2. 中国科学院亚热带农业生态研究所, 动物营养生理与代谢 过程湖南省重点实验室, 亚热带农业生态重点实验室, 畜禽养殖污染控制与资源化技术国家工程实验室, 湖南省畜禽健康养殖工程技术研究中心, 农业部中南动物营养与饲料科学观测实验站, 长沙 410125;
3. 湖南畜禽安全生产协同创新中心, 长沙 410128
2. Institute of Subtropical Agriculture, Chinese Academy of Sciences, Key Laboratory of Animal Nutritional Physiology and Metabolic Process in Hunan Province, Key Laboratory of Agro-Ecological Processes in Subtropical Region, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Research Center of Healthy Breeding Livestock and Poultry, Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Changsha 410125, China;
3. Hunan Co-Innovation Center of Animal Production Safety, Changsha 410128, China
动物肠道内定植着大量的微生物，统称为肠道微生物(intestinal microbiota)。肠道微生物的定植开始于动物个体出生，并随着动物生长发育而改变，最后形成一个动态平衡的肠道微生态系统。人类肠道微生物个体总数量约为1×1014个，涵盖500~1 000个属，其所编码的基因约是人类基因组的100倍[1-2]。肠道微生物区系的组成与宿主的营养和健康状态密切相关，可以调节宿主的稳态和健康，具体表现在调节营养物质的消化、吸收与代谢、黏膜免疫功能及减少病原体定植等。肠道微生物也可以提升动物饲料转换率和采食量，影响平均日增重和体重。肠道微生物易受多种因素的影响，包括环境状况、饮食、药物使用、宿主个体基因型、免疫反应以及病源微生物感染，而饮食结构的变化是影响肠道微生物区系组成的最重要的因素之一。
脂肪酸(fatty acids，FAs)是机体中主要的能量来源，是多种脂质，包括磷脂的信号分子的前体以及细胞膜的主要成分，对细胞膜的柔韧性起着重要作用。同时，FAs也是许多生化途径的代谢底物和细胞信号分子，调节机体免疫反应以及肠道微生物[3]。近年来，通过改变饮食结构或补充功能性成分有益地影响微生物的组成引起了人们越来越多的关注。本文综述了机体中肠道微生物与FAs的相互作用及其机制，以期为饮食中FAs种类的选择以及配比提供理论依据。
1 肠道微生物对机体FAs的影响在哺乳动物中，肠道微生物对宿主的脂质代谢和胆固醇代谢有重要影响。研究表明，肠道双歧杆菌数量与血浆高密度脂蛋白含量存在显著的正相关，肠道红蝽菌科数量与血浆非高密度胆固醇含量存在高度的负相关关系[4]，肠道Fusicatenibacter数量与血浆胆固醇含量存在高度的负相关关系[5]，肠道拟杆菌可以增加短链脂肪酸(short-chain fatty acids，SCFAs)产生[6]。
在空肠中，肠道微生物获取的能量主要来自果糖和甘露糖的糖酵解和糖异生反应；然而，在回肠中，可能由于肠道内有梭菌目，主要通过FAs、丙酮酸代谢和二甲苯降解获取能量[7]。在机体中，厚壁菌门和拟杆菌门是相对丰富的2种菌门。其中，拟杆菌门主要产生乙酸和丙酸，并与许多碳水化合物代谢途径密切相关，通过产生糖苷水解酶和多糖裂解酶，降解多糖和寡糖，从而降解黏蛋白和植物性碳水化合物[8-9]；而厚壁菌门主要产生丁酸，与运输系统相关，主要参与动物能量代谢。此外，厚壁菌门和拟杆菌门在体内也调节脂肪代谢，并可以通过消化残留物质产生SCFAs，为宿主提供能量[10]；普氏菌门也可以发酵、水解饮食纤维产生乙酸和丙酸，并在合成复合膳食多糖的过程中至关重要[11]。
2 FAs对肠道微生物的影响 2.1 SCFAs在宿主代谢中，SCFAs不仅是体内重要的能量来源，参与葡萄糖和脂质合成代谢，还可以调节肠道微生物组成，促进肠道有益菌增殖，抑制有害菌生长(表 1)，其原因可能是SCFAs降低了消化物pH，提供了酸性环境，促进了有益菌的生长，进一步排除有害菌的生长，维持了肠道微生物平衡[12]。因此，FAs对肠道微生物的调节主要为：1)促进肠道有益菌(乳酸杆菌)的生长，减少有害菌(大肠杆菌、沙门氏菌)的繁殖；2)提高肠道微生物多样性。
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表 1 SCFAs对肠道微生物的影响 Table 1 Effects of SCFAs on intestinal microbiota |
在机体中，由于MCFAs和中链甘油三酯(medium-chain triglycerides，MCTs)可以有效地吸收和代谢，并及时为肠细胞提供能量和调节肝脏代谢，因此可以用于幼龄动物营养调控。此外，MCFAs可以影响肠道微生物的组成(表 2)以及抑制消化道中细菌(主要为沙门氏菌和大肠杆菌[19])的浓度，其机制可能是MCFAs在细胞质中裂解为质子和阴离子，降低pH，导致细胞质酶失活，从而诱导细菌细胞死亡[20]。
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表 2 MCFAs对肠道微生物的影响 Table 2 Effects of MCFAs on intestinal microbiota |
n-3长链多不饱和脂肪酸(long chain-polyunsaturated fatty acids，LC-PUFAs)具有抗炎和抗菌的功效。在肠外营养模型完全胃肠外营养(total parenteral nutrition，TPN)中供应n-3LC-PUFAs可能通过提高宿主免疫反应，减少了炎症性肠道微生物数量[26]。胆汁主要由胆汁酸(bile acids, BAs)、胆固醇、磷脂、胆绿素组成。BAs在肝脏由胆固醇转变形成，通过促进脂肪的乳化和溶解，对胆固醇、膳食脂肪和脂溶性维生素等的吸收起着重要作用。研究表明，胆汁通过溶解细菌的细胞膜，调控细菌增殖，从而可能具有抗菌功能[27-28]。Lavallee等[29]研究发现，在仔猪TPN模型中，不同油脂添加改变了微生物组群，其机制可能是改变了宿主生理反应，BAs流动减少了炎症因子[白细胞介素-8(IL-8)]表达。
肠道中n-3PUFAs浓度也可以通过影响碱性磷酸酶基因表达水平和活性，提高肠道屏障功能，改善肠道微生物的区系组成[30]。每日摄入4 g二十碳五烯酸(EPA)和二十二碳六烯酸(DHA)混合物，连续8周，提高了双歧杆菌、颤螺菌属、氏菌属和毛螺菌属数量，减少了粪球菌属、粪杆菌属数量[31]。研究发现，供应n-3PUFAs可以有效改善肠道微生物紊乱，提高宿主肠道微生物恢复力，其机制可能是FAs摄入影响了细菌黏附[32]。富含PUFAs的饮食可以提高有益菌如拟杆菌、普氏菌丰度[33]。然而，也有研究表明，富含n-6PUFAs的饮食提高了潜在致病菌肠杆菌科数量，促进了促炎肠道微生物的生成[34]。
3 肠道微生物与FAs相互作用机制研究目前，探讨肠道微生物在宿主脂质代谢中的研究较少，主要分析关于转录谱和所选脂质种类的丰富度。肠道微生物群参与了复杂的消化、免疫、代谢和内分泌过程，其中通过调节宿主的营养和能量获取，可以影响肥胖、胰岛素抵抗和糖尿病的发展。在机体代谢过程中，肠道微生物产生的SCFAs是宿主的重要能量来源。肠道微生物通过间接和直接2种方式调节脂质代谢和FAs生成。
3.1 肠道微生物间接调控方式肠道微生物可以调节能量代谢和脂质信号传导，是调节宿主代谢中一个重要的环境因子。肝脏是维持整体脂质平衡的重要器官，在许多代谢疾病中发挥着重要作用，特别是2型糖尿病[35]。Bäckhed等[36]研究发现，与传统(conventionally raised，CONV-R)小鼠相比，无菌(germ-free，GF)小鼠肝脏FAs和脂肪组织甘油三酯(TG)合成显著降低，其机制可能是肠道微生物通过发酵碳水化合物产生了SCFAs，随后在肝脏中被吸收用于合成TG，以及肠道微生物抑制了禁食诱导的脂肪因子的相关表达和分泌了一种脂蛋白脂酶(lipoprotein，LPL)抑制剂。
磷脂酰胆碱是核受体过氧化物酶体增殖激活受体(peroxisome proliferator-activated receptor，PPAR)α生理激动剂，可以促进FAs氧化、脂质转运、酮体生成、糖异生和诱导LPL表达。Velagapudi等[37]也发现，GF小鼠影响了磷脂酰胆碱的种类，可能通过抑制PPARα降低了LPL活性，减少了肝脏TG含量；血清中丙酮酸和三羧酸代谢物含量的升高可以影响肠道微生物，肠道微生物通过改变TG和磷脂酰胆碱的种类调节血清、白色脂肪组织和肝脏中脂质代谢。因此，肠道微生物主要通过调节TG含量调节脂质代谢。BAs不仅可以直接或间接的影响肠道菌群，也可以促进BAs耐受细菌的存活。研究表明，肠道微生物通过调节胆碱、BAs和产生乙醇的细菌，可以调节肠道通透性，缓解炎症，影响非酒精性脂肪肝(NAFLD)[38]；BAs从肠道中摄取，并在体内循环，作为一种信号分子，可以结合细胞受体，如核受体法呢醇X受体(farnesoid X receptor，FXR)和细胞膜表面受体G蛋白偶联受体5(cell membrane surface receptor-G protein coupled receptor 5，TGR5)等，从而激活外周器官TGR5和FXR，有助于宿主的整体代谢[39]。研究发现，肠道微生物通过调节FXR、TGR5信号影响脂质和葡萄糖的代谢，促进能量支出，避免饮食诱导的肥胖[40]。
宿主肠道微生物与胆碱转化为有毒的甲胺过程中存在相互作用，改变肠道微生物组成和代谢胆碱能力对于调节脂质代谢非常重要。胆碱，一种含有三甲胺的化合物和磷脂酰胆碱头群的一部分，参与调节肝脏的脂质代谢和极低密度脂蛋白合成，饮食中胆碱水平供应不足显著影响小鼠[41]和人类[42]肠道微生物平衡和肝脏脂肪变性。肠道微生物通过代谢胆碱、磷脂酰胆碱可以产生三甲胺(trimethylamine，TMA)，后进入肝脏经黄素单氧化酶氧化为三甲胺-N-氧化物(trimethylamine-N-oxide，TMAO)。研究表明，在肝脏中，TMAO减少了BAs池的大小，降低了BAs合成和转运蛋白以及脂肪酸合成酶胆固醇7-羟化酶(cholesterol 7-alpha hydroxy-lase, CYP7A1)的表达，其中CYP7A1为BAs合成的关键酶和胆固醇分解代谢中限速酶。在体内，TMAO、胆碱和肉碱通过肠道微生物依赖机制抑制胆固醇逆向转运，肠道中TMAO浓度依赖性降低胆固醇转化为BAs，影响脂质吸收和胆固醇稳态，减少胆固醇代谢[43]。
3.2 肠道微生物直接调控方式SCFAs可以激活孤儿型G蛋白偶联受体(G-protein-coupled receptor，GPR)41和GPR43。GPR41可以与Gi/o蛋白结合作为G蛋白异质三聚体α亚基，在交感神经系统和肠道中作为肠道微生物相关能量传感器[44]。GPR43可以结合Gi/o蛋白或者Gq蛋白作为另一个G蛋白异质三聚体α亚基，主要表达于脂肪组织、肠道和免疫组织[45]，并通过促进瘦素分泌、脂肪生成以及抑制脂肪组织和脂肪细胞脂解，调节能量代谢[46]。通过基因敲除小鼠模型发现，GPR43在调节肠道微生物群对宿主肥胖和免疫力的影响发挥重要作用[45, 47]。Kimura等[48]报道，肠道微生物通过产生SCFAs，调节GPR41和GPR43，从而抑制肝脏FAs合成和脂肪组织的脂质积累。其中，产生丙酸可能是肠道微生物影响脂质代谢的机制之一[49]，结肠中，可溶性膳食纤维通过肠道微生物发酵产生SCFAs，其中丙酸显著降低了肝脏胆固醇合成，调节脂质代谢[50]。同时，研究发现，通过移植拟杆菌和另枝菌(Alistipes)调节乙酸的产生可以提高脂质代谢[51]。普氏菌门通过降解植物细胞壁的蛋白质和多糖，产生SCFAs，也可以提高脂质沉积和生成[11, 52]。此外，供应短双歧杆菌通过利用或吸收某些PUFAs(亚麻酸)或者在肠道中影响了饮食FAs的吸收，提高了脂肪组织EPA、DHA含量和肝脏中共轭亚油酸(CLA)含量[53]。
肠道微生物可以影响营养物质MCFAs和SCFAs的消化和吸收，而SCFAs与整体脂肪代谢呈一定正相关，并与提高血清和肝脏FAs代谢有一定联系[54-55]。研究报道，SCFAs通过调节FAs代谢酶的表达，可以促进脂质积累[56]。研究发现，肠道微生物通过产生SCFAs提高了棕榈酸盐和胆固醇的合成，促进了肝脏脂质积累[57]。SCFAs乙酸(FA 2 : 0)是肝脏长链FAs合成的重要前提。肠道微生物通过降解饮食纤维，产生了FA 2 : 0，改变了甘油磷脂的种类，从而促进了肝脏FAs代谢[58]。
4 小结肠道微生物平衡在维持机体健康中发挥着重要作用，饮食可以调节肠道微生物平衡，反之，肠道微生物也可以调节营养物质吸收与代谢。目前，关于FAs与肠道微生物相互作用研究对机体的健康调控是研究的热点，并且肠道微生物具有潜在的个体独特性生理功能，可能作为预测疾病风险的靶标。但是，肠道微生物与机体FAs代谢之间的关系和确切的作用机理还不明确。因此，深入地了解肠道微生物与FAs互作机制，合理的调控饲料中FAs的组成及含量，对高效环保饲粮的配制以及动物的健康生长具有重要的指导意义。
致谢:
感谢湖南农业大学动物科学技术学院杨泰和湖南师范大学生命科学学院贺玉敏2位博士对文稿所提的宝贵意见。
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