肠上皮细胞表面覆盖着杯状细胞合成分泌的大量黏液，可避免肠黏膜组织受潜在的病原体、诱变剂、物理和化学损害，从而抑制感染和炎症，避免疾病的发生。小肠黏液层较薄且不连续[1]，而结肠黏液有2层，1层疏松，1层牢固[2]。黏液的主要成分是黏蛋白(MUC)，迄今发现21种MUC基因，这些基因编码2类MUC：分泌型(MUC2、MUC5AC、MUC5B、MUC6、MUC7、MUC9)和膜结合型(MUC1、MUC3A、MUC3B、MUC4、MUC12、MUC13、MUC15、MUC16、MUC17、MUC20)。正常结肠与直肠中的主要MUC为MUC1、MUC2、MUC3A、MUC3B、MUC4、MUC13和MUC17[3]，其中MUC2是肠道黏液的主要分泌物和凝胶形成的组分，MUC1、MUC3A、MUC3B、MUC4、MUC13和MUC17同膜结合形成结合型MUC，并参与细胞信号传导、黏附、生长和免疫调节[4]。MUC2利用自身密集的网状结构及富含碳源糖基侧链来捕获和黏附细菌，并通过不断地更新与补充将细菌和肠上皮细胞隔离开来，防御病菌对肠上皮细胞的侵袭以发挥屏障功能[5]。MUC2通过与肠内树突细胞(DC)直接相互作用，参与传递免疫调节信号来限制肠道抗原的免疫原性，保护肠上皮细胞免受腔内细菌和食物抗原的侵害，增强肠道稳态和耐受，从而预防炎症[6]。MUC2形成的肠道黏液层与肠上皮细胞、微生物群和宿主免疫防御之间呈动态相互作用，维持肠黏膜稳态。而MUC2的缺陷使黏液屏障功能减弱和肠黏膜渗透性增加，引起肠黏膜细胞的炎症和损伤。因此，MUC2在动物肠道疾病发生发展中具有重要作用。本文简要总结了MUC2的分泌、结构、合成分泌调控以及其在动物肠道疾病发生发展中的作用。
1 杯状细胞分泌MUC2肠上皮细胞按其功能作用可分为肠细胞、杯状细胞、潘氏细胞、肠内分细胞、微体细胞和杯型细胞[7]。MUC由杯状细胞合成分泌，MUC2属于最早被鉴定和表征的分泌型凝胶状MUC，染色体11P15位点有编码MUC2基因序列。杯状细胞质核糖体翻译的MUC2单体转移至内质网上通过分子间二硫键结合成二聚体，接着被移送到高尔基体在一系列糖基转移酶催化下进行O型糖基化，蛋白质核心区域连接着大量寡糖侧链，完全糖基化和加工完的MUC2被密集包装并储存在分泌颗粒或囊泡中，被运送到细胞表面，释放后进入肠腔，与大量的水和其他一些物质形成黏液凝胶。释放途径主要有2种：一种是依赖于细胞骨架运动分泌颗粒的基础型，呈现连续低剂量的分泌；另一种是涉及到外界活性因子刺激的胞吐作用的调节型[8]，如胆碱能激动剂、激素、微生物、微生物产物、毒素、炎性细胞因子、活性氧(ROS)和氮物质等。释放后的MUC2形成COOH-末端二聚体和NH2-末端三聚体，构成复杂分层的大型聚合物网状结构作为黏液层的骨架。MUC2进入肠内后体积很快扩大千倍以上，以六边形网络状瓦片般铺叠在一起，附在肠上皮细胞表面(图 1)[9]。
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ER：内质网endoplasmic reticulum；Golgi：高尔基体Golgi apparatus；TGN：反面高尔基体网状结构trans Golgi network；Secretory granules：分泌颗粒；Lumen：肠腔；Folding：折叠；N-glycosylation：N-糖基化；Dimerization：二聚体；Trimerization：三聚化；Packing：填充；Expansion secretion：分泌扩张；Secreted polymer：分泌聚合物。 图 1 在杯状细胞中装配MUC2 Fig. 1 Assembly of MUC2 in goblet cells[9] |
MUC2是一种高分子质量(约为2.5 Mu)、高糖基化的糖蛋白，其单体结构约含有5 179个氨基酸，形成了多个结构域的多肽链，最重要的是富含脯氨酸(Pro)、苏氨酸(Thr)、丝氨酸(Ser)的中心串联重复的结构域，称之为PTS区域，PTS区域被2个小的CysD区域隔开，并且串联4个vWD(von Willebrand D domain)区域，3个在N-末端，1个在C-末端[2]，还有C-末端半胱氨酸(CK)结构域(图 2)[10]。PTS结构域的这3种氨基酸含量约占整个肽链氨基酸含量的50%，通过O-糖苷键连接到许多不同长度和组成的寡糖侧链。
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图 2 MUC2蛋白骨架 Fig. 2 Skeleton of MUC2 protein[10] |
糖基化是MUC2转录翻译后的加工修饰，也是MUC2发挥功能作用的决定性因素。MUC2有30个潜在N-糖基化区域，N-糖基化的存在控制MUC2的正确折叠和二聚化的正常进行，O-糖基化更丰富[11]。MUC2糖链占MUC2总量的50%~80%，能使MUC2质量增加5倍，完全糖基化的MUC2分子质量高达2.5 Mu。
MUC2进行O-糖基化的第1步是将尿苷二磷酸-N-乙酰半乳糖胺(UDP-GalNAc)中的N-乙酰半乳糖胺(GalNAc)添加到PTS结构域的Ser或Thr残基上，形成GalNAcα-Ser/Thr结构，称为Tn抗原[12]。该过程由一类特殊的同源多肽N-乙酰半乳糖胺基转移酶(GalNAc-T，亦称ppGalNAcTs)催化，Tn抗原也是核心1β1, 3-半乳糖基转移酶(C1GalT1或T-合酶)和核心3β1, 3N-乙酰氨基葡萄糖氨基转移酶(C3GnT)的底物，形成Core 1结构和Core 3结构，并在此基础上衍生出更多寡糖链。Core 1和Core 3在核心2β1, 6 N-乙酰氨基葡萄糖氨基转移酶(C2GnTs)催化下衍生出Core 2和Core 4结构。Core 1、2、3、4结构聚糖在肠MUC中最常见(图 3)[13]。Core 3结构是在人体肠道MUC2中最主要的聚糖结构，已经证明人体乙状结肠中MUC2聚糖主要是Core 3结构[14-16]。小鼠十二指肠、空肠、回肠MUC中Core 2结构占主导地位，也有Core 1结构[17]。这些核心结构可用GalNAc、半乳糖(Gal)、N-乙酰氨基葡萄糖(GlcNAc)、岩藻糖(Fuc)和唾液酸(NeuAc)糖残基进一步延伸，后2个残基经常占据末端位置[18]。小鼠小肠MUC中大多数是唾液酸化和硫酸化聚糖[17]，人类的乙状结肠MUC同样具有很高的唾液酸和硫酸盐残基[19]。因此，MUC的聚糖链在肠道中有不同分布和不同性质，MUC的聚糖链可利用性影响着肠道微生物的组成[20]。研究发现在多种炎症和恶性肠道疾病中MUC表达和糖基化发生了改变[21]。
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-OH：羟基；Ser：丝氨酸serine；Thr：苏氨酸threonine；ppGalNAcTs：多肽N-乙酰半乳糖胺基转移酶polypeptidyl GalNAc transferases；MUC2 PTS Domain：黏蛋白2PTS结构域；UDP：尿苷二磷酸uridine diphosphate；Tn antigen：Tn抗原；CMP：一磷酸胞苷cytidine monophosphate；ST6GalNAc：α2, 6唾液酸转移酶α2, 6 sialytransferase；C1GalT1：核心1β1, 3-半乳糖基转移酶1 core 1 β1, 3 N-galactosyltransferase；C3GnT：核心3β1, 3N-乙酰氨基葡萄糖氨基转移酶core 3 β1, 3 N-acetylglucosaminyltransferase；C2GnT1，2 or 3：核心2β1, 6 N-乙酰氨基葡萄糖氨基转移酶1，2，3 core 2 β1, 6 N-acetylglucosaminyltransferases 1, 2, 3；T antigen：T抗原；GalNAc：N-乙酰半乳糖胺N-acetylgalactosamine；Gal：半乳糖galactose；GlcNAc：N-乙酰氨基葡萄糖N-acetyleneglucosamine；Sialic Acid：唾液酸；Sialyl Tn antigen：唾液酸化Tn抗原；O-glycans：氧型聚糖；N-terminal trimers：氮末端三聚体；C-terminal dimers：碳末端二聚体；MUC2：黏蛋白2 mucin 2。 图 3 MUC2核心聚糖链的合成路径 Fig. 3 Synthesis of MUC2 core glycans[13] |
微生物及其代谢产物可以影响MUC2的合成与分泌，调节MUC2的生成。铜绿假单胞菌的脂多糖(LPS)激活非受体酪氨酸激酶(c-Src)-鸟苷酸结合调节蛋白(Ras)-Ser/Thr蛋白激酶(Raf)-丝裂原活化蛋白激酶激酶(MEK)-细胞外信号调节激酶(ERK)-90 Ku核糖体S6激酶(pp90rsk)信号通路，使核转录因子-κB(NF-κB)活化，被激活的NF-κB与MUC2基因5’端侧翼的κB位点结合诱导MUC2转录[22]。金黄色葡萄球菌中的脂磷壁酸刺激人HM3和NCI-H292细胞分泌MUC2，可能是通过激活Ras/Raf/MEK/ERK/pp90rsk/NF-κB通路[23]。溶组织性变形杆菌通过激活黏液颗粒上存在的囊泡网膜囊泡相关膜蛋白8(VAMP8)调节杯状细胞的胞吐作用，增加MUC2的分泌[24]。创伤弧菌分泌一种弹性蛋白酶(VveP)介导肠上皮细胞脂筏诱导ROS的产生及MUC2启动子诱导区域的高甲基化，从而抑制MUC2的表达[25]。微生物代谢物次级胆汁酸通过激活表皮生长因子受体(EGFR)/蛋白激酶C(PKC)/Ras/Raf/MEK/ERK/环磷腺苷效应元件结合蛋白(CREB)、磷脂酰肌醇3-激酶(PI3K)/蛋白激酶B(Akt)/NF-κB抑制蛋白(IκB)/NF-κB和p38丝裂原激活蛋白激酶(p38)/丝裂原和应激活化蛋白激酶1(MSK1)/CREB通路，从而上调MUC2的转录[26]。霉菌毒素脱氧雪腐镰刀菌烯醇(DON)极易引起猪的呕吐，抑制抵抗素样分子β的双链RNA依赖性蛋白激酶(PKR)和丝裂原活化蛋白激酶(MAPK)阻抑杯状细胞表达MUC2[27]。志贺菌、具核梭杆菌、黄曲霉毒素M1和赭曲霉毒素都能上调MUC2的表达[28-30]，艾美球虫(EM)和产气荚膜梭菌(CP)抑制MUC2的分泌[31]。病毒也会影响MUC2生成，禽流感病毒亚型H9N2和轮状病毒等都对MUC2的分泌有抑制作用[32-33]。微生物还直接影响MUC2的结构组成，改变MUC2的分子结构。微生物产生的某些碳水化合物活性酶(CAZymes)通过切割MUC2中的特定键来降解O-连接的聚糖，像糖苷水解酶(GH)家族、M60样蛋白酶和硫酸酯酶等对聚糖有靶向识别作用[7]。GH2含有β-半乳糖苷酶活性，GH98可将末端三糖从A或B型血型结构释放出来，GH101可以裂解与肽连接的GalNAc。产气荚膜梭菌的锌金属蛋白酶(ZmpB)可以断裂糖基化的Ser和Thr残基相连肽键。粪便拟杆菌(Bacteroides caccae)型菌株参与低膳食纤维诱导的结肠黏液层破坏[34]。肠道微生物及其代谢产物调控MUC2的合成分泌过程是通过激活各种信号通道和肠上皮细胞产生的细胞因子来实现的(图 4)[35]。脆弱芽孢杆菌在体外降解猪结肠MUC中O-聚糖的能力有限，但是当纯化的结肠MUC作为唯一碳源时，足以支撑其在培养基中的生长[36]。MUC2的O-聚糖可作为产正丁酸菌的内源性发酵产物[37]。MUC2自身的O-聚糖成为特异性细菌黏附位点，为肠道细菌提供寄居场所及能量来源。因此，MUC2与微生物共生互作存在双向调节。
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Normal：正常；Outer Mucus Layer：外部黏液层；Mucus Secretion：黏液分泌；Nutrients/SCFA：营养物/短链脂肪酸；Inner Mucus Layer：内部黏液层；Antigens：抗原；CD103+DC：CD103+树突细胞；Increase Treg：调节性T细胞增加；Inflammation：炎症；Perturbed：扰动；Adhesion：黏附；Mucolysis：黏液溶素；Bacterial Products：细菌产物；Altered Microbiota：菌群改变；Hypersecretion：分泌过多；Mucus Depletion：黏液损耗；Colonization：定植；Composition & Thickness：组成&厚度；Decrease Goblet cells：杯状细胞减少；Genetic Predisposition：遗传易感性；CX3CR1+DC：CX3CR1+树突细胞；Decrease Treg：调节性T细胞减少；Cytokines：细胞因子；Goblet cell：杯状细胞；Enterocyte：肠上皮细胞。 图 4 肠黏液层与宿主-微生物群相互作用 Fig. 4 Intestinal mucus layer and host-microbiota interactions[35] |
细胞因子是免疫细胞、上皮细胞、内皮细胞和成纤维细胞等多种细胞被激活并与病原体相关的分子模式(PAMP)接触时分泌的生物活性因子[35]。细胞因子可为Th1类细胞因子和Th2类细胞因子。细胞因子可调节多种细胞类型中MUC2的转录表达[35]。几种Th1类细胞因子调节MUC2的合成和分泌，如白细胞介素(IL)-1β和肿瘤坏死因子-α(TNF-α)。IL-1β通过PKC/MEK/ERK/磷脂酰肌醇3激酶(PI3K)信号途径上调MUC2的表达[38]。TNF-α通过NF-κB诱导激酶(NIK)和PI3K/Akt 2条通路介导的NF-κB活化正调节MUC2转录，也通过激活c-jun氨基末端激酶(JNK)途径负调节MUC2转录，但NF-κB转录激活能够抵消JNK途径的抑制作用[38]。Th2类细胞因子(IL-4、IL-6、IL-9、IL-10、IL-13)在体外和体内均可诱导MUC2基因表达。IL-4和IL-13通过激活MAPK的磷酸化来增加MUC2基因的表达[39]。IL-6增加了LS180细胞中MUC2的表达并刺激其分泌[40]。IL-9诱导了气道上皮细胞MUC2表达的增加[41]。IL-10可增强杯状细胞中MUC2的正确折叠防止内质网应激来促进MUC2的分泌[42]。
3.3 营养素与MUC2MUC2在动物断奶应激引起腹泻、感染病原微生物引起肠炎、肠黏膜功能障碍等疾病中发挥着屏障、免疫功能，保护着动物肠道健康。维持健康不可或缺的重要营养素调控MUC2的合成和分泌，起到了对肠道的保护作用。食物难以消化的碳水化合物(可溶性膳食纤维、低聚糖、抗性淀粉等)可被肠道微生物发酵成短链脂肪酸[38]。短链脂肪酸可以作为结肠上皮的营养物质[43]，增加MUC2的产生[44]。膳食纤维联合非淀粉多糖降解酶增加猪回肠杯状细胞数量和MUC2的表达[45]。膳食豌豆纤维改变肠道短链脂肪酸谱增加MUC2的表达[46]。断奶猪仔胃中注入短链脂肪酸增加小肠MUC2表达，改善肠黏膜屏障功能[47]。断奶仔猪饲粮中添加羧甲基纤维素提高消化液黏度、回肠杯状细胞数量和成熟度[48]，增加MUC2的生成。罗望子木葡聚糖降低了Toll样受体4(Toll-like receptor 4，TLR4)、髓样分化因子(myeloid differentiation factor 88，MyD88)、IκB和NF-κB的表达同时降低了MUC2的表达[49]。β-葡聚糖增加断奶仔猪空肠MUC2的表达，改善肠道屏障功能[50]。甘露寡糖可显著增加鸡胚MUC2 mRNA的水平[51]。高可发酵蛋白质饲粮增加断奶仔猪MUC2等多种MUC的表达[52]。膳食奶酪乳清蛋白增加大鼠粪便排泄物中MUC2的含量，可保护其肠道抵抗轻度右旋糖酐硫酸钠引起的结肠炎[53]。Thr对维持肠道健康非常重要，增加断奶仔猪小肠MUC2表达[54]，接种在鸡卵中增加肠道MUC2的表达，有利于改善肠黏膜的形态和功能[55]。非氧化鱼油在增加仔猪肠道MUC2保护肠道健康方面效果比氧化鱼油要好[56]。维生素A缺乏症会损害MUC2表达并抑制雏鸡呼吸道的黏膜免疫功能[57]。微量元素锌也能影响MUC2的表达，有机锌增加雏鸡MUC2的表达，缓解肠道损伤[58]。
4 MUC2在肠道疾病发生发展中的作用 4.1 肠道应激性疾病肠道应激性疾病是动物在应激状态下肠黏膜结构和生化异常导致的肠屏障障碍和肠功能紊乱性疾病，多致腹泻。人容易因精神受到刺激出现心理应激，家畜经常受饲粮、温度、断奶等刺激产生生理应激。应激在神经系统、内分泌系统、免疫系统等多方面影响肠黏膜致其损伤，通过刺激神经[59]、促进炎症因子的分泌[60]、抑制免疫细胞使肠黏膜对细菌与病原体通透性增加[61]。因此，应激状态下杯状细胞大量分泌MUC2来抵御通透性的增加，提高屏障功能，但长时间作用后，杯状细胞的消耗将加剧肠道黏膜屏障的损害。鼠模型常用于研究MUC2在应激状态下的作用及变化，应激期释放的促肾上腺皮质激素释放因子激活神经元和肥大细胞促进结肠杯状细胞MUC2分泌，在后期杯状细胞出现损耗[62]。MUC2-/-小鼠易患结肠炎，将其断奶后结肠炎症状加重[63]。慢性应激大鼠结肠MUC2分泌减少[64]，O-聚糖出现改变[65]。断奶是仔猪必须经历的过程，仔猪断奶后因缺乏母乳中的营养成分且肠道生理机能发育不成熟出现应激反应，损害猪肠黏膜屏障功能的发挥[66]，影响肠道的形态、结构、生理和肠道免疫反应[67]，干扰MUC2的合成分泌，肠道结构功能改变影响肠屏障功能紊乱从而引起腹泻。仔猪断奶1 d后肠道MUC2基因表达增加，7 d后肠道MUC2基因表达降低；断奶后MUC2表达先增加可能是肠道应对应激的保护机制，后期杯状细胞损耗导致MUC2表达减少[68]。热应激改变猪肠道通透性，发生肠道炎症反应[69]，使猪肠上皮杯状细胞凋亡，减少MUC2的分泌。热应激引起肉鸡肠道MUC2表达减少[70]，破坏肠黏膜完整性。应激引起动物肠道黏液MUC2生成异常，MUC2构成的肠道黏液屏障破坏，肠道微生物发生易位并接触黏膜上皮细胞引起炎症，这可能是肠道应激性疾病所致腹泻的重要原因。
4.2 肠道感染性疾病当动物患肠道感染性疾病时，杯状细胞的数量和MUC2的分泌均有上升，因其润滑和隔离作用可以加快病原体的排出，保护肠黏膜。而肠道慢性炎症使杯状细胞的数量耗损，导致MUC2的合成和分泌下降。肠道感染寄生虫后，黏液层被破坏降解。溶组织内阿米巴原虫产生的半胱氨酸蛋白酶分解MUC2，破坏MUC网络结构[71]。鞭虫产生的丝氨酸蛋白酶特异性识别MUC2的N-末端聚合域，降解MUC2来破坏黏液网络[72]。肝片吸虫产生蛋白酶也能破坏黏液层。巴西钩虫和旋毛型线虫通过Th2免疫应答IL-13和IL-4介导杯状细胞增殖，促进MUC2分泌[73]。缺乏MUC2的小鼠感染蠕虫，驱除蠕虫会延迟，黏液增加可以捕捉寄生虫，避免其黏附在肠上皮表面，限制其移位及存活能力，且有助于保护肠黏膜清除蠕虫排除线虫[74]。定植于脊椎动物肠道的空肠弯曲杆菌黏附在MUC2上，损伤黏液层[75]。感染鼠伤寒沙门氏菌的猪结肠出现微观变化产生炎症，MUC表达减少[76]。健康猪感染胞内劳森菌减少MUC2的产生，破坏黏液屏障，加剧其对细胞的侵袭[77]。猪结肠感染猪痢疾短螺旋体导致黏液样出血性腹泻和黏液层变化，刺激MUC2分泌增加[78]。细菌代谢的硫化物能破坏MUC2的二硫键，从而裂解MUC2的网状结构，破坏黏液屏障[79]。鸡感染肠炎沙门氏菌引起MUC2基因表达显著降低[80]，造成肠道损伤。人感染艰难梭状芽孢杆菌，造成其肠道MUC2合成减少及寡糖链组成改变，引起菌群定植[81]。肠道感染病毒后，MUC2合成分泌受到影响。鸡感染禽流感亚型H9N2病毒，回肠MUC2合成分泌减少，肠道发炎出现损伤[32]。小鼠感染轮状病毒造成MUC2的表达减少和肠道结构改变[82]。感染仔猪猪流行性腹泻病毒(PEDV)后肠道结构破坏、杯状细胞分泌MUC2的功能明显下降[83]，黏液中MUC2含量的下降可能是感染PEDV所致腹泻的重要原因。动物患肠道感染性疾病，肠道黏液中MUC2分子受到破坏，其黏性下降，肠黏膜通透性增加，肠上皮细胞与肠道中的毒素和病原微生物接触增加，诱导肠道损伤和炎症。
4.3 坏死性肠炎新生儿坏死性小肠结肠炎(NEC)是一种由多因素导致新生儿肠黏膜的损害从而出现小肠结肠弥漫性或局部坏死的重症肠道疾病。家畜坏死性结肠炎的发病率呈逐年上升的趋势，成为兽医临床上主要多发病。Martin等[84]研究表明，NEC病人回肠杯状细胞数目明显减少，而胆汁酸含量显著上升，胆汁酸的主动运输减少MUC2的分泌，在NEC发展中起重要作用。Jing等[85]通过对新生大鼠供氮气和灌胃脂多糖建立NEC模型，发现NEC大鼠MUC2表达降低。Tian等[86]发现MUC2表达上调可保护肠黏膜的物理和免疫屏障功能，改善NEC大鼠的症状和降低发病率。Rasmussen等[87]和Puiman等[88]发现早产仔猪肠黏膜屏障功能减弱，易患坏死性结肠炎，MUC2合成减少。禽类感染产气荚膜梭菌(CP)易患坏死性结肠炎，原因是CP分泌的NetB外毒素会降解MUC2，破坏肠道黏液屏障影响禽类肠道健康[89-90]。Forder等[91]通过用CP和艾美球虫(EM)感染肉雏鸡建立坏死性肠炎模型，发现肠道MUC2合成分泌减少。肠黏膜受损和MUC2合成分泌减少是坏死性结肠炎的主要特征，但MUC2在坏死性肠炎的发生发展中的作用及其机制仍不清楚。
4.4 炎症性肠病炎症性肠病(IBD)是一种原因尚不明确的慢性肠炎，包含溃疡性结肠炎(UC)和克罗恩病(CD)2种类型。在IBD中，MUC2分泌和MUC糖链结构的变化，影响黏液完整性和通透性，减弱黏液屏障功能[4]。在CD和UC患者的末端回肠和结肠中MUC2的基因表达都已发生改变[92]。UC患者杯状细胞MUC2 mRNA水平显著降低，发炎的CD患者末端回肠MUC2的mRNA水平较低，而在非发炎的IBD患者中MUC2表达水平明显升高。MUC2糖基化的改变也与IBD有关[93]。C1GalT1缺乏症主要导致远端结肠炎的发作，而同时缺乏C1GalT1和C3GnT的小鼠在结肠远端和近端区域都出现结肠炎症现象，这表明C3GnT在近端结肠中起保护作用[94]。UC患者杯状细胞数量减少，黏液层变薄，糖基化程度下降。Larsson等[95]表示活动性UC患者中MUC2的糖基化异常，其中唾液酸转移酶的上调导致MUC2的唾液酸-GalNAc-S/T增加，并产生了较短的糖链。CD患者的黏液层与UC相反，黏液层变厚，可能因为活化碱性螺旋-环-螺旋转录因子Hath1基因和Kruppel样因子4(KLF4)，加快杯状细胞增生，促进MUC2的分泌；但其糖链长度减少了50%，唾液酸化却增加，黏液层的黏性、弹性下降，屏障功能削弱[96-97]。内层黏液MUC2分泌不足或结构改变可能促进了结肠炎的发生[98]。Faure等[99]在葡聚糖硫酸钠(DSS)大鼠模型中发现整个肠道的MUC中Thr和Ser含量明显降低，这可能导致潜在的O-糖基化位点减少。Lu等[93]发现MUC2缺陷导致2和4周龄MUC2-/-小鼠自发炎症反应，4周龄的MUC2-/-小鼠还表现出肠上皮屏障功能的降低和肠上皮细胞增殖的减少。MUC2的异常导致黏液稳态失衡，进而诱导肠道黏膜炎症，恢复黏液MUC2功能有望成为防治炎症性肠病的途径之一。
5 小结MUC2具有物理屏障和免疫调节双重功能，在抵抗感染和防止消化道疾病的发生和发展中扮演着重要角色。MUC2的合成、分泌缺陷以及糖基化结构的改变会导致肠道疾病的发生，成为相关肠道疾病发生发展的研究热点。MUC2的糖链作为内源多糖影响着肠道微生物的组成和分布，MUC2的变化影响肠道通透性及肠黏膜免疫功能，进而影响肠黏膜屏障。黏液层、肠上皮细胞、微生物群和宿主免疫防御之间的平衡和动态互作，共同调控肠道稳态，影响动物肠道健康，但它们之间的关系以及调控方式仍不清楚，需要进一步揭示黏液MUC2与肠道菌群、营养调控之间的关系，为动物肠道健康提供理论依据。
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