修回日期: 2014-12-23
接受日期: 2014-12-30
在线出版日期: 2015-02-08
肠上皮细胞(intestinal epithelial cells, IECs)是机体抵御病原微生物的第一道防线, 是联系宿主和肠道微生物的主要桥梁. IECs与微生物的相互作用可能会引起免疫失调, 然而益生菌能通过屏障与免疫调节功能来预防肠道疾病的发生. 首先, 益生菌具有生物拮抗功能, 可以通过争夺营养, 代谢产物, 以及占位效应来调节肠道内微生物菌群, 抑制肠道外源性潜在致病菌的生长; 其次, 益生菌能够改善机体的免疫功能, IECs通过模式识别受体识别益生菌及代谢产物, 调节多个信号通路, 调控受体的表达, 激发机体自身非特异性免疫应答, 从而产生一系列的免疫保护反应. 另外, 益生菌能够诱导肠道上皮细胞产生大量富含黏蛋白的黏液, 黏液保护肠黏膜不与病原微生物接触, 阻止细菌黏附于上皮细胞, 从而保护肠道的屏障. 临床试验进一步证实了益生菌是潜在的感染性肠炎如克罗恩病和溃疡性结肠炎治疗方式.
核心提示: 益生菌对肠道上皮细胞的保护机制主要表现在两个方面, 一方面是维持肠道微生态平衡, 增强内源性防御屏障; 另一方面改善肠道免疫防御屏障, 抑制肠道过度炎症反应. 实验研究和临床的应用证实了不同菌种、不同剂量的益生菌可能引起不同作用, 因此仔细选择恰当的细菌种类和使用的标准剂量, 在临床应用是必要的.
引文著录: 杨金霞, 杨金彩. 益生菌对肠道上皮细胞保护机制的研究进展. 世界华人消化杂志 2015; 23(4): 577-583
Revised: December 23, 2014
Accepted: December 30, 2014
Published online: February 8, 2015
Intestinal epithelial cells (IECs), the first line of defense against pathogens, are an initial point of contact between the host and intestinal microbes. Growing evidence suggests that the interactions between the host and intestinal microbes may lead to dysregulated immune responses, while probiotics can reinforce the barrier function and exert a modest stimulation of the immune system to prevent this situation. On one hand, probiotics exert antagonistic functions via competition for nutrients, metabolites, and occupying effect. Therefore, probiotics can regulate the endogenous gastrointestinal flora and restrain exogenous pathogenic bacteria. On the other hand, IECs recognize probiotics and their metabolites through pattern recognition receptors to stimulate the non-specific immune responses. In addition, probiotics can induce IECs to produce the mucus layer covering the entire intestinal tract and prevent attachment and invasion of various bacterial pathogens. Clinical trials have also shown beneficial effects of probiotics as a potential preventive method for inflammatory bowel disease such as Crohn disease and ulcerative colitis.
- Citation: Yang JX, Yang JC. Mechanisms underlying protective effects of probiotics on intestinal epithelial. Shijie Huaren Xiaohua Zazhi 2015; 23(4): 577-583
- URL: https://www.wjgnet.com/1009-3079/full/v23/i4/577.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v23.i4.577
益生菌是一类能产生确切健康功效从而改善宿主微生态平衡、发挥有益作用的活性有益微生物的总称. 目前, 研究以及应用最多的益生菌为双歧杆菌、乳酸杆菌及酵母菌. 益生菌能够黏附于肠道中, 并通过短暂的定植来平衡和改善肠道内微生物菌群, 改善机体的免疫功能, 保护肠道的天然屏障, 有助于人体胃肠道内环境的稳态. 临床中益生菌应用于预防和治疗肠道免疫失调诱发的一些肠道的慢性感染性疾病如克罗恩病、溃疡性结肠炎[1,2]以及肠易激综合征[3]. 另外一些荟萃分析认证了益生菌在治疗急性感染性腹泻中的作用[4]. 随着益生菌的广泛应用, 其对人肠道上皮细胞的屏障保护成为热门研究的课题, 研究[5]表明不同益生菌与宿主相互作用的保护机制各不相同. 其具体机制总结如下.
肠道中正常的微生态平衡对人体的健康至关重要, 微生态的紊乱可能会导致多种肠道疾病的发生. 研究证实益生菌至少可以通过以下3方面的作用起到维持肠道微生物稳态的作用.
肠道微生态失衡会出现包括肠道内细菌过度繁殖、肠道通透性增加以及宿主免疫功能低下等现象. 给动物服用双歧杆菌、乳酸杆菌等益生菌有助于肠道内优势种群的再形成, 以维持肠道微生态区系平衡, 改善肠道健康状况[6]. 此外, 肠道中双歧杆菌、乳酸杆菌等益生菌具有生物拮抗功能, 可以通过争夺营养[7], 抑制肠道外源性潜在致病菌的生长.
黏附素是病原微生物重要的毒性因子[8], 致病菌通过黏附素黏附于肠道黏膜表面受体, 进而产生一系列临床症状. 益生菌一方面与病原微生物竞争肠上皮上相同的复合糖受体, 阻止致病菌的定植; 另一方面益生菌占据病原微生物的附着位点后促进机体形成保护屏障, 抑制致病菌群的生存繁殖能力, 进而抑制病原菌在肠道内繁殖.
肠上皮细胞(intestinal epithelial cells, IECs)通过Toll样受体(Toll-like receptors, TLRs)和NOD样受体(NOD like receptors, NLRs)等模式识别受体(pattern recognition receptors, PRRs)识别益生菌及代谢产物的病原相关分子模式(pathogen associated molecular patterns, PMAPs)[13]、调节核因子-κB(nuclear factor kappa B, NF-κB)、丝裂原激活蛋白激酶(mitogen activated protein kinases, MAPK)、过氧化物酶增殖激活受体γ(peroxisome proliferators activated receptor gamma, PPARγ)等信号通路, 从而促进或者抵御炎症[14].
研究[13]表明益生菌的脂磷壁酸(lipoteichoic acid, LTA)及某些蛋白的不同糖基化形式或许在其与宿主细胞的相互作用过程中起到了重要的功能. 一篇结构与功能的相关性研究[15]表明LTA的脂链在LGG(L. rhamnosus GG)与TLR2-6的相互作用及激活NF-κB信号通路的过程中起重要作用. 最近的研究[16,17]证明乳酸杆菌与细胞膜接触的蛋白确实会发生糖基化, 这些蛋白包括LGG的p75蛋白以及L. plantarum上的一种起类似功能的蛋白.
TLR4在促进肠道上皮细胞增殖, 损伤的修复, 维持肠道黏膜屏障的完整性和肠道的稳态至关重要. 活体研究[18]表明LGG可以上调大鼠结肠中TLR4的表达. TLR4刺激引起环氧化酶2(cyclooxygenase-2, COX-2)的转录, 产生大量前列腺素E2(prostaglandin E2, PGE2), 激活表皮生长因子受体(epidermal grow factor receptor, EGFR), 由磷脂酰肌醇-3-羟激酶/蛋白激酶B(phosphatidylinositol 3-kinase/protein kinase B, PI3K/Akt)、蛋白激酶C(protein kinase C, PKC)等通路完成信号从EGFR到转录因子的传导[19], 从而调节细胞生长、迁移、分化和增殖[20,21].
体外研究[22,23]表明, 人肠道上皮细胞中位于顶膜的TLR9可以识别LGG的CpG DNA会抑制NF-κB抑制蛋白(inhibitor of NF-κB, IκB)和p38磷酸化, 进而抑制NF-κB的激活及白介素-8(interleukin 8, IL-8)的表达, 以维持肠道上皮细胞的完整性, 顶膜的TLR9也会引起机体对其他TLRs信号的耐受, 降低由TLR2信号产生的IL-8的表达. 致病菌感染细胞后常会造成细胞的损伤或者入侵到细胞内而激活基底膜侧TLR9信号引起炎性反应, 而益生菌则不能越过肠道上皮屏障, 只能被顶膜的TLR9识别, 故引起抗炎反应, 维持肠道微生态的平衡.
体外研究[24,25]表明, NOD1和NOD2也参与识别肠道共生菌, 介导炎症反应, 促进肠道内环境稳衡. TLRs和NLRs通过协同作用, 在抵御入侵病原菌时, 激发最大的免疫应答反应[26,27]. NLRs是胞质内的受体, NOD1识别二氨基庚二酸(diaminopimelic acid, DAP), 可抑制IκB激酶和NF-κB的激活[28]. 另有研究[24]显示, 肠道内的共生菌可以通过NOD1调节肠道淋巴组织相关基因的表达, 维持肠道内环境的稳态.
LGG可以上调IPEC-J2细胞TLR2的表达并抑制IL-6的应答[29]. L. sobrius降低IPEC-J1细胞中趋化因子IL-8, 升高抗炎因子IL-10的水平[30]. IL-10是机体重要的抗炎因子, 有报道[31]称TLR2信号通路刺激IL-10的分泌, 保护上皮细胞紧密连接蛋白. Lactobacillus reuteri可以通过抑制转录因子活化蛋白-1(activating protein 1, AP-1)相关信号通路, 阻止由脂多糖(lipopolysaccharide, LPS)引起的巨噬细胞肿瘤坏死因子α(tumor necrosis factor α, TNF-α)大量分泌[32]. Peña等[33]通过体外实验揭示鼠李糖乳杆菌也能够抑制小鼠巨噬细胞分泌过量的TNF-α. Kim等[34]的研究表明LGG和L. rhamnosus GR-1能够促进THP-1细胞产生抗炎因子IL-10和粒细胞集落刺激因子(granulocyte-colony stimulating factor, G-CSF). 另外的研究显示, L. rhamnosus GR-1诱导人肠黏膜固有层单个核细胞以及分泌较E. coli刺激更多的G-CSF[35], 另有研究[36]表明在轻到中度溃疡性结肠炎患者中合用嗜酸乳杆菌较单用柳氮磺胺吡啶治疗, 能显著降低病变结肠组织中IL-6的含量以及TNF-α、NF-κB的mRNA表达.
根据上述我们可以推断益生菌能够调节IECs中抗炎细胞因子、促炎细胞因子以及趋化因子的mRNA转录和相应蛋白表达, 一方面可以适度刺激IECs, 维持细胞抵御外来病原微生物的能力, 另一方面, 避免了过度炎症反应引起细胞损伤, 从而有效平衡细胞的炎症反应与抗炎反应, 控制病原微生物感染引起的过度炎性反应对细胞产生损伤. 这提示我们益生菌的抗炎作用有可能是多种模式识别受体协同作用的结果, 而不同的细胞因子的表达可能是由相应的模式识别受体主导.
肠上皮屏障包括IECs表面的理化屏障、上皮细胞层、上皮细胞间的紧密连接蛋白. IECs可以分泌黏蛋白、抗菌多肽(如防御素及血管生成素)以及碱性磷酸酶(intestinal alkaline phosphatase, IAP)[37], 在肠道上皮细胞表面形成一层理化屏障, 防止病原微生物黏附; 其次, IECs通过模式识别受体识别肠道内微生物, 发挥免疫调节功能; 另一方面IECs可通过紧密连接(tight junctions, TJs)调控细胞旁路运输, TJs由多种跨膜蛋白(occludin、claudin等)通过闭锁小带(zona occluden, ZO)-1、ZO-2和ZO-3等与细胞骨架相连, 以维持肠上皮完整性及正常生理屏障功能[38,39].
研究[40]表明益生菌能够诱导肠道上皮细胞产生大量富含黏蛋白的黏液, 黏液保护肠黏膜不与病原微生物接触, 阻止细菌黏附于上皮细胞, 从而抑制致病菌及毒素对肠上皮的定植, 为IECs提供安全的环境. 黏液中具有与上皮细胞相似的细菌结合受体, 一旦细菌与黏蛋白上的受体结合, 就不能接近上皮细胞. 黏液则随肠道的不断蠕动进入肠腔, 排出体外. 杯状细胞分泌黏液重新补充于肠道上皮细胞表面. 周而复始, 这也是部分益生菌为何只能短暂定植的原因. 实验结果显示, 在HT29细胞中加入益生菌及致病性大肠杆菌共培养, 益生菌诱导黏蛋白3(mucin 3, MUC3) mRNA的大量表达, 促进MUC3的分泌, 并减少大肠杆菌的黏附[41].
紧密连接是由多种蛋白组合而成的复合蛋白, 包括ZO-1、occludin、claudin等. 他就像缝线一样将细胞侧壁紧紧"缝合"在一起, 降低上皮细胞的通透性, 使水分、电解质、外界的病原微生物和有害的物质不能渗透进入机体内. 一些病原菌和促炎因子可能导致上皮细胞间的紧密连接破坏, 使得有毒物质趁机通过细胞旁通路进入机体, 破坏肠道内环境的稳态, 引起肠道的损伤[30]. 体外研究[42]表明, LGG可以阻抗E. coli O157: H7对上皮细胞结构及细胞间TJs的损害. 益生菌相应的病原相关分子模式如脂磷壁酸或其分泌的相关分子被PRRs识别后引起相关信号通路的活化, 起到保护IECs[43], 抵抗由肠道病原菌对TJs的破坏的作用. 首先, 益生菌通过促进抗炎因子IL-10的分泌, 抑制趋化因子IL-8的分泌抵抗由肠道病原菌、促炎因子、化学因素对TJ的破坏[30,31]; 其次, 益生菌引起PKC的激活, 增加ZO-1的表达, 维持IECs屏障的完整性[44]; 再次, LGG产生的短链脂肪酸能够促进IECs的分化, 降低IECs的通透性, 增加跨膜电阻[45], 保护IECs屏障[46]; 另外, LGG分泌的低分子量可溶性多肽可以上调具有细胞保护性的热应激蛋白(heat shock protein, Hsp)25和Hsp72的表达, 有效保护IECs之间的紧密连接蛋白, 并通过活化PI3K/Akt通路, 增强上皮细胞屏障.
IAP存在于上皮细胞的顶端微绒毛的表面, 是IECs分化的一个重要指标. 他的活力反映了隐窝微绒毛的完整性, 目前对于IAP在维持肠道内稳态的功能尚不完全了解. 已有的研究[47]表明, LGG能通过增加IAP活力, 从而参与调节肠道表面的pH, 限制细菌侵入上皮细胞, 通过去磷酸化控制LPS引起的炎性反应以及肠道的严重损伤. 因此IAP对于维持肠道屏障的稳态起到至关重要的作用.
有研究[48]表明, LGG分泌的可溶性蛋白p75和p40可以激活PI3K/Akt信号通路, 刺激肠道上皮细胞分泌保护性热应激蛋白Hsp72和Hsp25, 增强肠道上皮细胞的增殖, 并有效抑制由TNF诱导的细胞凋亡. 另外, LGG诱导G-CSF大量分泌, G-CSF一方面刺激JAK2/STAT3通路, 抑制氨基末端激酶(Jun N-terminal kinase, JNK)的活化, 降低E. coli引起的TNF-α合成与分泌[34]; 另一方面, G-CSF可以抑制TNF-α介导的凋亡前体p38的活化而具有特异的抗细胞凋亡作用[49]. 此外, G-CSFR活化后可以通过Src迅速激活Akt信号通路. 体内和体外实验表明, TLR2通过PI3K/Akt通路激活接头分子MyD88, 增强细胞的存活能力, 维持应激条件下细胞紧密连接蛋白的完整性. 另有研究[44,50-52]表明, PKCα可以调节Akt的信号, 抑制细胞的凋亡, 调节细胞的完整性和细胞膜的通透性.
益生菌对肠道上皮细胞的保护机制主要表现在两个方面, 一方面是维持肠道微生态平衡, 增强内源性防御屏障; 另一方面改善肠道免疫防御屏障, 抑制肠道过度炎症反应. 近年来关于益生菌保护机制的研究广泛涉及到动物及人的模型, 越来越多的研究证实益生菌能预防和治疗胃肠道失调疾病. 对益生菌可作一种防治感染性肠道炎性疾病的创新方法人们也寄予厚望. 尽管LGG预防和治疗胃肠道疾病的效果并未得到充分证实, 但鉴于其超强的肠黏膜黏附能力, LGG常被选作为预防胃肠道感染和腹泻的潜在的治疗方法. 另外3个Meta分析研究显示使用LGG能够治疗儿童的急性腹泻[53-55]. 将腹泻的发病时间缩短1.05 d, 以高剂量的LGG效果尤其明显. 在住院的儿童中, 通过发酵乳制品每天摄入LGG也能够降低医源性胃肠道感染的风险[56]. 然而实验研究和临床的应用证实了不同菌种、不同剂量的益生菌可能引起不同作用, 因此仔细选择恰当的细菌种类和使用的标准剂量, 在临床应用是必要的.
益生菌是一类能产生确切健康功效从而改善宿主微生态平衡、发挥有益作用的活性有益微生物的总称. 目前, 研究以及应用最多的益生菌为双歧杆菌、乳酸杆菌及酵母菌. 益生菌能够黏附于肠道中, 并通过短暂的定植来平衡和改善肠道内微生物菌群, 改善机体的免疫功能, 保护肠道的天然屏障, 有助于人体胃肠道内环境的稳态.
段义农, 教授, 南通大学医学院病原生物学系
肠上皮细胞(intestinal epithelium cells, IECs)是机体抵御病原微生物的第一道防线, 是联系宿主和肠道微生物的主要桥梁. IECs与微生物的相互作用可能会引起免疫失调, 然而益生菌能通过屏障与免疫调节功能来预防肠道疾病的发生. 研究表明不同益生菌与宿主相互作用的保护机制各不相同, 故对其具体机制进行综述.
临床中益生菌应用于预防和治疗肠道免疫失调诱发的一些肠道的慢性感染性疾病如克罗恩病和溃疡性结肠炎及肠易激综合征等疾病. 另外一些荟萃分析认证了益生菌在治疗急性感染行腹泻中的作用.
益生菌具有生物拮抗功能, 可以通过争夺营养, 代谢产物, 以及占位效应来调节肠道内微生物菌群, 抑制肠道外源性潜在致病菌的生长. 其次, 益生菌能够改善机体的免疫功能, IECs通过模式识别受体识别益生菌及代谢产物, 调节多个信号通路, 调控受体的表达, 激发机体自身非特异性免疫应答, 从而产生一系列的免疫保护反应. 另外, 益生菌能够诱导肠道上皮细胞产生大量富含黏蛋白的黏液, 黏液保护肠黏膜不与病原微生物接触, 阻止细菌黏附于上皮细胞, 从而保护肠道的屏障.
近年来关于益生菌保护机制的研究广泛涉及到动物及人的模型, 越来越多的研究证实益生菌能预防和治疗胃肠道失调疾病. 对益生菌可作一种防治感染性肠道炎性疾病的创新方法人们也寄予厚望, 可作为预防胃肠道感染和腹泻的潜在的治疗方法.
益生菌: 是一类能产生确切健康功效从而改善宿主微生态平衡、发挥有益作用的活性有益微生物的总称.
益生菌能够调节肠道内微生物菌群, 改善机体的免疫功能, 保护肠道的屏障, 对预防病原微生物入侵起到重要作用, 近年来成为人们关注的一个热点. 进行这方面的文献综述, 对人们了解最新研究进展具有重要价值.
编辑:韦元涛 电编:闫晋利
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