2. 内蒙古自治区农牧业科学院动物营养与饲料研究所, 呼和浩特 010031
2. Institute of Animal Nutrition and Feed Science, Inner Mongolia Academy of Agricultural & Animal Husbandry Sciences, Hohhot 010031, China
在短短的几十年里，奶牛的生产性能大幅度提高，然而随着产奶量的增加，奶牛膳食营养管理需求变得越来越艰难[1]。目前在许多奶牛场，由于高产奶牛不易满足能量和纤维的需求，奶牛的产奶量会因过度饲喂高精料饲粮而暂时增加[2-3]，高淀粉、低纤维素饲粮可增加能量摄入并使奶牛患亚急性瘤胃酸中毒(SARA)的风险上升[2-6]，而SARA是高产奶牛公认的一种消化系统疾病，对奶牛健康和牛群整体盈利能力有负面影响[7-11]。SARA可造成奶牛不同器官和组织的炎症效应，其后果是多样而复杂的，包括采食量降低、乳脂率降低、胃肠黏膜损伤、肝脓肿和跛足等[12-13]。因此，奶牛场可能存在SARA的较高风险，多数是过于重视奶牛的生产力，而忽略由于精粗饲料的配比不平衡引起瘤胃内易消化的碳水化合物类型精饲料的快速发酵，由此在瘤胃内形成较多的短链脂肪酸(SCFA)。通常情况下，形成的SCFA会被瘤胃上皮细胞吸收，使瘤胃内环境维持正常的pH范围。如果多次多量投喂精饲料而少量的粗饲料，会造成瘤胃上皮细胞吸收SCFA的速度低于其形成的速度，进而多余的SCFA在瘤胃中积累，瘤胃内环境中pH下降，使SARA的发生率升高[14-15]。
处于SARA时，瘤胃内环境稳态受到破坏，使瘤胃上皮组织的屏障功能受损。钠离子耦合单羧酸转运蛋白1(SLC5A8)与氢离子耦合单羧酸转运蛋白1(MCT1)是瘤胃上皮细胞内SCFA的转运蛋白，当瘤胃内环境处于正常pH范围时，瘤胃中SCFA可促进SLC5A8和MCT1基因的表达，使其发挥正常功能。当反刍动物发生SARA时，瘤胃内SCFA形成的速度过快，以至于负责转运SCFA的SLC5A8和MCT1蛋白受到抑制，而不能及时调控瘤胃pH范围，造成瘤胃pH长时间处于低值，影响了瘤胃上皮细胞对SCFA的吸收和转运功能。本文就SLC5A8和MCT1对瘤胃上皮细胞内SCFA的转运机制的影响进行综述，并一步探讨在SARA发生时，SLC5A8和MCT1可能存在的保护作用机制，并对SLC5A8和MCT1基因家族的转运机制根据最新研究进展进行补充。
1 SARA的定义目前SARA的定义和瘤胃pH阈值因研究而异。SARA是指瘤胃pH处于5.2~6.0较长时间而发生的营养代谢性疾病[16]。Plaizier等[17]在饲喂奶牛4 h后使用胃管时，得出结果以瘤胃pH为6.0作为阈值。Garrett等[18]使用瘤胃穿刺法将SARA的阈值定义为5.5。Duffield等[19]通过观察发现胃管采集的瘤胃液比瘤胃穿刺采集的瘤胃液pH会高0.33和0.35个单位，当通过瘤胃穿刺、胃管和使用口腔探针采集瘤胃液，pH都有所差别，SARA的pH阈值显示分别为5.5、5.8和5.9。在SARA期间，由于SCFA的积累和瘤胃缓冲液不足，瘤胃pH每天会下降数小时[12]。通常情况下，瘤胃pH在晨饲前几乎为中性，晨饲后为酸性。在饲粮精粗比适宜条件下，瘤胃内环境pH在6~7，是纤维素分解菌繁殖和发育的最适条件。随精料含量的增加，瘤胃pH在6以下会周期性下降。因此，1 d内超过3 h瘤胃pH低于5.6界定为发生SARA。引发SARA发生的因素及其机制很多，SCFA是其中之一。
2 SCFA的调节机制SCFA是瘤胃微生物菌群中一类低于6个碳原子的脂肪酸，在瘤胃内经发酵产生的乙酸、丙酸、丁酸以及戊酸等构成的总体名称，SCFA在瘤胃液中所占总酸的比重较大[20]，是瘤胃中最主要的脂肪酸。SCFA在瘤胃中存在的2种形式：可解离的SCFA(SCFA-)和非解离的SCFA(HSCFA)，其SCFA-形式占SCFA的大部分，主要在瘤胃内环境pH偏低时，SCFA-与H+结合形成HSCFA，占总体SCFA较小部分，使其吸收多余的SCFA并中和瘤胃的酸性环境。总之，SCFA在一定程度上可调节反刍动物瘤胃内环境的pH[21]。艳城[22]试验发现，在反刍动物采食1.5 h后检测瘤胃液pH可达到最低值，之后随时间延长pH有所回升，说明瘤胃内SCFA的积累可造成pH的降低，进一步刺激瘤胃上皮细胞对SCFA的吸收。当SCFA在瘤胃内产生较多时，会导致瘤胃内环境H+浓度短时间内升高，而瘤胃内环境pH处于低值范围，因此SCFA的吸收有利于瘤胃pH的稳定[23]。王忠豪等[24]试验证实了反刍动物在采食后瘤胃微生物产生的SCFA高于瘤胃上皮细胞吸收的SCFA，从而使多余的SCFA在瘤胃内蓄积，进一步导致了瘤胃内环境pH的降低，促使SARA发生。范雪等[25]的研究表明，适宜添加外源性SCFA可改进瘤胃pH和微生物种群，使有益微生物在瘤胃中定植并加强瘤胃的发育。学者总结了SCFA的多种生物学功能，在饲粮中适宜添加外源性SCFA可提高动物的抗病力，维持肠道的完整性[26-28]。这说明在瘤胃内SCFA吸收能力与瘤胃上皮细胞的结构相关。因此，在反刍动物瘤胃中，不论是机体内产生的还是外源性添加的SCFA，适宜浓度的SCFA可正向促进瘤胃组织的发育，在反刍动物发生SARA时，瘤胃内的SCFA吸收能力低于微生物产生SCFA的能力，由于过多的SCFA会抑制其吸收和转运的蛋白，而导致滞留在瘤胃中的SCFA大量蓄积，使瘤胃内环境有利于耐酸微生物的生长，抑制降解酸的微生物生长，从而加剧瘤胃酸中毒，造成反刍动物的能量代谢和瘤胃内环境稳态失衡。曾霖等[29]研究通过SCFA调控宿主细胞的肠道菌群和肝脏等代谢性疾病，从而减缓机体全身性炎症，这表明SCFA对机体代谢性疾病起到主要调节机制。
2.1 在糖、脂代谢方面的调节机制SCFA是瘤胃微生物种群中的代谢产物，以纤维性饲料发酵产生，然后被吸收到肠系膜上下静脉，汇入门静脉到肝脏，进而一部分的SCFA被用作糖异生途径、酮体和脂质合成的底物，为机体的糖、脂代谢供能；另一部分的SCFA以游离脂肪酸的形式经肝静脉进入外周循环参与其他途径。对于反刍动物来说，瘤胃内以SCFA的吸收和转运为主，通过瘤胃上皮吸收或转运到肝脏进行糖、脂代谢，作为能量物质为动物机体所利用。而非反刍动物以肠道中微生物发酵产生SCFA为主。程雅婷等[30]总结了SCFA可促进猪肠道营养物质的转化速率，并作为一种绿色、安全的饲用抗生素添加剂在猪养殖上有较高的应用前景。SCFA可通过调节β细胞功能，改善胰岛素抵抗以调控糖代谢。Li等[31]研究发现，SCFA中的丁酸盐可抑制含脂肪高的饮食诱导的β细胞凋亡，试验结果表明SCFA在胰岛素敏感程度上有调节作用[32]。SCFA还可通过多种途径调控糖、脂代谢，SCFA可通过激活腺苷酸活化蛋白质激酶(AMP-activated protein kinase，AMPK)而促进脂肪酸转化、分解和加速线粒体生物代谢, 从而抑制脂肪合成[33]。Den Besten等[32]研究丁酸可调节肝脏和肌肉中过氧化物酶体增殖物激活受体γ(PPARγ)，使其表达下降并促进线粒体代谢，并激活AMPK通路，抑制脂肪合成[34]。
2.2 在能量代谢方面的调节机制SCFA在反刍动物能量来源占比60%~70%，可直接参与维持细胞稳态来提供能量来源，减少营养代谢性疾病的发生。研究发现，细胞膜表面存在与SCFA特异性结合的受体, 即G蛋白偶联受体(G-protein coupled receptor，GPCR)，例如GPR43、GPR41和CPR109A等[35]，其作为信号因子参与机体代谢有着重要意义。SCFA主要通过三大途径来调控机体的能量代谢，分别为减少摄食、提高产热效率和激活肠道糖异生：1)SCFA中的丙酸盐与相应细胞膜上的受体蛋白GPR41、GPR43结合，并促使机体细胞释放的短肽YY(PYY)和胰高血糖素样肽-1(GLP-1)的增加，经过“脑-肠轴”神经循环途径来达到饱腹感从而减少摄食[36-37]。2)SCFA通过增加肝脏和肌肉中过氧化物酶体增殖物激活受体γ共激活因子-lα(peroxisome proliferator activated receptor γ coactivator-lα，PGC-lα)和一磷酸腺苷激活蛋白酶的表达进一步使动物机体产生热量。由于PGC-1α是线粒体生物发生的重要调控因子, 与能量代谢关系密切，而AMPK激活可磷酸化转录共刺激因子PGC-lα。因此，活化的AMPK还能通过磷酸化转录因子EB(transcription factor EB，TFEB), 促使其入核与PGC-1a基因的启动子结合，调节对PGC-1α转录的活性，促进其表达，进而控制SCFA的能量代谢。SCFA通过促进棕色脂肪(BAT)中线粒体解偶联蛋白，增加其解偶联蛋白-1(UCP-1)的表达并促进BAT分解放热，使机体集中产生热量[38]。3)肠道糖异生(IGN)对维持机体葡萄糖稳态有重要作用[39]，丁酸盐可直接促进葡萄糖-6-磷酸酶和磷酸烯醇式丙酮酸羧激酶1的表达，通过环磷酸腺苷(cAMP)依赖机制触发IGN反应，使下丘脑食欲调节神经肽的表达量下降，从而使机体食欲降低，维持机体葡萄糖内环境的平衡[40]。杨东明等[41]总结SCFA从机体代谢的分子机理上到受体蛋白再到表观遗传学调控了机体的能量代谢，如果SCFA代谢失衡，会引起机体多联级炎症反应，因此SCFA在机体能量代谢中发挥重要作用。
2.3 在维持屏障和减轻炎性反应的调节机制SCFA可为瘤胃上皮细胞提供能量、降低渗透压、保持肠道健康，并参与瘤胃上皮细胞微生物屏障的构建，使之免受病原微生物的侵害，同时刺激反刍动物免疫系统的发育和成熟，调控瘤胃上皮的新陈代谢[42]。如果瘤胃内SCFA不断产生，瘤胃上皮组织吸收转运受到抑制，会促使瘤胃内的微生物种群结构失衡，瘤胃内环境pH长时间处于酸性范围，反刍动物发生SARA概率增加，由于瘤胃上皮细胞对组胺的渗透性低，革兰氏阴性细菌对低pH的敏感性，会促使瘤胃内脂多糖(LPS)和组胺浓度升高[43]，通过血液循环易诱发机体炎症反应，并有损瘤胃上皮屏障机能，最终影响反刍动物的健康和生产性能[44]。Ametaj等[45]通过代谢组学方法，研究发现试验组瘤胃内LPS浓度是对照组的14倍，并可促使瘤胃内其他微生物的参与，共同侵蚀瘤胃上皮屏障，进而说明高浓度LPS可损害机体屏障机能。反刍动物发生SARA时，促进机体的免疫细胞以及炎性因子的释放，而SCFA可调节免疫细胞趋化性[46]，付阳[47]通过SCFA对内皮细胞中的Nod样受体蛋白3(NLRP3)调节的试验结果，发现SCFA可对NLRP3炎症体激活有影响。乙酸与GPR43结合作用于中性粒细胞，可提高先天性免疫反应，使大量中性粒细胞集聚在炎症部位发挥作用[48]。而Zhao等[49]的研究表明，由于高精料的饲喂而引起机体产生SARA，进一步在动物的血液和瘤胃液中发现高浓度的LPS[50]，这一机制可刺激瘤胃上皮细胞促炎因子[如肿瘤坏死因子-α(TNF-α)、白细胞介素(IL)-6、IL-1β][51]和MAPK的表达，并参与损坏瘤胃屏障功能。而SCFA可抑制核因子-κB(NF-κB)信号通路，减少IL-6、IL-12等促炎因子的释放，并可下调多种趋化因子的表达，进而增加IL-10、IL-4等抗炎因子的释放，修复机体屏障。SCFA还可使肠黏膜屏障免受损而减缓炎症的产生，可通过维持肠道屏障稳定性而抑制乙醇等有毒物质的转运，使血液和瘤胃液中LPS的浓度下降，因此减小机体炎症反应[52]。
3 SLC5A8和MCT1在SCFA中的转运机制 3.1 SLC5A8在SCFA转运中的机制SLC5家族即以钠离子为底物的转运体基因家族(sodium substrate symporter family, SSSF)，是葡萄糖转运蛋白的第2个家族，其中已经有12个被证实存在于人类基因组且在不同组织中表达。SLC5A8是Rodriguez等[53]在2002年发现的，从人肾cDNA文库中克隆鉴定的编码610个氨基酸蛋白的序列，位于人类染色体的12q13-23。SLC5A8基因是通过Na+耦合方式对SCFA进行转运。由于SLC5A8转运体有效的辅助转运，SCFA在瘤胃上皮细胞层可达到很高的浓度。因此, 瘤胃内免疫细胞的SCFA受体在这种生理环境下被激化表达，瘤胃肠道菌群新陈代谢产物所激活的肠道免疫系统与各种炎症相关的生理及病理状态之间便产生联系。陈娜[54]研究表明，SLC5A8基因表达主要位于结直肠组织细胞的胞质中，当发生SARA时，瘤胃微生物群体失衡，会导致瘤胃上皮组织屏障受损，因此, SLC5A8基因的正常表达对保护瘤胃上皮细胞免于炎症至关重要。SLC5A8基因在多种组织中发现有表达，由于其在分子层面上对正常细胞有保护机制，因此在人类多种癌症方面研究较多。在反刍动物主要分布于瘤胃上皮细胞，通过SLC5A8蛋白有效转运SCFA，使其浓度回到正常水平，如果SCFA的转运蛋白受到抑制会使正常细胞生理功能失常，影响瘤胃上皮细胞正常代谢和增殖，因此对于维持瘤胃上皮细胞屏障免于炎症损害有很大的必要性。Sivaprakasam等[55]研究SLC5A8基因通过介导SCFA进而可对机体炎症性疾病进行调控。在刘岩[56]的研究中发现，SLC5A8基因通过影响微生物环境而预防组织器官的免疫屏障(T细胞亚群)发生炎性病变，证实SLC5A8基因表达对T细胞产生干扰素-γ(IFN-γ)具有抑制作用，使瘤胃内环境稳定。George等[57]的试验发现，SLC5A8蛋白不正常转运会破坏胃黏膜免疫屏障。王亚洲[58]试验证实了在发生SARA时，大量的SCFA积聚在瘤胃中，SLC5A8基因表达受到抑制，使转运和吸收机制减缓，因此瘤胃pH内环境得不到缓冲呈现酸性环境。岳文炬[59]总结了SLC5A8基因表达对于炎症性直肠病免疫应答时血清中IL-10及转化生长因子-β1(TGF-β1)含量的影响，进而对维持肠道免疫屏障CD4+T细胞有重要作用。因此，对于探究反刍动物发生SARA时，SCFA在瘤胃内的迅速增加，通过瘤胃上皮细胞上SLC5A8蛋白的吸收和转运，可有效减缓SCFA在瘤胃内的蓄积，进一步减轻SARA的发生，这一发生机制有重要意义。SLC5A家族转运体的组织分布及调节机制见表 1。
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表 1 SLC5A家族转运体的组织分布及调节机制 Table 1 Tissue distribution and regulatory mechanism of SLC5A family transporters |
在pH常态下，瘤胃中SCFA以离子形式存在，吸收和转运依赖于MCT。MCT家族已发现有14位成员，具有相似的生化特征，并在不同组织中有表达[71]。MCT1~4是离子共转运载体，其介导的单羧酸转运与H+相偶联共同转运。其中MCT1的分布最为广泛，含有12个跨膜区的55 kDa蛋白[72]，MCT1蛋白通过H+耦合方式对SCFA进行转运，为机体各组织代谢提供代谢基底物并参与运输。研究发现，MCT1基因在反刍动物瘤胃中表达最高[58]，高精料饲粮可引起反刍动物发生SARA。Metzler-Zebeli等[73]研究发现，高精料饲粮的配比与反刍动物瘤胃上皮MCT1基因的表达量呈正相关。瘤胃上皮细胞中MCT1蛋白通过与H+耦合转运SCFA进入血液，此过程也使多余的H+转运出去，进而降低瘤胃上皮细胞酸中毒风险，最终维持瘤胃pH内环境稳定。MCT1基因表达水平的升高降低了瘤胃内的酸负担，加速了SCFA的转出速度，从而为机体提供能量来源。而一些研究结果显示，MCT1基因表达情况与SCFA含量呈现负相关，与pH呈现正相关情况[24, 74]。闫磊等[75]分别饲喂山羊精料含量为10%和35%的2种饲粮，结果表明35%高精料饲粮可引起山羊瘤胃上皮MCT1基因表达升高。刘军花等[76]发现高谷物饲粮可促进山羊瘤胃上皮的MCT1基因表达并引起瘤胃pH降低和SCFA浓度升高，从而发生SARA。一些研究表明，当奶牛处于SARA时，瘤胃上皮细胞中的SLC5A8和MCT1基因可能受到抑制而不能正常表达，因此不能及时吸收和转运SCFA，结果导致SCFA在瘤胃内环境中长时间发酵集聚，最终瘤胃内环境pH下降[58, 77]。MCT家族转运体的组织分布及功能见表 2。
4 小结SLC5A8和MCT1在吸收和转运瘤胃上皮细胞内SCFA具有重要意义。机体处于SARA时，瘤胃内环境中嗜酸性微生物大量繁殖，使pH处于酸性范围，最终影响了瘤胃上皮细胞对SCFA的吸收和转运功能。SLC5A8和MCT1作为瘤胃上皮细胞内SCFA的单羧酸转运蛋白，可将产生的SCFA适宜地转运和吸收到其他循环系统中利用，从而使瘤胃内环境处于正常pH范围。瘤胃中SCFA可促进SLC5A8和MCT1基因表达，使其发挥适宜的转运机制，有其相互作用的联系。当反刍动物发生SARA时，瘤胃内淀粉性饲料由于其转化速度快，不断累积形成SCFA，瘤胃内浓度较高SCFA使负责转运的SLC5A8和MCT1蛋白受到抑制，不能及时转运和吸收多余的SCFA，堆积在瘤胃中，造成瘤胃pH长时间处于低值，可能触发动物机体炎症的发生。因此，研究SLC5A8和MCT1基因调控SCFA，从而减缓动物SARA的发生机制具有深远意义。
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