动物肠道是机体重要的消化吸收场所，也是机体最大的免疫器官。肠道黏膜作为机体与外环境进行互作的重要场所，能保护机体免受外来病原微生物侵扰以及保障机体免疫能力[1]。乳酸菌是国际上公认的益生菌，具有很高的理论研究和生产应用价值，乳酸菌可通过提高肠道黏膜免疫、减轻炎症反应，来改善动物肠道健康和促进生长发育[2-4]。胞外多糖(EPS)是乳酸菌在生长代谢过程中分泌到细胞壁外的一种糖类化合物，研究表明，乳酸菌胞外多糖在调控肠道屏障功能、维护肠道健康上具有重要功能[5-7]。本文对乳酸菌胞外多糖调控动物肠道屏障功能的作用及机制作一概述，为其在动物生产中的推广应用提供指导。
1 乳酸菌胞外多糖概述 1.1 乳酸菌胞外多糖的分类乳酸菌是一类可利用碳水化合物而产生大量乳酸的细菌，根据Bersy细菌学手册中分类法，乳酸菌包括乳杆菌属、链球菌属、明串珠菌属、双歧杆菌属和片球菌属5个属[8]。乳酸菌胞外多糖是乳酸菌在生长代谢过程中分泌到细胞壁外，并与菌体分离的一类多糖化合物，主要包括黏液多糖和荚膜多糖2类[9]。从化学组成上，乳酸菌胞外多糖又分为同型多糖和杂型多糖。同型多糖是由10个或以上相同的单糖组成的胞外多糖，主要由葡萄糖和果聚糖组成；杂型多糖则是由多种单糖组成的重复单元，每个重复单元包括3~8个单糖，主要由半乳糖、葡萄糖、鼠李糖和N-乙酰基半乳糖胺等组成[10]。胞外多糖的产量和组成主要依赖于乳酸菌的培养和发酵条件，但由于同型多糖结构较简单，通常情况下同型多糖比杂型多糖的产量更高[11]。
1.2 乳酸菌胞外多糖的主要作用 1.2.1 抗氧化功能氧化应激通过破坏机体内生物大分子(脂质、蛋白质、DNA和RNA)导致组织损伤并引起多种疾病的发生。乳酸菌胞外多糖有较强的抗氧化能力，发酵乳杆菌S1所产胞外多糖具有清除机体内1，1-二苯基-2-三硝基苯肼(DPPH)自由基和羟自由基的活性[12]，而Xu等[13]研究表明，植物乳杆菌KX041产生的胞外多糖能清除DPPH/2, 2’-联氨-双-3-乙基苯并噻唑啉-6-磺酸(ABTS)自由基和保护DNA损伤。研究证实，胞外多糖的抗氧化活性具有较强的剂量依赖效应，即胞外多糖的浓度越高，清除自由基的能力越强；也有研究认为，胞外多糖的抗氧化活性与其分子质量相关，分子质量越小的胞外多糖抗氧化活性越强[14-15]。
1.2.2 抗肿瘤功能1982年Shiomi等首次报道乳酸菌胞外多糖具有抗肿瘤活性。目前，已有20多种乳酸菌(如干酪乳杆菌、鼠李糖乳杆菌、嗜酸乳杆菌、植物乳杆菌和双歧杆菌等)胞外多糖被证实具有抗肿瘤、抗癌作用[16-21]。乳酸菌胞外多糖能抑制人结肠癌细胞HT-29的增殖，并能诱导G0/G1细胞周期停滞和引起细胞凋亡[18]。嗜酸乳杆菌20079所产的胞外多糖能刺激结肠癌细胞Caco-2免疫应答和抑制核因子-κB(NF-κB)炎症通路，并通过促凋亡作用对细胞产生毒性，抑制细胞生长[19]。植物乳杆菌NCU116的胞外多糖(EPS116)通过Toll样受体2(TLR2)，并依赖于原癌基因(c-Jun)和凋亡相关因子受体/配体(Fas/Fas L)信号通路引起结肠癌细胞CT26凋亡，从而发挥抗肿瘤的作用[20]。以上研究结果表明，乳酸菌胞外多糖主要通过抑制癌细胞增殖、促进细胞凋亡或影响胞内信号传导来发挥抗肿瘤活性，从而预防癌症的发生。
1.2.3 免疫调节功能乳酸菌胞外多糖主要通过激活免疫细胞以及诱导细胞因子的产生来调节机体免疫功能。胞外多糖能增强巨噬细胞的吞噬作用，促进肿瘤坏死因子-α(TNF-α)、白细胞介素-6(IL-6)、白细胞介素-10(IL-10)和白细胞介素-12(IL-12)的分泌，上调树突细胞中主要组织相容性复合体Ⅱ(MHCⅡ)和白细胞分化抗原86(CD86)表达来促进细胞成熟，同时还能促进T细胞的增殖和分化[22-23]。乳酸菌胞外多糖还能增加淋巴细胞增殖和肠黏膜免疫球蛋白A(IgA)含量，促进白细胞介素-2(IL-2)和TNF-α的分泌来增强小鼠的免疫功能[24]。研究认为，乳酸菌胞外多糖的免疫调节作用与其结构或分子质量有关，含硫酸基或磷酸基的胞外多糖能更有效地诱导免疫细胞的活化与增殖，刺激其分泌细胞因子等活性物质[25-26]，而低分子质量的胞外多糖比高分子质量胞外多糖更能诱导巨噬细胞产生更多的炎性因子[27]。
2 乳酸菌胞外多糖调控动物肠道屏障功能肠道屏障是由肠机械(上皮)屏障、化学屏障、微生物屏障和免疫屏障4个部分组成的复杂结构。肠上皮细胞及细胞间的紧密连接构成肠机械屏障；化学屏障是指肠上皮细胞分泌的黏液、消化液及肠腔里的抑菌物质；正常微生物菌群与肠黏膜一起抵抗外来致病菌的定植，同时维持肠道微生态平衡，形成了微生物屏障；肠上皮细胞分泌的抗体及肠相关淋巴组织组成免疫屏障[28]。完整的肠道屏障对生物体的肠道功能至关重要，任何一方面受到损害，都能导致肠道功能紊乱。研究显示，乳酸菌胞外多糖通过调节肠道黏膜屏障、促进乳酸菌的黏附、调节菌群平衡以及提高肠黏膜免疫力来提高动肠道屏障功能。因此，本文主要从肠机械屏障、微生物屏障以及免疫屏障3方面来阐述乳酸菌胞外多糖是如何在动物肠道中发挥益生作用的。
2.1 乳酸菌胞外多糖调节肠机械屏障功能肠机械屏障是畜禽肠腔和内环境之间的第1道防线，主要通过形成物理屏障、分泌抗菌肽和黏蛋白等化学屏障来保护机体不受病原微生物及毒害物质的侵入，减少炎症反应。肠机械屏障上的紧密连接复合体主要包括闭合小环蛋白-1(ZO-1)、闭锁蛋白(occludin)和闭合蛋白(claudins)，它们在维持肠道屏障的通透性中发挥重要作用[29]。Zhou等[30]研究发现，EPS116能减弱葡聚糖硫酸钠(DSS)诱导的小鼠结肠炎症，EPS116通过磷酸化和激活信号传导与转录激活因子3(STAT3)，促进STAT3与occludin和ZO-1的启动子结合，提高紧密连接蛋白的表达，修复损伤的肠机械屏障，从而保护肠道屏障的完整性。健康受试者服用嗜热链球菌ST10所产的胞外多糖后，用尿中乳糖醇/甘露醇和三氯蔗糖浓度分别评估小肠和结肠渗透性，与对照组相比，发现小肠和结肠通透性均出现显著下降，肠道屏障功能得到改善[31]。还有研究发现，乳酸菌胞外多糖在肠道内可代谢产生短链脂肪酸，短链脂肪酸(尤其是丁酸)可被肠上皮细胞吸收利用，并促进肠上皮细胞增殖，从而增加肠机械屏障的强度[32]。
目前发现的乳酸菌胞外多糖对肠机械屏障的作用机制主要包括：1)依赖于转录因子信号通路，促进紧密连接蛋白表达；2)在肠上皮细胞表面形成与肠道屏障黏液层相似的亲水凝胶层，降低肠道通透性；3)产生肠上皮细胞的重要能源分子—短链脂肪酸，从而发挥其保护肠机械屏障的作用。
2.2 乳酸菌胞外多糖调节肠道微生物屏障功能乳酸菌胞外多糖能调节肠道内微环境和肠道微生物菌群，并改变宿主肠道菌群多样性。布氏乳杆菌TCP016所产胞外多糖(EPS016)能减少小鼠肠道螺杆菌科、毛螺菌科和肠杆菌科的丰度，增加乳杆菌属、理研菌科、拟杆菌科和普雷沃氏菌科的丰度，EPS016还通过调节肠道菌群来减轻脂多糖/D-半乳糖胺诱导的肝损伤[33]；Zhang等[34]则发现，饲喂植物乳杆菌YW11所产胞外多糖能改变衰老小鼠肠道菌群结构，肠道Flexispira的丰度显著降低，布劳特氏菌属和Butyricicoccus的丰度显著增加。此外，罗伊氏乳杆菌和阴道乳杆菌所产胞外多糖在体外能抑制大肠杆菌和鼠伤寒沙门氏菌生长[15]，从牛奶发酵的开菲尔酒中提取出马乳酒样乳杆菌，其胞外多糖对单核细胞增生李斯特氏菌和肠炎沙门氏菌具有抗生长作用[35]，证实乳酸菌胞外多糖在体外也能抑制病原菌的生长。胞外多糖是乳酸菌的主要黏附素，会影响乳酸菌在肠道上皮中定植的能力，研究表明，鼠李糖乳杆菌和干酪乳杆菌所产胞外多糖影响它们对肠上皮细胞的黏附，对乳杆菌去糖基化后黏附效率显著降低[36-37]。胞外多糖对肠上皮细胞的黏附作用有助于乳酸菌在肠道定植，抑制病原菌的定植[38]。短双歧杆菌UCC2003所产的胞外多糖能降低肠道鼠柠檬酸杆菌定植水平，促进上皮细胞释放抑菌物质来抑制有害菌的生长[39]。产肠毒素大肠杆菌(ETEC)能导致仔猪严重腹泻，Chen等[40]研究发现，罗伊氏乳杆菌胞外多糖能拮抗ETEC对仔猪肠黏膜的黏附，减少因ETEC感染引起的体液流失。细胞试验也证实，罗伊氏乳杆菌胞外多糖预处理能显著抑制ETEC对猪肠上皮细胞的黏附性[41]。
微生物屏障是肠道微生物群对抗病原体的重要保护屏障，乳酸菌胞外多糖主要通过调节肠道菌群平衡、促进乳酸菌的生长和抑制病原菌的黏附定植来调节动物肠道微生物屏障功能，但具体分子机理目前尚不清楚，需进一步研究。
2.3 乳酸菌胞外多糖调节肠道免疫屏障功能肠道免疫屏障主要由肠上皮细胞、肠上皮内淋巴细胞、固有层免疫细胞、派伊氏结和肠相关性淋巴组织组成，肠道免疫系统可分泌免疫球蛋白、干扰素和白细胞介素等因子调节肠道免疫功能[42-43]。Matsuzaki等[44-45]研究发现，明串珠菌NTM048所产的胞外多糖通过促进IgA的分泌来刺激黏膜免疫系统，从而增强肠道黏膜免疫屏障。干酪乳杆菌胞外多糖通过促进小鼠肠淋巴结上CD4+T淋巴细胞分化为辅助性T细胞17(Th17)来提高肠黏膜免疫力[46]。乳酸菌胞外多糖可依赖于Toll样受体(TLRs)及其参与的信号通路发挥免疫作用，研究发现，2株乳杆菌所产的胞外多糖均能降低TLR功能缺陷细胞的炎性因子表达，后续试验发现胞外多糖通过防辐射蛋白105/髓样分化蛋白1(RP105/MD1)途径下调肠上皮细胞的炎症反应[47-48]。Gao等[49]研究发现，鼠李糖乳杆菌胞外多糖通过调节TLRs的表达，并抑制丝裂原活化蛋白激酶(MAPK)和NF-κB信号传导来减少肠上皮细胞的炎症因子。瑞士乳杆菌和嗜酸乳杆菌所产的胞外多糖能显著提高人肠上皮细胞促炎因子白细胞介素-8(IL-8)的表达水平，调节细胞TLRs表达[7]。乳酸菌胞外多糖处理能增加细胞对细菌抗原的敏感性，并通过与肠上皮细胞的特异性互作从而在肠道稳态中发挥作用。Tkáčiková等[50]用转录组学分析罗伊氏乳杆菌L26所产胞外多糖对ETEC感染的猪肠道上皮细胞基因表达的影响，发现ETEC能够通过激活模式识别受体引起先天免疫应答，而胞外多糖预处理能够减轻ETEC引起的基因过表达，说明胞外多糖能抑制ETEC引起的炎症反应。胞外多糖还能调节肠道抗病毒的免疫效力，体外试验证实德氏乳杆菌所产胞外多糖能提高抗病毒因子干扰素-α(IFN-α)和干扰素-β(IFN-β)、黏病毒抗性蛋白A(MxA)和核糖核酸酶L(RNase L)的表达，下调IL-6和促炎性趋化因子的表达，调节由Toll样受体3(TLR3)激活触发引起的细胞先天免疫应答[51]。胞外多糖还能通过减少病毒复制和调节炎症反应来提高细胞对轮状病毒感染的抵抗力[52]。
近年来，越来越多的研究证实，乳酸菌胞外多糖通过在动物肠黏膜上发挥抗炎、抗病毒作用，从而提高肠道免疫屏障功能，在一定程度上提高机体免疫力(表 1)，涉及到的机制主要包括：1)促进肠黏膜IgA的分泌，调节肠道保护性免疫力，维持肠道稳态，并通过释放细胞因子影响全身免疫；2)激活肠道免疫细胞的活性，促进重要生长因子的生成，保护肠道免疫屏障功能；3)调控TLRs及其所参与的信号通路，或通过细胞表面模式识别受体改变细胞信号传导和转录因子，从而发挥免疫作用。但不同胞外多糖调节肠道免疫屏障的具体机制不相同且并不明确，需进一步研究确证。
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表 1 乳酸菌胞外多糖对动物肠道免疫屏障功能的作用 Table 1 Effects of lactic acid bacteria exopolysaccharide on intestinal immunological barrier function of animals |
乳酸菌是人和动物胃肠道内重要的益生菌，而乳酸菌重要代谢产物——胞外多糖在其和宿主肠道细胞互作过程中发挥了重要的作用。多个研究证实，乳酸菌胞外多糖能通过多种途径(肠机械屏障、微生物屏障及免疫屏障)保护动物肠道屏障功能、维护肠道健康。由于乳酸菌胞外多糖转化效率低且生产成本高，目前应用到工业化生产的胞外多糖较少，因此，需要对胞外多糖功能及其发挥的机制进一步研究和确定，通过基因工程手段获得高产胞外多糖菌株并应用到生产中。乳酸菌胞外多糖调节肠道屏障功能的研究目前主要集中在小鼠及体外细胞模型上，对于其在猪、羊、鸡等畜禽上的研究还较少。今后的研究可通过在畜禽上开展更多体内和体外试验，探明其调控畜禽肠道屏障功能的作用及其机制，为乳酸菌胞外多糖作为饲料添加剂或动物保健药物应用于在畜牧业中提供依据。
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