillus rhamnosus GG,LGG)能够通过激活巨噬细胞增加白细胞介素(Interleukin,IL)的表达增强机体的免疫应答反应。活体研究[51]表明,罗伊氏乳杆菌能够帮助恢复肠道微生态的稳定性,通过腺苷A2A受体抑制由调节性T细胞缺陷介导的自身免疫疾病,减少多器官炎症的发生。同时,研究[52]发现植物乳杆菌能够通过调节Toll样受体(Toll-like receptor,TLR)、核因子-κB (Nuclear factor kappa B,NF-κB)和丝裂原活化蛋白激酶(Mitogen-activated protein kinase,MAPK)途径维持跨上皮电阻(Transepithelial electrical resistance,TEER),抑制TJs蛋白的破坏,减少肠产毒性大肠杆菌K88诱导的促炎细胞因子的表达。临床上,前期采用抗生素治疗的儿童,在使用植物乳杆菌DSM9843 (LP299V)干预后,不再出现AAD的症状,而对照组仍出现了一定频率和强度的AAD症状[53]。这表明在抗生素治疗期间,植物乳杆菌的摄入可以在一定程度上预防AAD的发生,并用于AAD的治疗。此外,布拉氏酵母菌(Saccharomyces boulardii,Sb)可以增强分泌性IgA的释放,增加血清中IgM的含量,调节宿主的胃肠免疫系统;上调IL-1β、IL-12、IL-6和IL-10等细胞因子的表达,减少病原体微生物的感染[54]。2015年,一项综合性临床数据分析证实Sb能够有效降低儿童和成人抗生素相关性腹泻的风险[55]。临床上,Sb能够有效预防肺炎婴幼儿AAD的发生,降低腹泻严重程度,缩短治疗时间,而且安全性较高[56]。与此同时,研究[57]表明双歧杆菌也可以促进TLR-4和TLR-9的表达,显著上调NF-κB,从而改善先天性免疫,减少细菌迁移,维持肠道菌群平衡。其中,双歧杆菌BB04菌株产生的一种新型广谱细菌素能够诱导大肠杆菌细胞的形态和细胞内组织的改变,影响大肠杆菌细胞的跨膜电位,增加细胞膜的通透性,介导细胞膜孔的形成,从而破坏膜的完整性,使大肠杆菌细胞完全崩解[58]。临床上,双歧杆菌还常与其他菌属的益生菌组成联合益生菌制剂预防和治疗AAD,单独使用双歧杆菌制剂可以减少新生儿AAD发生率,减轻AAD的症状[59-60]。
3.2 调节肠道菌并维持肠道微生态的平衡益生菌能够定殖于IECs表面,通过分泌大量抑菌物质与病原菌或IECs相互作用,抑制病原微生物的黏附和侵袭,阻止其生长繁殖,从而维持肠道微生态的平衡。例如:布拉氏酵母菌能够通过分泌结合蛋白与细菌结合,阻止部分病原体微生物黏附于肠黏膜,从而限制其生长[61]。双歧杆菌在代谢过程中产生细胞外糖苷酶和结合胆汁酸水解酶等物质。细胞外糖苷酶可以降解IECs上复杂多糖,减少细菌内毒素与其结合,阻止致病菌对IECs的侵袭。结合胆汁酸水解酶可分解结合性胆酸,提高游离态胆酸的浓度,增强其抑菌作用,抑制病原细菌的生长[62]。LGG在肠道内定殖后能够大量分泌凝集素样蛋白(Lectin-like protein,Llp),其中Llp1和Llp2对复合聚糖具有特异性,参与LGG对IECs黏附定殖过程,两者的凝集素结构域对沙门氏菌属具有明显的抑制活性[63]。值得注意的是,针对使用青霉素造成的肠道不良反应,LGG作为益生菌制剂的疗效并不显著,但LGG可以有效减少使用大环内酯类抗生素引起的胃肠道不适[64]。临床上,罗伊氏乳杆菌可以有效治疗婴儿腹痛,早期使用罗伊氏乳杆菌DSM 17938还可以减少病原体在婴儿肠道的定殖,从而改善肠道微生态[65-66]。同时,罗伊氏乳杆菌DSM 17938可以有效缓解抗生素治疗期间的不良反应,预防AAD的发生,显著降低儿童和成人发生AAD的频率和强度[67-68]。
3.3 增强IECs的屏障功能IECs屏障主要包括IECs表面的上皮细胞层、理化屏障和上皮细胞间紧密连接的蛋白。LGG能够大量分泌可溶性蛋白和短链脂肪酸。短链脂肪酸促进IECs的分化,降低IECs的通透性,增加跨膜电阻[69];可溶性蛋白p75和p40激活PI3K/Akt信号通路,刺激IECs分泌保护性热应激蛋白(Heat shock protein,Hsp),促进IECs的增殖,增强IECs的稳定性[70]。此外,双歧杆菌能够分泌醋酸、乳酸和甲酸等多种具有抑菌作用的有机酸形成肠道化学保护屏障,抑制致病菌繁殖[62]。
3.4 其他最新一项研究[71]指出Sb的抗炎症作用可能涉及部分miRNA表达水平的改变。与此同时,Piewngam等[72]通过人群分析和小鼠实验发现,肠道内产脂肽芬荠素(Fengycins)的枯草芽孢杆菌(Bacillus subtilis)可通过抑制金黄色葡萄球菌的群体感应系统对其进行清除,从而减少金黄色葡萄球菌的定殖。上述结果提供了基于新的益生菌作用机制或新型益生菌来治疗AAD的新方法。同时,部分乳制品也可预防和治疗AAD,产生与益生菌制剂相似的临床效果,这可能与其中的益生菌群及其代谢的活性抗菌物质有关[73-74]。
4 结语与展望近年来,随着广谱抗生素的大量使用,AAD的发生率逐步提高,而AAD的发生与肠道菌群的种类、数量和分布密切相关。近年来,基于测序技术的发展,一些针对AAD患者粪便样本肠道微生物的分析方法有效地检测和揭示了与AAD相关的肠道菌群结构变化,但这些方法对肠道微生物与宿主肠道相互作用的反映能力却十分有限[75]。而最新的一项研究[76]构建了一种新的基于序列扩增和流式细胞计数的粪便微生物定量分析方法,该方法能够更为准确地对不同人类个体的肠道菌群特征进行描述和分析,同时将不同人的肠道菌群与他们自身的肠道差异联系起来,更加真实地反映人类肠道的微生态。临床上虽然可以利用各类益生菌制剂预防和治疗AAD,但前期诊断的方法还尚不完善。最新研究显示部分肠道菌可以用作诊断儿童腹泻潜在的标志微生物[77]。相信在不久的将来,通过逐步深入地认识肠道菌群与AAD的关系,研究者们将研究出新的策略,以更加精确有效地预防、诊断和治疗AAD。
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