雷静1, 刘泽世2, 雷珂2, 薛丽2, 耿燕1,2
1. 陕西中医药大学医学技术学院, 陕西 咸阳 712000;
2. 西安交通大学第二附属医院检验科, 陕西 西安 710000
收稿日期:2020-10-10;修回日期:2020-12-28;网络出版日期:2021-01-11
基金项目:陕西省重点研发计划(2017SF-128)
*通信作者:耿燕, E-mail: wsw87679358@163.com.
摘要:耐碳青霉烯类肠杆菌科细菌(carbapenem-resistant Enterobacteriaceae,CRE)在肠腔中定殖通常先于或并存于CRE的感染。正常情况下,定殖的CRE、肠道菌群和宿主相互作用,处于稳定平衡的状态,当肠道菌群出现失调时,肠道正常菌群失去对定殖CRE的抵抗力,增加CRE感染的风险。大量研究表明通过肠道共生菌群对CRE的定殖抗性不仅可以预防感染,而且也可以降低医疗环境中患者间相互传播的风险。本文就CRE的流行现状、肠杆菌科细菌定殖机制以及肠道共生菌群对CRE定殖抗性机制作一综述,以期为CRE感染的防控工作提供新思路和新方法。
关键词:肠道菌群耐碳青霉烯类肠杆菌科细菌定殖定殖抗性
Research progress on the colonization resistance of intestinal flora to carbapenem-resistant Enterobacteriaceae
Jing Lei1, Zeshi Liu2, Ke Lei2, Li Xue2, Yan Geng1,2
1. School of Medical Technology, Shaanxi University of Chinese Medicine, Xianyang 712000, Shaanxi Province, China;
2. Department of Laboratory, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710000, Shaanxi Province, China
Received: 10 October 2020; Revised: 28 December 2020; Published online: 11 January 2021
*Corresponding author: Yan Geng, E-mail: wsw87679358@163.com.
Foundation item: Supported by the Key Research and Development Program of Shaanxi Province (2017SF-128)
Abstract: The colonization of carbapenem-resistant Enterobacteriaceae (CRE) in the intestinal lumen usually precedes or coexists with CRE infection. The intestinal flora and host normally interact with the colonized CRE to achieve a stable equilibrium state. When dysbacteriosis happens, the intestinal flora losses its resistance to the colonized CRE, increasing the risk of CRE infection. A large number of studies suggest that the resistance of intestinal symbiotic flora to the colonization of CRE can not only prevent infection, but also reduce the risk of mutual transmission among patients exposed to the medical environment. To provide a new idea and method for prevention and control of CRE infection, we studied the prevalence of CRE, the colonization mechanisms of Enterobacteriaceae, and the mechanisms of colonizing resistance to CRE of intestinal flora.
Keywords: intestinal microbiotacarbapenem-resistant Enterobacteriaceaecolonizationcolonization resistant
耐碳青霉烯类肠杆菌科细菌(carbapenem- resistant Enterobacteriaceae,CRE)引起的感染在全球范围内持续增加,在儿童、老年人、住院患者、移植受者和免疫抑制患者等易感群体中具有较高的发病率和死亡率,已逐步成为全球重大公共卫生威胁,目前对CRE感染的预防、控制和治疗等均面临着巨大挑战[1]。两项基于基因组学的研究表明[2-3],感染菌株与定殖菌株之间的同源性可达80%,因此定殖是进展为感染的一个重要中间环节,存在CRE定殖的患者发生感染的风险显著增加。由于抗CRE药物有限,WHO将CRE列为优先且迫切需要研发新型抗菌药物的细菌种类[4]。但抗菌药物的研发并非易事,即使研制出新的抗菌药物,细菌最终也可能会产生耐药性。因此,为更好地减少CRE感染且有效避免细菌耐药的问题,我们需采取有效的策略以预防CRE定殖与感染。
大量研究表明肠道共生菌群在营养代谢、免疫调节、防止病原微生物定殖和维持肠道屏障功能等方面有重要的作用[5-6]。肠杆菌科细菌是肠道中常见的定殖菌之一,正常情况下并不足以致病,但当肠道菌群失调、抗菌药物的使用等干扰事件发生时,在抗菌药物选择压力下,对药物敏感的肠道共生菌被清除,导致肠道菌群失调,肠道菌群失去对其的定殖抵抗力,易出现肠杆菌易位和感染[7]。在动物模型研究和生物治疗制剂的临床试验中证实肠道中正常的微生物菌群,如双歧杆菌属和乳杆菌属等具有抗感染的能力[8]。因此,在干扰事件特别是在使用广谱抗菌药物的同时,维持肠道菌群对CRE的定殖抗性可作为医疗实践中预防CRE感染的手段之一[9]。
1 CRE的流行现状 自1996年在美国北卡罗来纳州首次发现产KPC酶的肺炎克雷伯菌后,CRE在世界范围内迅速传播。SENTRY抗菌药物监测项目数据显示[10-11],1997–2016年来,美国、欧洲、亚太地区CRE检出率分别上升了1.5%、1.9%和2.8%,拉丁美洲上升更为显著,从0.8%上升到6.4%。欧洲细菌耐药监测网(EARS-net)统计2017年整个欧盟地区耐碳青霉烯类肺炎克雷伯菌的耐药率为0%–65%[12],不同地区间存在较大差异。我国2019年细菌耐药监测网数据显示[13],CRE检出率逐年增加,其中以肺炎克雷伯菌增长最为显著,其对美罗培南的耐药率为26.8%,相比2005年的2.9%,增长幅度达8倍以上。
产碳青霉烯酶CRE是院内传播和感染暴发的主要原因,碳青霉烯酶通常由携带在质粒和转座子等可移动遗传元件上的基因编码,使其易在同种甚至异种菌株之间水平传播[14]。目前广泛流行的碳青霉烯酶主要是KPC、NDM酶,其次是VIM、IMP和OXA-48酶。含不同碳青霉烯酶基因的耐碳青霉烯类肠杆菌科细菌在地理分布上存在较大差异,希腊、以色列、拉丁美洲、美国和中国等(blaKPC),印度次大陆、巴尔干半岛以及欧洲某些国家(blaNDM),土耳其、中东和北非(blaOXA-48)被认为是各种产碳青霉烯酶CRE发生率最高的地区和国家[15-17]。
2 肠杆菌科细菌定殖机制 肠杆菌科细菌不断进化机制,使其能够存活、定殖在不同的环境中,而耐碳青霉烯类肠杆菌科细菌在肠道中的定殖更是其发展为感染的关键一步。
2.1 粘附作用 肠杆菌科细菌粘附宿主细胞从而逃避宿主免疫系统以及肠道蠕动的清除是其成功定殖的最重要因素之一。细菌一旦与宿主细胞粘附稳定,则以此位点进行增殖并表达多种因子,发挥抗吞噬作用,保护细菌免受宿主攻击,促进自身在宿主体内的扩散[18]。
肠杆菌科细菌的菌毛,即黏附素,是定殖的关键因子,其参与细菌与宿主细胞的结合,使之易定殖于肠道中。细胞外基质(extracellular matrix,ECM)是宿主细胞周围由多种大分子组成的网架结构,其广泛分布于结缔组织和基底膜中,包括胶原蛋白、弹性蛋白、纤维连接蛋白和层粘连蛋白等,这些分子是细菌粘附的物质基础。肠杆菌科细菌可通过直接与整合素相互作用,粘附并内化到宿主细胞中,如耶尔森菌分泌的侵袭素与β1整合素受体高度亲和,介导细菌的初始粘附和侵袭,随后表达耶尔森菌黏附素(YadA)和粘附侵袭位点基因(attachment invasion locus,ail),促进其与纤维连接蛋白和胶原蛋白的紧密粘附,维持细菌定殖[19-20]。此外,侵袭性大肠埃希菌也可通过1型菌毛黏附素(fimH)识别回肠上皮细胞中的CEACAM6受体,粘附于回肠肠上皮细胞,导致克罗恩病的发生[21]。
粘附作用在细菌定殖和早期存活中起着不可或缺的作用。细菌的粘附作用也与生物膜形成高度相关,生物膜的形成增加了细菌对抗菌药物的抵抗力,产生致病性和生存力更强的菌株[22-23]。抑制细菌的粘附作用在减少感染方面具有很大潜力,目前已有研究证明甘露糖苷衍生物能够有效阻断fimH与含甘露糖的宿主细胞受体之间的粘附,且不产生细胞毒性作用[24]。此外,一种口服fimH抑制剂也被证明可显著减少耐多药的尿路致病性大肠埃希菌在膀胱定殖并防止急性尿路感染[25]。然而,目前抗粘附作用还未成为新兴的抗感染治疗手段,主要的原因之一可能是细菌表达多种粘附因子,未来的抗感染治疗可以考虑针对多个粘附分子的抑制剂与抗菌药物联合使用。
2.2 生存机制 粘附宿主细胞表面是细菌定殖的关键第一步,然而仅靠粘附作用并不足以维持定殖,细菌还需适应不断变化的肠道环境,来维持自身长期的生存和增殖。肠道中的营养物质随时间和空间的改变而变化,肠杆菌科细菌能够有效利用其中的一种或几种,从而获得生存优势,例如肠道中多种单糖为大肠埃希菌的增殖提供了丰富的营养物质[26]。此外,肠杆菌科细菌可在低密度氧的肠道环境中表达细胞色素氧化酶变体,增加氧亲和力,使之能利用氧和其他分子作为末端电子受体产生ATP,在肠道中进行增殖[27]。
3 肠道共生菌群与定殖抗性机制 肠道菌群由多种共生细菌组成,可通过直接和间接多种平行机制提供定殖抗性,包括对定殖菌的抵抗和清除等方面[28]。直接定殖抗性的特点是共生菌群通过细菌因素限制外源性微生物定殖或防止内源性致病微生物过度生长。而间接定殖抗性机制表现为肠道菌群调控宿主衍生因子,以提供拮抗外源性病原体的保护作用。其他机制可能涉及中断群体感应(quorum sensing, QS),例如,嗜酸乳杆菌La-5可在体外抑制自体诱导物-2(AI-2)并降低大肠埃希菌O157:H7部分毒力因子的表达[8]。这些机制限制CRE在肠道内定殖的能力,从而降低宿主肠源性感染的易感性[29]。
3.1 直接定殖抗性
3.1.1 竞争营养物质: 肠道菌群的营养物质几乎完全来自于食物和宿主提供的碳水化合物,碳水化合物的丰富程度决定肠道菌群的结构和组成。肠道内细菌对营养物质竞争十分激烈,各微生物群在进化过程中形成交叉喂养模式和底物偏好,以最大限度地利用现有的营养[27]。在稳态条件下,外源性菌株不太可能找到一个无竞争的生态龛,并将被迫与肠道中正常菌群竞争营养物质。大肠埃希菌能够利用黏液层中存在的多种糖,包括半乳糖、岩藻糖、甘露糖和N-乙酰氨基葡萄糖等,大肠埃希菌的共生菌株可以通过糖的重复利用对致病性大肠埃希菌O157产生定殖抗性[30]。这表明,在没有外源性致病菌的情况下,肠道中的菌株能够与利用相似营养物质的致病菌竞争。与此相反,如果肠道菌群中存在与外源性菌株相关的类群,外源性菌株在肠道中成功定殖的几率就会增加[31]。
除竞争碳源和能源物质外,致病菌还与微生物群争夺微量金属元素。例如,益生菌大肠埃希菌Nissle 1917菌株以依赖于铁摄取的方式保护小鼠不受致病性沙门菌感染[32]。此外,霍乱弧菌和空肠弯曲菌的锌摄取途径对其与肠道中正常定殖的共生菌群竞争至关重要[33]。
3.1.2 通过分泌细菌素直接产生拮抗作用: 由微生物衍生的细菌素已被确定对革兰阳性和革兰阴性病原体都有活性,其通常对亲缘关系密切的细菌有活性,有的可能活性范围更广[27]。细菌素种类繁多,如乳酸菌代谢产生的细菌素可以抑制多种细菌、真菌和病毒,其抗菌作用机制包括破坏细胞膜,形成跨膜离子通道以及细菌素的胞内作用,干扰细菌的正常代谢[34]。
细菌素还可能在肠道内持续拮抗相关病原体,但细菌素在抵抗相关病原体定殖中具体起多大作用还不清楚[35]。最近研究发现,细菌素NAI-107对少数革兰阴性病原体有活性,与多粘菌素协同作用,可抑制更广泛的革兰阴性病原体,包括肺炎克雷伯菌和大肠埃希菌[36]。肠杆菌科的一些菌株携带有编码大肠埃希菌素基因的质粒,大肠埃希菌素可调节菌群数量,对不能分泌特异性大肠埃希菌素免疫蛋白的近缘细菌具有杀灭作用[27]。因此,细菌素的抗菌杀菌作用在解决致病菌耐药的问题上具有潜在的应用价值。
3.1.3 通过Ⅵ型蛋白分泌系统(T6SS)介导杀伤作用: Ⅵ型蛋白分泌系统(T6SS)由膜核心复合体(membrane core complex of TssJLM)、基座复合体(baseplate of TssAEGFK)和VgrG三聚体、管状结构(Hcp内管和VipA/B外鞘)以及ATP酶ClpV四个核心组件构成[37-39]。Hcp内管和VipA/B外鞘组成的螺旋结构为T6SS穿透靶细胞膜和细胞壁提供足够的穿透力[40]。目前,T6SS仅在革兰阴性细菌中被发现,人类肠道中半数以上的拟杆菌基因组和四分之一以上的变形杆菌基因组都含有T6SS基因[41],其具有很强的杀菌能力,通过细胞间直接接触和物理性穿透转运有细胞毒性的分泌蛋白至邻近细胞和真核细胞内,可提供对致病菌的定殖抗性[42]。T6SS传递的效应分子通过降解NAD(P)+和肽聚糖等多种作用机制来拮抗邻近细胞[43]。但为避免自身靶向作用,T6SS+菌株还必须编码一种免疫蛋白抑制效应蛋白的活性[44]。
3.2 间接定殖抗性
3.2.1 短链脂肪酸(SCFAs)对细菌毒力和复制的抑制作用: 研究表明,高浓度的SCFAs对肠杆菌科细菌有抑制作用,大部分SCFAs产生于结肠近端,被宿主吸收以支持肠上皮细胞代谢,高浓度SCFAs的产生导致肠腔内酸化,诱发肠杆菌科细菌酸化到抑制其复制的水平[45]。有文献报道,肠杆菌科细菌能够利用氧或硝酸盐作为呼吸电子受体,为其在肠道中定殖获得很强的生存优势[46]。在宿主上皮细胞中,SCFAs可通过激活宿主信号, 包括过氧化物酶体增殖物激活受体γ(PPAR-γ),减少CRE对氧气和硝酸盐的利用,同时产生抗菌肽,抑制CRE生长[47]。可见,补充一种代谢高水平SCFAs的肠道菌群,如拟杆菌门和厚壁菌门,可作为一种潜在的治疗方法,提高对肠道中CRE的清除。
3.2.2 上皮屏障的维持: 粘膜屏障是抵御病原微生物的第一道防线,在防止肠道菌群易位,维持肠道内环境稳态中起着重要的作用。除黏蛋白外,杯状细胞分泌的Fcgbp、潘氏细胞分泌的抗菌肽(如β-防御素和溶菌酶)以及肠上皮细胞分泌的分泌型IgA等,这些生物物质使肠道具有较为完善的功能隔离区[48]。肠道共生菌可影响粘膜免疫细胞的发育、成熟以及肠上皮细胞的稳态,并可通过上调肠粘膜紧密连接蛋白的表达来提高肠道的完整性,改善胃肠屏障功能[49-50]。Miele等研究表明,肠上皮细胞之间的紧密连接受损可导致大量细菌和细菌内毒素易位进入血液循环[51]。Wrzosek等[52]发现,多形拟杆菌可通过增加杯状细胞的分化,调节黏液相关基因的表达,对黏液层的厚度和组成产生积极的影响。嗜酸乳杆菌A4可通过上调黏蛋白-2(MUC2),显著降低大肠埃希菌O157:H7对肠上皮细胞的粘附程度[53]。此外,从鼠李糖乳杆菌GG(LGG)中纯化的两种分泌蛋白(p40和p75)也可以通过抑制细胞因子诱导的上皮细胞凋亡来促进肠上皮的稳态[54]。
4 小结和展望 肠道是耐药菌的储存库,也是耐药基因发生交换的有利场所,引发院内感染的一个潜在风险是存在耐药菌定殖[55]。定殖菌、肠道菌群和宿主之间相互作用,影响菌群的结构和组成,并决定细菌能否在肠道中定殖成功。抗菌药物干扰后通常会导致临床上相关病原体感染,对药物敏感的肠道共生菌群会被清除,可能导致肠道菌群丧失对致病菌的牵制作用。
CRE是常见的多药耐药菌,除碳青霉烯类抗菌药物外,其他类抗菌药物也会导致肠道菌群失调,失去肠道菌群对CRE定殖的抵抗力,导致CRE在肠道中的定殖。早在2012年,美国CDC就提出进行CRE主动筛查可以减少CRE传播扩散[56]。我国有关CRE主动筛查价值评估的研究报道,实行CRE主动筛查并采取干预措施可以有效减少ICU中患者间的交叉感染[57-58]。随着国内CRE定殖率和感染率逐年增长[59],我国应根据国内实际医疗情况制定具体筛查标准及干预措施,积极开展CRE主动筛查项目,化被动为主动,有效鉴别存在CRE定殖、感染或传播风险的患者,关键是做到早发现、早干预和早治疗[60]。
薛丽等[50]研究结果显示,肠道中的有益菌群可以抑制需氧菌增殖,同时也可增加厌氧菌比例和肠道菌群的定殖抗性。因此,考虑到肠道中菌群的竞争牵制作用,在广谱抗菌药物使用的同时,考虑重建肠道共生菌群恢复对CRE的定殖抗性, 以降低机体发生肠源性感染的风险。
目前,已有研究表明粪便菌群移植(FMT)有效地治疗了由艰难梭状芽胞杆菌引起的复发性感染[61]。2013年,张发明等[62]报道首例应用标准化FMT成功治疗严重克罗恩病合并肠内瘘感染的患者。FMT主要作用机制是重建肠道菌群,纠正菌群失调以恢复肠道内环境稳态,其治疗预期效果取决于菌群失调对疾病的贡献程度,贡献度越大,治疗获益也越大[63]。目前也有研究表明,FMT可减少CRE的定殖,减少随后发生CRE感染的风险[64-65]。随着特异的定殖抗性途径的确定,以及与这些途径相关的肠道共生菌群组成,未来有望设计出最小的功能性菌群来提供定殖抗性或清除特定的临床相关病原菌。
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