微小RNA對(duì)腸道健康的影響及作用機(jī)制

陳 芳 張 昊 魏金濤 楊雪海 趙 娜 張 巍

(湖北省農(nóng)業(yè)科學(xué)院畜牧獸醫(yī)研究所，動(dòng)物胚胎工程及分子育種湖北省重點(diǎn)實(shí)驗(yàn)室，武漢430064)

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微小RNA對(duì)腸道健康的影響及作用機(jī)制

陳 芳 張 昊 魏金濤 楊雪海 趙 娜 張 巍

(湖北省農(nóng)業(yè)科學(xué)院畜牧獸醫(yī)研究所，動(dòng)物胚胎工程及分子育種湖北省重點(diǎn)實(shí)驗(yàn)室，武漢430064)

腸道既是機(jī)體營(yíng)養(yǎng)物質(zhì)消化吸收的主要場(chǎng)所，也是防御腸道微生物感染的先天性屏障，腸道健康是機(jī)體正常生長(zhǎng)發(fā)育的關(guān)鍵。微小RNA(miRNAs)是基因轉(zhuǎn)錄后調(diào)控的重要因子。本文主要對(duì)腸道m(xù)iRNAs表達(dá)情況，miRNAs在腸道細(xì)胞中的增殖、分化、凋亡，miRNAs在營(yíng)養(yǎng)代謝、腸道屏障功能、腸道相關(guān)疾病進(jìn)程調(diào)控中的作用以及腸道對(duì)外源miRNAs攝取等方面的研究進(jìn)行綜述，以期為相關(guān)研究的開展提供參考。

miRNAs；腸道；影響；作用機(jī)制

腸道是機(jī)體營(yíng)養(yǎng)物質(zhì)消化吸收的主要場(chǎng)所，也是防御腸道微生物感染的先天性屏障，腸道健康是機(jī)體正常生長(zhǎng)發(fā)育的關(guān)鍵。微小RNA(microRNAs，miRNAs)是一類長(zhǎng)度20～24 nt的非編碼單鏈小分子RNA，是基因轉(zhuǎn)錄后調(diào)控的重要因子[1]。目前，腸道相關(guān)miRNAs的研究主要集中在人和小鼠腸道疾病發(fā)生發(fā)展調(diào)控方面。然而，越來(lái)越多研究表明miRNAs在腸道形態(tài)結(jié)構(gòu)維持、內(nèi)穩(wěn)態(tài)維持、營(yíng)養(yǎng)代謝等方面亦發(fā)揮重要調(diào)控作用。畜禽腸道健康相關(guān)miRNAs的研究也越來(lái)越受到關(guān)注。本文擬就miRNAs對(duì)腸道健康的影響及作用機(jī)制進(jìn)行綜述，以期為相關(guān)研究的開展提供參考。

1 腸道m(xù)iRNAs表達(dá)

miRNAs在腸道中表達(dá)豐富，Coutinho等[2]在牛小腸中檢測(cè)到559種miRNAs，且187種為小腸特異性表達(dá)miRNAs；Sharbati等[3]在仔豬腸道中鑒定出332種miRNAs，且201種為腸道中新發(fā)現(xiàn)miRNAs。除此之外，不同腸段形態(tài)結(jié)構(gòu)、營(yíng)養(yǎng)物質(zhì)消化吸收以及微生物定植存在較大差異，相應(yīng)地，miRNAs在不同腸段的表達(dá)亦存在較大差異，且miRNAs在腸道的表達(dá)隨著腸道組織的發(fā)育存在時(shí)間性差異[4]。

2 miRNAs與腸道細(xì)胞增殖、分化和凋亡

小腸黏膜上皮是一個(gè)快速自我更新的組織，腸道細(xì)胞的增殖、分化和凋亡與腸道健康密切相關(guān)，這一過程受阻將導(dǎo)致腸道功能紊亂。Dicer1酶是miRNAs合成的關(guān)鍵酶，Dicer基因缺失可導(dǎo)致小鼠空腸和結(jié)腸隱窩細(xì)胞凋亡劇增，空腸細(xì)胞遷移亦顯著增加[5]；miR-29b參與調(diào)控小腸黏膜生長(zhǎng)，過表達(dá)miR-29b可使細(xì)胞停滯于G1期[6]；miR-375亦參與調(diào)控腸內(nèi)分泌細(xì)胞發(fā)育等[7]。綜上所述，miRNAs參與調(diào)控腸道細(xì)胞增殖、分化和凋亡，在維持腸道形態(tài)結(jié)構(gòu)完整和正常功能行使中起重要作用。

3 miRNAs與腸道營(yíng)養(yǎng)代謝

腸道作為營(yíng)養(yǎng)物質(zhì)消化吸收的主要器官，miRNAs參與腸上皮對(duì)營(yíng)養(yǎng)物質(zhì)的消化吸收過程，如miR-494參與腸道氯化鈉(NaCl)吸收及電解質(zhì)平衡調(diào)控[8]；miR-584可通過調(diào)控小鼠乳鐵蛋白受體表達(dá)，參與新生動(dòng)物營(yíng)養(yǎng)代謝過程[9]。腸道內(nèi)容物中的營(yíng)養(yǎng)物質(zhì)亦可通過影響腸道組織miRNAs表達(dá)參與相關(guān)代謝通路調(diào)控。微量元素硒可通過相關(guān)miRNAs調(diào)控Caco-2細(xì)胞花生四烯酸代謝、谷胱甘肽代謝及氧化應(yīng)激等通路[10]。多酚類物質(zhì)如槲皮素可通過調(diào)控腸道相關(guān)miRNAs表達(dá)影響腸道對(duì)鐵離子的吸收轉(zhuǎn)運(yùn)[11]。除此之外，miRNAs可介導(dǎo)營(yíng)養(yǎng)物質(zhì)對(duì)相關(guān)疾病的營(yíng)養(yǎng)調(diào)控過程。高紅肉飲食可通過提高miR-17-92表達(dá)水平增加結(jié)腸癌風(fēng)險(xiǎn)，而抗性淀粉作用剛好相反[12]。核桃中多不飽和脂肪酸通過上調(diào)小鼠大腸腫瘤組織中相關(guān)miRNAs表達(dá)，調(diào)控抗炎、抗增殖和細(xì)胞凋亡相關(guān)靶基因的表達(dá)[13]。綜上所述，miRNAs在腸道營(yíng)養(yǎng)物質(zhì)吸收、代謝與功能行使過程中起重要調(diào)控作用，相關(guān)miRNAs可為營(yíng)養(yǎng)調(diào)控提供新靶點(diǎn)與新思路。

4 miRNAs與腸道屏障功能

腸道屏障功能是腸道防止有毒有害物質(zhì)通過腸黏膜進(jìn)入機(jī)體的結(jié)構(gòu)和功能總和，是維持機(jī)體內(nèi)環(huán)境穩(wěn)態(tài)的重要保障。腸道屏障功能破壞會(huì)影響機(jī)體健康，導(dǎo)致多種疾病發(fā)生。

4.1 腸道黏膜上皮屏障

腸道黏膜上皮屏障主要包括上皮細(xì)胞表面的黏液層和腸上皮細(xì)胞及其之間的緊密連接。腸道上皮屏障的破壞可導(dǎo)致腸黏膜通透性增加及細(xì)菌移位，并觸發(fā)炎癥等一系列病理過程。眾多研究結(jié)果表明，miRNAs參與腸道上皮屏障功能調(diào)控。覆蓋于腸上皮表面的黏液層由杯狀細(xì)胞分泌，而miRNAs參與調(diào)節(jié)小腸上皮杯狀細(xì)胞分化[14]，小腸特異性缺失Dicer1酶的小鼠結(jié)腸上皮中杯狀細(xì)胞數(shù)量明顯減少，并導(dǎo)致小腸黏膜免疫力缺失[15]。另外，miRNAs參與腸道上皮緊密連接通透性的調(diào)控過程：miRNAs介導(dǎo)酒精等對(duì)腸道上皮緊密連接通透性的影響[16]；miRNAs參與年齡對(duì)腸道通透性的影響[17]；miRNAs亦參與應(yīng)激等造成的腸道上皮損傷調(diào)控[18]；等。

4.2 腸道免疫屏障

腸道黏膜免疫系統(tǒng)是動(dòng)物機(jī)體免疫系統(tǒng)的重要組成部分，在抵抗病原微生物入侵、保障機(jī)體健康方面起著重要作用。固有免疫系統(tǒng)是機(jī)體抵抗病原的第一重防御。miRNAs參與固有免疫細(xì)胞發(fā)育，如miR-181、miR-150、miR-15/16促進(jìn)自然殺傷細(xì)胞發(fā)育而miR-483、miR-583抑制其發(fā)育[19]；miR-155、miR-221等參與調(diào)控樹突狀細(xì)胞凋亡[20]。另外，miRNAs參與固有免疫應(yīng)答過程，如miR-122等可通過調(diào)控模式識(shí)別受體NOD樣受體(NLR)家族成員NOD2參與炎癥性腸病的病程調(diào)控等[21]。除此之外，miRNAs在機(jī)體特異性免疫系統(tǒng)中扮演重要角色。miRNAs參與免疫細(xì)胞成熟與激活，如miR-29、miR-155、miR-17-92參與Th1細(xì)胞分化及功能調(diào)控[22]，miR-21可通過一種T細(xì)胞內(nèi)源性途徑調(diào)控Th2細(xì)胞分化[23]。miRNAs亦參與免疫細(xì)胞功能發(fā)揮，如miR-146a可約束腸道T細(xì)胞群體的擴(kuò)張及減少免疫球蛋白A(IgA)的產(chǎn)生[24]。另外，miRNAs可通過調(diào)控其免疫相關(guān)靶基因的表達(dá)參與腸道特異性免疫反應(yīng)及腸道免疫穩(wěn)定維持，如miR-150與白細(xì)胞介素-1受體1激酶[25]，miR-212/132與白細(xì)胞介素-10[26]，等。miRNAs在自身免疫系統(tǒng)疾病乳糜泄病人十二指腸中異常表達(dá)亦證實(shí)miRNAs在腸道免疫屏障中的重要作用[27]。

4.3 腸道微生物屏障

腸道棲息著與機(jī)體共生的龐大微生物群體，構(gòu)成機(jī)體腸道的微生物屏障。腸道微生態(tài)穩(wěn)定是機(jī)體健康的保障。腸道共生菌與機(jī)體互作促進(jìn)腸道內(nèi)環(huán)境穩(wěn)定，而miRNAs參與該系列過程。腸道共生微生物影響腸道m(xù)iRNAs表達(dá)譜：與正常情況相比，無(wú)菌條件下飼養(yǎng)的小鼠盲腸中有16種miRNAs表達(dá)異常[28]。除此之外，腸道微生物參與細(xì)菌感染對(duì)宿主腸道編碼蛋白基因和miRNAs表達(dá)的調(diào)控：正常小鼠和無(wú)菌小鼠感染單核細(xì)胞增多性李斯特氏菌后，腸道多個(gè)miRNAs表達(dá)的變化和腸道微生物存在與否有關(guān)[29]。

益生菌廣泛用于促進(jìn)人和動(dòng)物健康水平，其在分子水平發(fā)揮作用的一種可能機(jī)制是調(diào)控腸道m(xù)iRNAs和免疫相關(guān)基因表達(dá)。仔豬飼喂屎腸球菌NCIMA 10415可提高回腸和空腸淋巴細(xì)胞中miR-423-5p表達(dá)進(jìn)而參與免疫調(diào)控[30]。慢性酒精刺激可誘導(dǎo)miR-122a表達(dá)，最終導(dǎo)致腸道屏障功能破壞，而鼠李糖乳酸桿菌GG株培養(yǎng)上清液可通過抑制酒精誘導(dǎo)的miR-122a表達(dá)上調(diào)保護(hù)腸道完整性[31]。因此，研究miRNAs在益生菌與腸道互作中的調(diào)控作用，對(duì)開發(fā)利用益生菌具有重要意義。

5 miRNAs與腸道疾病

miRNAs參與炎性腸疾病病程發(fā)展調(diào)控。例如，miR-125參與調(diào)控節(jié)段性回腸炎病人病程發(fā)展[32]，而miR-19b可減少其炎癥反應(yīng)[33]；miR-29a參與調(diào)控潰瘍性結(jié)腸炎的發(fā)病過程[34]，而miR-155參與其腸肌纖維細(xì)胞炎癥表型[35]；等。因此，這些miRNAs有望成為預(yù)測(cè)炎性腸病病程發(fā)展標(biāo)記及治療靶點(diǎn)。另外，miRNAs在2種炎癥性腸病間表達(dá)變化的差異可作為鑒定和區(qū)別兩者的生物標(biāo)記，如miR-19a、miR-21、miR-31、miR-101、miR-146a和miR-375[36]。結(jié)腸直腸癌是腸道常見的惡性腫瘤，多種miRNAs參與其病程發(fā)展。例如，miR-214表達(dá)與結(jié)腸炎相關(guān)結(jié)腸癌病程發(fā)展相關(guān)[37]；miR-17-92在結(jié)腸癌的發(fā)展過程中起重要作用，可靶向調(diào)控多個(gè)誘導(dǎo)腫瘤血管發(fā)生相關(guān)基因的表達(dá)[38]；等。除此之外，miRNAs可作為癌癥診斷的生物標(biāo)記，如miR-26b在潰瘍性結(jié)腸炎相關(guān)的結(jié)腸癌組織和血清中表達(dá)上調(diào)且與疾病惡化程度相關(guān)，而在散發(fā)性結(jié)腸癌中表達(dá)顯著下調(diào)，因此其可作為區(qū)分潰瘍性結(jié)腸炎相關(guān)的結(jié)腸癌和散發(fā)性結(jié)腸癌的生物標(biāo)記[39]?？傊琺iRNAs在腸道疾病病程中起重要調(diào)控作用，并在具有相似癥狀疾病間存在表達(dá)變化的差異性，可為腸道疾病的檢測(cè)治療提供新靶點(diǎn)與新思路。

6 飲食中miRNAs對(duì)腸道的影響

飲食中包含大量的外源miRNAs。有研究結(jié)果表明，外源miRNAs可通過進(jìn)食獲得并進(jìn)入受體細(xì)胞調(diào)控相關(guān)靶基因表達(dá)進(jìn)而影響受體細(xì)胞功能[40]。牛奶中外泌體miRNAs可通過腸道內(nèi)吞作用進(jìn)入新生兒機(jī)體內(nèi)并在新生兒免疫系統(tǒng)發(fā)育中扮演重要角色[41]。但到目前為止，通過進(jìn)食獲得外源miRNAs功能的研究還存在較大爭(zhēng)議。Snow等[42]在進(jìn)食蘋果和香蕉后人血清中幾乎沒有檢測(cè)到植物源miRNAs。飼喂高表達(dá)miR-30b轉(zhuǎn)基因小鼠奶的幼鼠血液、小腸、肝臟、肺臟和腎臟中miR-30b水平與飼喂野生型小鼠奶亦無(wú)顯著性差異[43]。若外源性miRNAs可通過腸道吸收調(diào)控相關(guān)靶器官基因表達(dá)則使口服miRNAs作為相關(guān)疾病的治療手段成為可能。另外，腸道作為直接攝取外源miRNAs的器官，miRNAs作為腸道疾病治療手段可能更易于其他器官。因此該方向的研究依然值得關(guān)注。

7 畜禽腸道健康相關(guān)miRNAs研究進(jìn)展

在畜禽養(yǎng)殖過程中，腸道健康是影響其生產(chǎn)性能的關(guān)鍵因素。近年來(lái)，與畜禽腸道健康相關(guān)miRNAs研究也越來(lái)越受到重視。斷奶應(yīng)激是影響仔豬生產(chǎn)的重大問題，相同日齡斷奶和哺乳狀態(tài)下仔豬腸道中多種miRNAs表達(dá)差異顯著，且主要參與腸道代謝、應(yīng)激及免疫反應(yīng)[44]；大腸桿菌F18感染易造成斷奶仔豬腹瀉和水腫病，該菌敏感型和抵抗型斷奶仔豬腸道中表達(dá)差異顯著的12種miRNAs可作為該菌易感性的候選標(biāo)記[45]。miRNAs亦參與了益生菌[30]、霉菌毒素[46]等對(duì)豬腸道健康的調(diào)控。在家禽研究方面，miRNAs參與病原感染引起的宿主反應(yīng)過程，如接種空腸彎曲桿菌的雞盲腸中4種miRNAs表達(dá)變化顯著[47]；另外，miRNAs參與腸道疾病和病原易感性的調(diào)控，如壞死性腸炎敏感性不同的2個(gè)白萊航雞品系腸道中10種miRNAs表達(dá)差異顯著[48]，馬立克病抵抗和敏感的不同品系雞腸道中多個(gè)miRNAs差異表達(dá)并參與炎癥相關(guān)基因調(diào)控[49]。綜上所述，miRNAs在畜禽腸道健康調(diào)控、疾病診斷、抗病育種等方面具有重要的研究?jī)r(jià)值，但現(xiàn)有研究主要停留在篩選階段，miRNAs具體作用機(jī)制還需進(jìn)一步深入研究。

8 小 結(jié)

人和小鼠模型等腸道健康相關(guān)miRNAs的研究已使我們充分認(rèn)識(shí)到miRNAs在腸道健康中的重要調(diào)控作用。但到目前為止，miRNAs在畜禽腸道中功能的研究還比較滯后。隨著miRNAs在畜禽腸道發(fā)育、營(yíng)養(yǎng)代謝以及各種應(yīng)激和腸道疾病中功能研究的進(jìn)一步深入，miRNAs及其靶基因形成的調(diào)控通路有望成為畜禽健康調(diào)控的新靶點(diǎn)，為畜禽腸道健康的營(yíng)養(yǎng)調(diào)控及相關(guān)疾病的抗病育種研究提供新思路，具有重要的研究意義與應(yīng)用前景。

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Author, CHEN Fang, assistant professor, E-mail: zhhchenfang0730@hotmail.com

(責(zé)任編輯 王智航)

MicroRNAs: Effects on Intestinal Health and Its Mechanisms

CHEN Fang ZHANG Hao WEI Jintao YANG Xuehai ZHAO Na ZHANG Wei

(HubeiKeyLaboratoryofAnimalEmbroyoEngineeringandMolecularBreeding,InstituteofAnimalHusbandryandVeterinarySciences,HubeiAcademyofAgriculturalSciences,Wuhan430064,China)

Intestine is the major organ of digesting and absorbing nutrients and plays an important role in protecting body against from bacterial infection. MicroRNAs (miRNAs) serve as important intracellular factor in post-transcriptional regulation of gene expression. In this paper, in order to provide reference for further study, we summarized recent researches in the expression of miRNAs in intestinal tissue, the effects of miRNAs on proliferation, differentiation and apoptosis of intestinal cells, the regulatory function on nutrient metabolism, intestinal barrier function and disease progression, and the absorption of external miRNAs in intestine.[ChineseJournalofAnimalNutrition, 2017, 29(1)：21-26]

miRNAs; intestine; effect; mechanism

10.3969/j.issn.1006-267x.2017.01.003

2016-07-14

湖北省農(nóng)業(yè)科學(xué)院青年基金(2015NKYJJ27)；湖北省創(chuàng)新團(tuán)隊(duì)項(xiàng)目(2016-620-000-001-028)

陳 芳(1987—)，女，四川眉山人，助理研究員，博士，主要從事動(dòng)物營(yíng)養(yǎng)調(diào)控機(jī)理與飼料資源開發(fā)利用研究。E-mail: zhhchenfang0730@hotmail.com

S852.2

A

1006-267X(2017)01-0021-06