近年来，兔养殖业在许多国家快速发展，其中中国是世界第一大生产国和出口国，兔肉年生产量为849 150 t，出口量占全球总产量的27%[1]。根据有关兔的疫情统计，在平均死亡率为24%的兔群中，就有75%以上的兔是因腹泻所致[2]，而肠道菌群紊乱是兔腹泻的主要原因。大量研究显示，健康的肠道菌群对于提高兔生长性能和免疫能力具有积极作用，主要原因包括肠道菌群可产生促进营养成分消化吸收的酶类如淀粉酶、蛋白酶和脂肪酶等[3]，分泌促进免疫系统调节和发育的短链脂肪酸(short chain fatty acids，SCFAs)等物质[4]；肠道菌群之间的拮抗作用还可在一定程度上抑制有害菌的生长，调节和促进肠道微生物的动态平衡[5]。我们可通过正确的饲粮配方以及科学的人工管理来调节仔兔肠道菌群，以降低兔死亡率和发病率。因此，本文将从仔兔肠道菌群早期结构特征和调控措施加以综述。
1 仔兔肠道菌群早期定植过程兔各肠段的菌群结构及其优势菌群会随其定植部位和生长阶段的不同而呈现不同的变化规律。兔肠道菌群的丰富性和多样性会随日龄的增加而显著增加，其优势菌门包括厚壁菌门(Firmicutes)、拟杆菌门(Bacteroidetes)、疣状菌门(Verrucomicrobia)和蓝藻门(Cyanobacteria)等，其相对丰度会显著变化[6]，直至兔成年，肠道菌群会逐渐趋于稳定、平衡。
胚胎期的兔肠道被认为几乎是无菌的，但晚期胚胎肠道内有微生物定植，数量为0.8×102~1.2×102 CFU/g，主要包括棒杆菌属(Corynebacterium)、微球菌属(Micrococcus)、蜡样芽孢杆菌(Bacillus cereus)和葡萄球菌属(Staphylococcus)等细菌[7]。刚出生的仔兔由于从母乳中获得抗菌物质，故具有与胚胎期相似的肠道菌群结构[8]。但刚出生的仔兔所接触的母兔粪便及饲养环境中的细菌会在肠道中定植[9]。随着母兔的哺乳行为等因素的影响，兔肠道菌群逐渐丰富。7日龄时，可在仔兔盲肠中检测到古细菌群落，并在35日龄达到最大值[10]。14日龄盲肠细菌群落以拟杆菌门、拟杆菌科和细菌素属为主[11]，其中，拟杆菌门在兔肠道消化过程中起着重要作用[12]，且此时兔盲肠厚壁菌门数量达到最大值[10]。
成长中兔的消化系统必须经历一段从乳汁喂养到完全依赖固体饲粮的适应期，这种适应过程不仅影响消化系统，而且还会影响肠道微生物群的定植和保护动物免受消化道疾病侵害的肠道屏障[13]。15日龄后，仔兔开始进食含有纤维的固体饲粮，纤维基质进入盲肠，与此同时，与纤维分解相关的细菌包括纤维素分解细菌、淀粉分解细菌、果胶和木糖降解细菌等在肠道中开始定植[2]。21日龄时，母兔的泌乳能力下降，通过补饲固体饲粮，可以增加仔兔存活率[14]，且此时仔兔盲肠总菌数量和拟杆菌属-普雷沃菌属(Bacteroides-Prevotella)数量达到最高值[10]。25日龄时，兔肠道中纤维降解菌群数量缓慢增加至107 CFU/g[15]，但若仔兔仅摄入母乳，即使35~42日龄兔子的肠道菌群也不会出现纤维素分解菌群[16]。28日龄时，仔兔胃中开始出现软粪[17]，软粪中有益菌对兔肠道菌群的构建具有极其重要的作用。
大多数农场的仔兔在28~35日龄断奶[2]。刚断奶时，由于饲粮的改变，仔兔肠道乳酸杆菌和肠球菌数量减少，而大肠杆菌数量增加，并高于乳酸杆菌数量[18]，再加上仔兔自身免疫及消化系统发育不全，断奶仔兔极容易腹泻。事实上，盲肠微生物区系在健康仔兔断奶时已基本建立，且其多样性会随日龄的增长有增加的趋势。30日龄时，仔兔盲肠中有较高的产乙酸菌和产甲烷菌含量，并随着日龄的增长，盲肠中的产乙酸菌含量会因宿主非饮食的因素而发生变化，最终趋于稳定[19]。60日龄时，仔兔肠道微生物群落以厚壁菌门、变形菌门、拟杆菌门、疣微菌门和放线菌门为主[20]。80日龄时，仔兔盲肠菌群以厚壁菌门、毛螺菌科和瘤胃科为主[11]。
2 仔兔肠道菌群的调控 2.1 饲粮饲粮是肠道菌群所需营养物质的主要来源，其营养素的组成及比例的不同都直接或间接地影响兔肠道菌群结构。饲粮降解产物不仅可通过提供营养基质直接影响肠道微生物的生长繁殖，还可通过改善肠道环境如肠道pH、氧化还原电位等指标间接调控肠道微生态。
饲粮组成类型是引起肠道菌群变化的主要因素之一。例如，兔断奶前后摄入脱水苜蓿，可显著提高瘤胃球菌科(Ruminococcaceae)/毛螺菌科(Lachinospiraceae)的比值，对兔肠道消化微生物群有利[21]。一些农业副产品如发酵玉米秸秆、越橘果渣和花生秧等也被用作仔兔高营养低成本的饲料来源，对肠道菌群的调节发挥着重要作用。发酵玉米秸秆作为仔兔的粗饲料可显著提高兔盲肠中双歧杆菌、乳酸菌及芽孢杆菌等有益菌的数量，并降低有害菌的数量，促进仔兔的生长繁殖[22]。越橘果渣可增加梭状芽胞杆菌、螺旋体、瘤胃球菌和瘤胃球菌科的相对丰度[23]。在饲粮中添加一定量的花生秧可降低变形菌门中一些致病菌的数量，从而降低肠道炎症等疾病的发生率[24]。
饲粮纤维在动物饲养中的重要性在于对肠道菌群的调控以及对消化系统健康的影响。兔作为小型单胃食草动物，其盲肠菌群中存在高效的纤维素酶[25]，对减少膳食纤维的摄入非常敏感，以缺乏纤维的饲粮喂养仔兔2周，其厚壁菌/拟杆菌比值极大下降[26]。因此，在兔饲粮组分中饲粮纤维占有重要地位，其包括中性洗涤纤维(neutral detergent fibre，NDF)和酸性洗涤纤维(acid detergent fibre，ADF)[27]。用NDF含量为350 g/kg的饲粮饲喂仔兔，菌群多样性显著增加，厚壁菌门以及产SCFAs的瘤胃球菌数量较高，该饲粮能通过调控盲肠微生物菌群有效预防胃肠道损伤并提高仔兔生长性能[28]。中性洗涤可溶性纤维(neutral detergent soluble fibre，NDSF)能够降低胃pH和影响盲肠微生物菌群，在断奶后和整个育肥期兔死亡率随NDSF水平的升高呈线性下降[29]；且较高水平的NDSF可降低兔盲肠弯曲杆菌、产气荚膜梭菌的检出率[30]，改善断奶兔的肠屏障功能。ADF可改善肠道形态，且随着ADF日摄入量的增加，氨氮(NH3-N)含量下降，饲粮日摄入量、挥发性脂肪酸含量以及盲肠内容物中纤维分解酶活性均增加[31]。除此之外，高纤维饲粮还可以预防与肠道菌群失调有关的疾病。但是，对于生长肉兔，高纤维水平饲粮并不能提高兔生长率[32]。因此，可将纤维与淀粉配合饲用，以增加饲粮能量，优化饲料效率并控制生长中兔的氮排泄，从而提高兔生长性能[33]。此外，纤维与淀粉的比例会显著改变兔盲肠微生物菌群的组成[34]，但其对兔盲肠古菌群落的多样性和相对丰度没有显著影响[35]。
饲粮中蛋白质和氨基酸的来源与组成也可导致兔肠道微生物的变化，特别是对早期断奶兔的健康有影响。饲粮中粗蛋白质的含量从209 g/kg降至179 g/kg时，会影响回肠微生物群的组成，降低氮化合物的回肠流量和仔兔的死亡率，尤其降低产气荚膜梭菌的检出率[36]。而将饲粮中粗蛋白质的含量从172 g/kg降至139 g/kg时，会线性降低盲肠中挥发性脂肪酸含量，同时降低断奶仔兔的生长性能和盲肠发酵活性[37]。因此适当降低粗蛋白质的饮食调节应被视为一种促进兔肠道健康的策略。氨基酸的作用不仅仅是为动物本身提供营养，也可被肠道菌群利用[38]。饲粮中添加1%的谷氨酰胺可降低兔死亡率、产气荚膜梭菌和幽门螺杆菌的检出率[39]。添加精氨酸(L-arginine，L-Arg)和N-氨基甲酰基谷氨酸(N-carbamylglutamate，NCG)可改变兔肠道微生物群落和相对丰度[40]，而且补充L-Arg和NCG还能促进仔猪盲肠乳酸菌和厌氧菌的生长[41-42]。因此，我们可以推测L-Arg和NCG对维持兔肠道健康和功能，以及肠道菌群平衡起着重要作用。
2.2 益生菌益生菌具有补充有益菌群、预防胃肠道疾病、产生多种酶类并促进生长等功能，能够促进肠内菌群生态平衡，且无毒副作用、安全可靠、环境友好，因此可作为“替抗物”用于兔养殖行业，成为了当前的研究热点。
目前关于兔用微生态制剂的产品及研发相对较少，其中已有研究报道中涉及的乳酸菌类益生菌主要有嗜酸乳杆菌(Lactobacillus acidophilus)、植物乳杆菌(Lactobacillus plantarum)、干酪乳杆菌(Lactobacillus casei)及粪链球菌(Enterococcus faecium)等，它们均可代谢产生具有抑菌活性的物质[43]、促进营养物质消化吸收、提高免疫力、降低因应激引起的肠道疾病的作用[44]。研究表明，给兔服用干酪乳杆菌可以增加肠道乳酸菌的相对丰度，降低肠埃希氏菌、志贺氏菌的相对丰度，促进蚓突的生长，刺激窗格细胞脱粒并诱导防御素-7样(DEFEN)和溶菌酶(LYS)的基因表达[45]。嗜酸乳杆菌添加到28日龄断奶仔兔的饲粮中，体增重显著增加[46]。给35日龄断奶仔兔饲喂粪肠球菌CCM7420，其平均日增重、空肠绒毛高度及表面积、绒毛高度/隐窝深度比值均增加，其中平均日增重增加了9.5%[47-48]。此外，布氏乳杆菌会使所有肠组织中的Toll样受体(TLR)2和TLR4基因表达下调，减少炎症细胞因子和肿瘤坏死因子-α(TNF-α)分泌，上调抗炎细胞因子白细胞介素(IL)-4基因和肠屏障相关基因的表达[49]，提高断奶仔兔的日增重和成活率以及降低其腹泻发生率。
具有益生作用的芽孢杆菌主要有枯草芽孢杆菌(Bacillus subtilis)、蜡样芽孢杆菌、地衣芽孢杆菌(Bacillus licheniformis)和丁酸梭菌(Clostridium butyricum)，均可以改善肠道菌群、提高免疫力，部分菌还可以增强消化酶的活性。而且，部分芽孢杆菌之间具有协同增效作用，如蜡样芽孢杆菌、枯草芽孢杆菌和地衣芽孢杆菌三者共同组合较单独饲喂对提高兔健康的效果更佳[50]；106 CFU/g混合枯草芽孢杆菌也使仔兔表现出更好的生长性能，并能显著提高兔感染大肠杆菌后的存活率[51]。此外，枯草芽孢杆菌HH2还可降低疾病活动指数、组织学损伤评分及TNF-α和IL-1β的基因表达，增强IL-10和紧密连接蛋白基因如闭合蛋白(Occludin)的mRNA表达，维持肠黏膜屏障功能，增加双歧杆菌科的相对丰度，降低类杆菌和变形杆菌的相对丰度[52]。1.0×105 CFU/g的丁酸梭菌也可显著提高35日龄仔兔的平均日增重，进一步的研究还表明了丁酸梭菌可增加肠道中的厚壁菌门、拟杆菌门、双歧杆菌等有益菌的相对丰度，并改善黏膜形态和抗氧化状态，维持小肠屏障功能，同时上调紧密连接蛋白基因的mRNA表达水平以及增加分泌型免疫球蛋白A(sIgA)的产生，降低包括IL-6、干扰素-γ(INF-γ)和TNF-α的促炎细胞因子数量，提高髓样分化初级反应基因88(MyD88)以及TLR2、TLR4基因的表达水平[53]。
酿酒酵母也是一种益生菌，而且具有可用性、安全性和廉价性三大特点，这为酿酒酵母培养物替代抗生素在生产上的应用提供了可能[54]。研究发现酵母类微生态制剂的添加量应适宜，并且其活菌数须达到一定数量才能形成微生物的生物屏障[55]。相对于0.08和0.16 g/kg剂量，在兔饲粮添加中0.12 g/kg的酿酒酵母可以更好地保持良好的健康状况，获得最高增重[(1.025+0.006) kg]以及最高饲料利用率(57.20%)，并能显著增高机体淋巴细胞和白细胞数量[56]。
2.3 益生元益生元是不易被动物或人体消化的但可被肠道微生物发酵的碳水化合物，主要包括糖醇、低聚糖(如菊粉型果糖、低聚半乳糖等)和多糖等。它们可以作为后肠发酵剂，选择性促进一些有益菌的生长，改善营养物质消化率，有助于通便，降低管腔的pH并扩展壁组织，提高氮在盲肠营养动物体内存留等[57-58]。总而言之，益生元在改善兔生长性能方面发挥着重要作用，且因其绿色、安全、高效等优点成为了当前饲料工业邻域的研究热点之一。
经研究发现，甘露寡糖、异麦芽寡糖、阿拉伯木聚糖寡糖和魔芋甘露寡糖均可以使兔体重增加、改善料重比，提高经济效益。甘露寡糖和异麦芽寡糖均可显著诱导不同组织中调控营养代谢、免疫和生长的一些主要关键基因的表达[57]。甘露寡糖和阿拉伯木聚糖寡糖都可以增加回肠绒毛长度，显示出更好的生长和肠道形态[59]。此外，通过比较研究发现，在饲粮中添加100 mg/kg魔芋甘露寡糖促进兔健康生长的效果最好，盲肠pH显著降低，双歧杆菌和乳酸杆菌数量分别增加了5.28%和4.90%，大肠杆菌数量减少了5.73%，总挥发性脂肪酸、乙酸和丁酸含量分别升高了27.28%、14.95%和57.14%，绒毛高度增加了36.19%，隐窝深度降低了22.98%[60]。益生元还可以预防球虫感染，可用于最大程度减少兔球虫病的不良反应，限制体重减轻[61]。大量证据表明了益生元对于兔的生长有很大的益处，可大力发展益生元类微生态制剂，作为绿色饲料添加剂应用到兔养殖业中。
2.4 酸化剂饲料酸化剂是一种非营养类饲料添加剂，具有降低肠道pH、影响肠道菌群和提高动物生长及免疫性能等作用。它可分为无机和有机酸化剂，无机酸化剂包括磷酸、盐酸和硫酸等；有机酸化剂主要包括苹果酸、甲酸、山梨酸等。现多以有机酸和无机酸配合使用为主，从而可达到互补协同作用，克服单一酸化剂的不足与缺陷。
关于有机酸对仔兔肠道微生物、黏膜免疫和生长性能影响的研究报道很少，而且部分结论存在矛盾[62]。研究表明，有机酸对盲肠细菌细胞完整性起直接作用，但是其作用方式尚不完全清楚[63]。此外，SCFAs还可能作为部分肠道微生物的生长底物[64]，提供营养物质，但尚需进一步研究。部分有机酸具有抗菌活性，可以减少革兰氏阴性和阳性致病菌造成的损害[65]。短链酸(C1~C7)一般具有特异抗菌活性[66]，但是也有研究指出丁酸、富马酸和甲酸没有显示出抗菌活性[67]。不管有机酸在食物、饲粮或肠道内的作用如何，其抗菌活性机理基本相同[68]，未解离的有机酸很容易穿过细胞膜，当进入微生物呈中性pH的细胞质中时，往往会解离。这样释放出来的质子可以通过抑制酶和/或运输系统来扰乱微生物的代谢[62]，从而降低有害菌数量。如辛酸经常被添加到饲养仔兔的饮食中以减少胃和盲肠中大肠杆菌的数量，降低死亡率，还可降低盲肠中的厌氧菌总数[69]。富马酸虽无抗菌活性[70]，但饲粮中添加10 g/kg富马酸，对饲粮消化率和微生物氮摄入量有积极作用，并且兔盲肠淀粉酶降解菌数量会随着富马酸添加水平的增加而明显增加[71]。此外，饮水中添加有机酸对兔胃蛋白酶活性、平均日增重呈二次函数增加效应；总细菌中大肠杆菌的比例呈线性降低，乳酸菌的相对比例呈线性增加趋势，胃底和胃中食糜酸度呈线性降低[72]。
2.5 天然提取物天然提取物常指来源于动植物的天然物质，相较于抗生素和无机化学药品其毒性较低、无有害残留物质，可作为饲料添加剂促进动物生长。此外，它还具有抗菌、消炎、提高动物免疫力和调节肠道菌群等作用，近年来受到饲料工业界的广泛关注。表 1是已报道的用于调节仔兔肠道菌群的天然提取物及其功能。
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表 1 常见天然提取物及相关功能 Table 1 Common natural extracts and related functions |
百里香油、昆虫脂肪、鱼油、乳香树脂和冷榨豆瓣菜油和椰子油混合物均能改善肠道菌群，提高兔宿主免疫力和生长性能。百里香油可降低十二指肠组织中丙二醛含量[73]；从黑水虻幼虫(Hermitiaillucens L.，HI)和黄粉虱幼虫(Tenebriomolitor L.，TM)中提取的2种脂肪可提高盲肠挥发性脂肪酸的含量，增加与NH3-N含量相关的艾克曼菌属(Akkermansia)和瘤胃球菌的相对丰度[74]；鱼油可提高兔肉和脂肪中有益的长链n-3脂肪酸含量，降低脂肪n-6/n-3的比例，但是早期断奶仔兔的饲粮中加入鱼油的生长性能略有下降[75]；乳香树脂、冷榨豆瓣菜油和椰子油混合物均具有抗氧化作用，且乳香树脂可将盲肠致病菌数量降至最低[76-77]。
黑醋栗渣提取物中花青素和黄酮醇含量较高，分别为48.9%和17.9%，将其添加于饲粮中可降低后肠消化道中SCFAs的含量和β-葡萄糖醛酸酶的活性[78]。原花青素B2和辣木提取物均能调节肠道菌群，对兔的生长发育和免疫功能均有明显的改善作用。原花青素B2通过显著提高拟杆菌门和艾克曼菌属的比例来调节兔肠道菌群[79]。辣木提取物能够提高盲肠总挥发性脂肪酸含量，降低丁酸酯的摩尔比例，并提高丙酸酯的摩尔比例[80]。单独或联合使用肠球菌素和鼠尾草提取物可改善兔子的空肠形态，降低粪便中大肠杆菌数量[81]。
3 小结兔既可作食品也可用作科研试验模型，具有非常高的应用及经济价值。近年来关于兔肠道菌群的研究很多，现已基本清楚兔生命早期肠道菌群的基本构成，这些研究主要集中于运用活菌计数法、16S rRNA基因高通量测序来探究兔肠道微生物组成，但是采用宏基因组测序等手段研究兔肠道微生物基因及其功能的文献报道还相对较少[83]。由于兔容易发生肠道疾病，尤其是在断奶期，因此，以前常在饲粮中添加抗生素来预防和治疗相关疾病，但是使用抗生素不仅容易产生耐药性，引起盲肠菌群的显著变化，增加生长兔的消化障碍和死亡率，而且容易造成食品安全问题，对人的身体健康有害。因此，欧盟和中国都已经禁止了非治疗性使用抗生素，但是抗生素治疗兔肠道相关疾病依然是一种常见且被允许的方式。为减少抗生素的使用，需要调节兔肠道菌群，减少其肠道疾病发生。目前常见的调节仔兔肠道菌群的方式有饲喂益生菌、益生元、合生元和饲粮纤维等。其中，益生菌与益生元干预仔兔肠道菌群报道较多，根据现有相关文献，给兔饲喂益生菌、益生元可以显著地促进兔肠道有益菌的生长繁殖，抑制一些致病菌的生长，但是现有报道对于其具体的调节机制研究较少。同时，兔源益生菌的筛选与应用研究，以及菌群间、菌群与宿主间的相互作用机制等还鲜见报道。此外，研究表明同时饲喂益生元和益生菌，兔回肠绒毛比单独饲喂益生菌更长，更好地改善了兔的生长和肠道形态[59]。因此，在理想情况下，合生元的健康益处应该是超加性的[84]，在饲粮中添加合生元能够显著改善兔生长性能，增强肠道健康[85]。但是，目前关于兔用合生元的研究还较少。此外，兔是单胃食草动物，饲粮纤维的正确使用也可改善兔肠道菌群，如在兔生命早期饲喂固体饲粮，能促进兔肠道形态成熟[86]，且有时调节肠道菌群的效果比益生元补充剂更强[87]。值得关注的是，除了饲粮以外，也可通过其他方式调控仔兔肠道菌群，例如，改善饲养环境的卫生水平对调节兔肠道菌群也具有重要作用，当兔住房卫生状况恶化时，其肠道菌群瘤胃科/毛螺菌科的比例会变高，这会对盲肠生物区参数(挥发性脂肪酸、氨、pH等)以及兔的免疫状态产生负面影响[88]；在冬季断奶后早期，饮用温水能通过增加粪球菌属_1(Coprococcus_1)、粪球菌属_3(Coprococcus_3)和纺锤链杆菌属(Fusicatenibacter)的相对丰度来促进兔的肠道健康，使仔兔的平均日增重和饲料转化率显著提高[89]。综上所述，仔兔肠道菌群的早期定植对兔的健康有重要影响，而影响兔肠道菌群的因素又较多，故在预防仔兔肠道疾病时可结合多种手段使用，同时在研究基础上开发出绿色、安全、健康的饲料添加剂以推动兔养殖行业的进一步发展。
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