單胃動物腸道菌群與宿主腸道免疫系統(tǒng)的互作關(guān)系及可能機(jī)制

李佳彥 陳代文 余 冰 何 軍 虞 潔 毛湘冰 羅鈞秋 鄭 萍 黃志清 羅玉衡

(四川農(nóng)業(yè)大學(xué)動物營養(yǎng)研究所，動物抗病營養(yǎng)教育部重點實驗室，雅安625014)

單胃動物腸道菌群與宿主腸道免疫系統(tǒng)的互作關(guān)系及可能機(jī)制

李佳彥 陳代文 余 冰 何 軍 虞 潔 毛湘冰 羅鈞秋 鄭 萍 黃志清 羅玉衡*

(四川農(nóng)業(yè)大學(xué)動物營養(yǎng)研究所，動物抗病營養(yǎng)教育部重點實驗室，雅安625014)

單胃動物的腸道中存在著龐大而復(fù)雜的菌群，它們與宿主腸道免疫系統(tǒng)協(xié)同進(jìn)化。腸道細(xì)菌及其代謝產(chǎn)物在維持腸道穩(wěn)態(tài)方面發(fā)揮著重要的作用。正常的腸道菌群能促進(jìn)免疫系統(tǒng)發(fā)育，參與維持宿主免疫功能，協(xié)同拮抗病原菌的增殖和入侵。反過來，宿主腸道免疫系統(tǒng)對腸道菌群又有制約和調(diào)控作用，如對正常共生菌表現(xiàn)為免疫耐受，對病原菌表現(xiàn)為免疫排斥。一旦這種動態(tài)平衡被破壞，就會導(dǎo)致疾病的發(fā)生。本文綜述了單胃動物腸道菌群與宿主腸道免疫系統(tǒng)的相互關(guān)系，并基于現(xiàn)有的研究結(jié)果，對其可能的互作機(jī)制做了較為系統(tǒng)的總結(jié)。

單胃動物；腸道菌群；腸道免疫系統(tǒng)；免疫細(xì)胞；潛在機(jī)制

動物體的微生物種類包括細(xì)菌(數(shù)量最多)、古菌、真菌、病毒等，其數(shù)量多達(dá)1013～1014個，是動物體本身細(xì)胞總數(shù)的10倍之多，其中大部分定植在胃腸道中[1]。單胃動物腸道菌群的分布具有空間特異性，其數(shù)量級從近端至遠(yuǎn)端消化道呈依次遞增趨勢，以結(jié)腸中的細(xì)菌數(shù)量最多(為1011～1012個)[2]。在腸道內(nèi)，從上皮細(xì)胞到腸腔內(nèi)，細(xì)菌的數(shù)量和種類依次遞增，且腸腔內(nèi)的菌群與附著在黏液層以及上皮隱窩中的菌群種類明顯不同[3]。這些共生微生物在促進(jìn)腸道相關(guān)淋巴組織(gut-associated lymphoid tissues,GALTs)的發(fā)育和抵抗病原體入侵等方面發(fā)揮著重要作用[4]。動物腸道菌群的結(jié)構(gòu)和分布可受遺傳[5]、飼糧[6]、環(huán)境[7]、抗生素的使用[8]等因素影響，其直接結(jié)果是使菌群結(jié)構(gòu)發(fā)生相應(yīng)改變。微生物群落間的動態(tài)平衡受到干擾，必然導(dǎo)致宏基因組功能的變化。動物的腸道不僅是營養(yǎng)物質(zhì)消化吸收的場所，同時也是機(jī)體的第1道防線，是重要的免疫器官之一。而宿主腸道黏膜中存在許多與免疫功能相關(guān)的受體或信號分子，細(xì)菌作為免疫識別最為重要的對象之一，菌群結(jié)構(gòu)的變化勢必引起宿主腸道免疫系統(tǒng)的快速響應(yīng)，這種免疫應(yīng)答反應(yīng)又反過來調(diào)控腸道菌群的組成和分布[9]。因此腸道菌群與機(jī)體免疫之間可能存在復(fù)雜的相互作用，但目前大多研究僅停留在表面，對具體哪些特定細(xì)菌影響何種免疫細(xì)胞的增殖分化及具體機(jī)制知之甚少。為此,本文綜合國內(nèi)外最新相關(guān)研究結(jié)果，系統(tǒng)綜述了單胃動物腸道菌群與宿主腸道免疫功能之間的相互作用及其可能的互作機(jī)制。

1 腸道菌群對宿主腸道免疫系統(tǒng)的調(diào)控

單胃動物的腸道免疫系統(tǒng)由三大屏障組成，即由腸黏膜上皮細(xì)胞和杯狀細(xì)胞等構(gòu)成的機(jī)械屏障、由腸道免疫細(xì)胞及其分泌的免疫因子構(gòu)成的免疫屏障以及由腸道正常菌群構(gòu)成的生物屏障[10]。越來越多的研究表明,腸道菌群能調(diào)控各種免疫細(xì)胞的分化和功能。腸道共生菌的存在對腸道和組織淋巴結(jié)構(gòu)發(fā)育有至關(guān)重要的作用。

1.1 介導(dǎo)GALTs的發(fā)育

GALTs包括集合淋巴小結(jié)(Peyer’s patches,PP)、孤立淋巴濾泡(isolated lymphoid follicles,ILF)和腸系膜淋巴結(jié)(mesenteric lymph nodes,MLN)[11]。研究表明，無菌小鼠GALTs的發(fā)育存在明顯缺陷，尤其是PP和ILF[12]。在胎兒時期，淋巴組織誘導(dǎo)細(xì)胞(lymphoid tissue inducer,LTi)能在無菌條件下誘導(dǎo)PP的發(fā)育[13]，而ILFs的發(fā)育則需要微生物的介導(dǎo)[14]。對無菌兔(GF-APX)的研究發(fā)現(xiàn)，將含1×109CFU的6種細(xì)菌[枯草芽孢桿菌(B.subtilis)、地衣芽孢桿菌(B.licheniformis)、短小芽孢桿菌(B.pumilus)、脆弱擬桿菌(B.fragilis)、表皮葡萄球菌(S.epidermidis)、近端梭菌(C.subterminale)]混合懸浮液注入GF-APX腸腔內(nèi)能通過誘導(dǎo)B細(xì)胞的增殖促進(jìn)GALTs的發(fā)育。為進(jìn)一步確定具體是哪一種細(xì)菌能誘導(dǎo)GALTs發(fā)育，作者將它們單獨或兩兩接種至GF-APX腸道內(nèi)，發(fā)現(xiàn)除了單獨或兩兩接種枯草芽孢桿菌與脆弱擬桿菌能誘導(dǎo)GALTs發(fā)育外，其他4種菌單獨或兩兩接種均不能誘導(dǎo)GALTs發(fā)育，暗示單一的某種細(xì)菌也許不能完全誘導(dǎo)GALTs的發(fā)育，保證腸道內(nèi)細(xì)菌的種類和多樣性對腸道免疫系統(tǒng)的充分發(fā)育來說是必需的[15]。

1.2 介導(dǎo)腸道輔助性T(helper T,Th)細(xì)胞的增殖分化

Th17細(xì)胞是一種特殊的CD4+Th細(xì)胞，對宿主的防御至關(guān)重要。Th17細(xì)胞通過產(chǎn)生促炎性細(xì)胞因子白細(xì)胞介素-17A(IL-17A)、白細(xì)胞介素-17F(IL-17F)和白細(xì)胞介素-22(IL-22)對自身免疫性疾病的發(fā)展起作用[16]。研究表明，Th17細(xì)胞的數(shù)量在經(jīng)過抗生素治療的動物或無菌動物的結(jié)腸中大大減少[17-18]，說明微生物對Th17細(xì)胞發(fā)育有重要作用。隨后Gaboriau等[19]發(fā)現(xiàn)腸道中存在一種共生梭狀芽胞桿菌，即分節(jié)絲狀菌(segmented filamentous bacteria,SFB)，其對Th17細(xì)胞的發(fā)育至關(guān)重要；同時，還發(fā)現(xiàn)缺乏SFB的C57BL/6成年小鼠的小腸固有層中Th17細(xì)胞數(shù)量較低，但植入SFB 2周后Th17細(xì)胞數(shù)量顯著增加，表明SFB能誘導(dǎo)小鼠小腸中Th17細(xì)胞的生成。此外，在無菌小鼠腸道中接種ASF(altered Schaedler flora)——含8種細(xì)菌的一種特定的菌群后，其結(jié)腸固有層中Th17細(xì)胞的數(shù)量也顯著提高，但其調(diào)控效果弱于SFB[20]。其他研究發(fā)現(xiàn)，對3～4周齡的無菌小鼠灌胃200 μL成人糞便樣品混懸液后同樣能誘導(dǎo)Th17細(xì)胞的增殖[21]，由于成人腸道類無SFB定植[22]，暗示動物腸道中可能存在大量其他種類的共生菌,這些共生菌能特異性誘導(dǎo)Th17細(xì)胞的增殖分化。

1.3 介導(dǎo)調(diào)節(jié)性T(regulatory T,Treg)細(xì)胞的增殖分化

叉頭/翼狀螺旋轉(zhuǎn)錄因子3+(forkhead box P3+,FOXP3+)Treg細(xì)胞也是CD4+Th細(xì)胞的亞群，在維持腸道功能穩(wěn)態(tài)中發(fā)揮重要作用。研究發(fā)現(xiàn)，在抗生素處理或無菌小鼠的腸道中雖然仍能檢測到Treg細(xì)胞，但其數(shù)量在小腸固有層中明顯下降，表明微生物有維持Treg細(xì)胞數(shù)量或促進(jìn)Treg細(xì)胞分化的作用[23]。目前已有幾種共生菌被證明具有誘導(dǎo)Treg細(xì)胞增殖分化的活性。對無菌小鼠灌胃46株梭桿菌屬細(xì)菌的混懸液可導(dǎo)致結(jié)腸固有層Treg細(xì)胞數(shù)量顯著增加，經(jīng)分離鑒定，這些細(xì)菌分屬于梭狀芽胞桿菌的2個類簇——梭狀芽胞桿菌Ⅳ簇和ⅪⅤa簇[23]。此外，接種ASF也可引起無菌小鼠結(jié)腸固有層Treg細(xì)胞的增殖，值得一提的是ASF中包含3株屬于梭狀芽胞桿菌ⅪⅤa簇的細(xì)菌[20]。Atarashi等[24]進(jìn)一步分離鑒定出人類腸道中的17株細(xì)菌(分屬于梭狀芽胞桿菌的Ⅳ簇、ⅪⅤa簇和ⅩⅧ簇)也能誘導(dǎo)腸道中Treg細(xì)胞的生成。此外，人類腸道中的共生菌脆弱擬桿菌也能促進(jìn)小鼠結(jié)腸中Treg細(xì)胞的增殖和細(xì)胞因子白細(xì)胞介素-10(IL-10)的產(chǎn)生[25]。

1.4 介導(dǎo)腸黏膜B細(xì)胞的增殖分化

早期B細(xì)胞的發(fā)育不僅發(fā)生在胎兒的肝臟和骨髓上，還發(fā)生在腸黏膜上[26]。微生物和腸道特異性B細(xì)胞之間存在密切的關(guān)系，B細(xì)胞通過產(chǎn)生免疫球蛋白A(IgA)來防止微生物感染[27]，反之微生物能誘導(dǎo)腸道B細(xì)胞的胞外信號調(diào)節(jié)受體[26]。無菌小鼠體內(nèi)因缺乏微生物介導(dǎo)的信號，導(dǎo)致PP的生發(fā)中心發(fā)育不成熟，從而降低B細(xì)胞的生成數(shù)量[28]。因此，在消化道內(nèi)，B細(xì)胞是通過共生菌群的刺激在PP中成熟的，但其具體機(jī)制尚屬未知。此外，小鼠結(jié)腸固有層的樹突狀細(xì)胞(dendritic cells,DCs)中，共生菌的鞭毛蛋白能通過促進(jìn)維甲酸的合成來誘導(dǎo)不同B細(xì)胞的分化[29]。

1.5 介導(dǎo)先天淋巴細(xì)胞(innate lymphoid cells,ILCs)的增殖分化

ILCs作為一種固有免疫細(xì)胞越來越受到關(guān)注，它的功能特性與T細(xì)胞相似[30]。淋巴前體可分化成3個ILCs亞型：T轉(zhuǎn)錄因子ILCs(T-bet+ILCs,ILC1s)、GATA結(jié)合蛋白-3 ILCs[GATA-binding protein 3 (GATA3+) ILCs,ILC2s]、維甲酸相關(guān)孤核受體γT ILCs[retinoicacid receptor-relaedorphan receptor-γt (RORγt+) ILCs,ILC3s][31]。微生物對ILCs的發(fā)展和功能作用一直飽受爭議。研究發(fā)現(xiàn)，無菌小鼠體內(nèi)RORγt+NKp46+CD127+NK1.1-ILCs或RORγt+NKp46+CD127+NK1.1intILCs的數(shù)量顯著降低，說明微生物對ILC3s的分化是必需的[32]。在缺乏腸道菌群時，由ILCs分泌的IL-22的含量顯著降低，表明共生菌還能調(diào)控ILCs的免疫功能[33]。相反，有研究發(fā)現(xiàn)腸道菌群對ILC3s的分化并無顯著影響，且會抑制IL-22的分泌[34]。

2 腸道菌群調(diào)控宿主腸道免疫系統(tǒng)的可能機(jī)制

2.1 調(diào)控GALTs發(fā)育

腸道菌群刺激GALTs發(fā)育主要是由DCs對細(xì)菌及其代謝產(chǎn)物的識別而實現(xiàn)的，細(xì)菌通過激活DCs上的各種模式識別受體(pattern recognition receptors,PRRs)來誘發(fā)這一過程[35]。常見的PRRs包括Toll樣受體家族(Toll-like receptors,TLRs)、NOD樣受體家族(nucleotide-binding oligomerizationdomain-like receptor,NLRs)等。TLRs識別細(xì)菌或其代謝產(chǎn)物后，進(jìn)一步激活髓樣分化蛋白88(MYD88)接頭蛋白樣蛋白(MAL)-MYD88和含Toll/白細(xì)胞介素-1受體(TLR)結(jié)構(gòu)域能誘導(dǎo)β型干擾素(IFN-β)的接頭分子(TRIF)相關(guān)接頭分子(TRAM)-TRIF信號通路，激活DCs[36]?；罨蟮腄Cs能誘導(dǎo)PP生發(fā)中心的T細(xì)胞增殖，促進(jìn)B細(xì)胞分泌IgA；通過淋巴血管到達(dá)MLN，誘導(dǎo)效應(yīng)T細(xì)胞增殖，使隱窩小結(jié)發(fā)育為成熟的ILFs。Bouskra等[12]研究發(fā)現(xiàn)ILFs還可通過NOD1(nucleotide-binding oligomerization domain 1)與細(xì)菌細(xì)胞壁上的聚肽糖相結(jié)合后而誘發(fā)其發(fā)育成熟。

2.2 調(diào)控Th17細(xì)胞增殖分化

越來越多的研究證明腸道菌群是通過LP的單核吞噬細(xì)胞包括DCs和巨噬細(xì)胞，來促進(jìn)腸道Th17細(xì)胞發(fā)育的。上文提到，SFB能特異性的誘導(dǎo)Th17細(xì)胞的分化，其具體的機(jī)制是，SFB通過刺激腸道上皮細(xì)胞分泌血清淀粉樣蛋白A(serum amyloid A,SAA)，SAA能促進(jìn)回腸固有層CD11c+DCs分泌細(xì)胞因子白細(xì)胞介素-6(IL-6)和白細(xì)胞介素-23(IL-23)，IL-6和IL-23是誘導(dǎo)Th17細(xì)胞分化的關(guān)鍵因素[37]。與Th17細(xì)胞分化有關(guān)的另一個關(guān)鍵細(xì)胞因子是白細(xì)胞介素-1β(IL-1β)，Shaw等[38]研究發(fā)現(xiàn)，無菌小鼠腸道中LP巨噬細(xì)胞分泌IL-1β減少，且敲除了IL-1β受體的小鼠腸道中Th17細(xì)胞數(shù)量顯著減少，表明共生菌還可能通過誘導(dǎo)IL-1β的產(chǎn)生來促進(jìn)腸道Th17細(xì)胞的發(fā)育；進(jìn)一步研究得出，MyD88敲除小鼠腸道中IL-1β和Th17細(xì)胞的含量都顯著降低[38]，推測共生菌是通過TLR-MyD88信號通路誘導(dǎo)腸道LP巨噬細(xì)胞產(chǎn)生IL-1β，進(jìn)而促進(jìn)Th17細(xì)胞分化的。

2.3 調(diào)控Treg細(xì)胞增殖分化

由于相關(guān)研究極少，目前尚不清楚特定腸道菌群誘導(dǎo)Treg細(xì)胞發(fā)育的機(jī)制。有限的研究表明，β型轉(zhuǎn)化生長因子(transfoming growth factor β,TGF-β)參與了腸道菌群對Treg細(xì)胞的誘導(dǎo)分化。梭狀芽孢桿菌Ⅳ簇和ⅪⅤa簇能通過刺激結(jié)腸上皮細(xì)胞產(chǎn)生TGF-β，誘導(dǎo)Treg細(xì)胞的分化[23]。除上皮細(xì)胞外，腸道LP DCs的某些亞群也能參與Treg細(xì)胞的誘導(dǎo)分化，如CD103+CD11b+CD11c+LP DCs和CD103+CD11b-CD11c+LP DCs能優(yōu)先誘導(dǎo)CD4+T細(xì)胞分化為Treg細(xì)胞[39]。CD103+LP DCs能表達(dá)驅(qū)動Treg細(xì)胞分化的相關(guān)因子，如TGF-β和視黃酸脫氫酶(retinoic acid dehydrogenase,RALDH)，視黃酸(retinoic acid,RA)也能有效誘導(dǎo)Treg細(xì)胞的分化[40]。此外，在TGF-β存在時，LP CD11b+CD11c-巨噬細(xì)胞能通過產(chǎn)生RA來誘導(dǎo)腸道Treg細(xì)胞的分化[41]。脆弱擬桿菌產(chǎn)生的多糖A(polysaccharide A,PSA)也能通過激活TLR2-MyD88信號通路來刺激Treg細(xì)胞的分化及IL-10的分泌[42]。

2.4 調(diào)控B細(xì)胞增殖分化

腸道共生菌可通過不同途徑來調(diào)控B細(xì)胞的分化。研究發(fā)現(xiàn)，MyD88缺失的小鼠腸道中CD11b+IgA+B細(xì)胞數(shù)量顯著下降[43]，說明共生菌能通過激活LP DCs或濾泡DCs上的MyD88信號，促進(jìn)IgA+B細(xì)胞的產(chǎn)生。在受到細(xì)菌刺激后，PPs中濾泡DCs通過分泌TGF-β、趨化因子CXCL13、B細(xì)胞活化因子(B-cell activating factor,BAFF)來促進(jìn)B細(xì)胞的分化和IgA+的生成[44]；LP DCs能通過分泌TGF-β、RA、腫瘤壞死因子α(tumor necrosis factor α,TNF-α)、BAFF、誘生型一氧化氮合酶(inducible nitric oxidesynthase,iNOS)和增殖誘導(dǎo)配體(a proliferation-inducing ligand,APRIL)來促進(jìn)IgA+B細(xì)胞的生成[45]。

2.5 調(diào)控ILCs功能

上文提到腸道菌群對ILCs的發(fā)育和功能同時存在正面與負(fù)面效應(yīng)，一方面，共生菌能促進(jìn)RORγt+ILCs分泌細(xì)胞因子IL-22產(chǎn)生相應(yīng)的免疫功能[46]；另一方面，共生菌能誘導(dǎo)腸道上皮細(xì)胞分泌白細(xì)胞介素-25(IL-25)，IL-25作用于固有層IL-17RB+DCs來抑制ILC3s分泌IL-22[47]。但其中的具體機(jī)制目前尚不清楚。

除上述的直接調(diào)控(圖1)外，腸道菌群的多種代謝產(chǎn)物均能對宿主腸道免疫系統(tǒng)進(jìn)行間接調(diào)控，如梭狀芽胞桿菌Ⅳ簇和ⅪⅤa簇的代謝產(chǎn)物丁酸能誘導(dǎo)CD4+T細(xì)胞分化為Treg細(xì)胞[48]；雙歧桿菌的代謝產(chǎn)物維生素D能促進(jìn)Th細(xì)胞分化[49]等。

SFB:分節(jié)絲狀菌 segmented filamentous bacteria；ASF:含8種細(xì)菌的一種特定的菌群 altered Schaedler flora；IgA+:免疫球蛋白A+immunoglobulin A+；SAA:血清淀粉樣蛋白A serum amyloid A；TGF-β:β型轉(zhuǎn)化生長因子 transfoming growth factor β；PSA:多糖A polysaccharide A；DCs:樹突狀細(xì)胞 dendritic cells；Th17 cell:輔助性T細(xì)胞17 T helper 17 cell；Treg:調(diào)節(jié)性T細(xì)胞 regulatory T cell；RA:視黃酸 retinoic acid；BAFF:B細(xì)胞活化因子 B-cell activating factor；Foxp3+:叉頭/翼狀螺旋轉(zhuǎn)錄因子3+forkhead/winged helix transcription factor 3+；TNF-α:腫瘤壞死因子α tumor necrosis f-actor α；APRIL:增殖誘導(dǎo)配體 a proliferation-inducing ligand；iNOS:誘生型一氧化氮合酶 inducible nitric oxidesynthase；SIgA+:分泌型免疫球蛋白A+secretory immunoglobulin A+；plasma cell：漿細(xì)胞；macrophage：巨噬細(xì)胞；RORγt+:維甲酸相關(guān)孤核受體γt retinoid related orphan receptor γt；IL：白細(xì)胞介素 interleukin；Reg Ⅲγ：胰島再生源蛋白3γ regenerating islet-derived protein Ⅲγ。

圖1 腸道微生物介導(dǎo)的腸道免疫系統(tǒng)發(fā)育(根據(jù)文獻(xiàn)[37-49]總結(jié))

Fig.1 The gut microbiota-mediated development of the intestinal immune system (summarized according to references[37-49])

3 宿主腸道免疫系統(tǒng)對共生菌群分布及功能的影響

3.1 影響菌群的空間分布

如前所述，共生菌群對宿主腸道免疫系統(tǒng)的發(fā)育有重要作用，但微生物的過度刺激也可能導(dǎo)致腸道中免疫細(xì)胞不適當(dāng)?shù)募せ詈湍c內(nèi)炎癥的發(fā)生。腸道黏膜屏障由腸黏膜表面的黏液層、腸上皮本身及其緊密連接、黏膜下固有層等組成，其作為物理屏障是抵御腸腔微生物的第1道防線，能減少微生物與小腸上皮的直接接觸[50]，有效阻止細(xì)菌穿透黏膜。此外，胰島再生源蛋白Ⅲγ(regenerating islet-derived protein Ⅲγ,RegⅢγ)可作為限制細(xì)菌滲透進(jìn)腸黏膜的另一道屏障[51]，ILC3s能分泌細(xì)胞因子IL-22，IL-22作用于上皮細(xì)胞，激活p38-絲裂原活化蛋白激酶(mitogen-activated protein kinase，MAPK)或信號傳導(dǎo)子及轉(zhuǎn)錄激活子3(signal transducer and activator of transcrip-tion3,STAT3)信號通路促進(jìn)RegⅢγ的生成[52]。Zheng等[53]研究發(fā)現(xiàn)IL-22能夠通過誘導(dǎo)小鼠小腸上皮細(xì)胞中RegⅢγ的表達(dá)來抑制鼠類檸檬酸桿菌(Citrobacterrodentium)感染結(jié)腸，ILC3s數(shù)量減少則會增加共生菌木糖氧化產(chǎn)堿菌(Alcaligenesxylosoxidians)進(jìn)入腸腔的機(jī)會，從而導(dǎo)致宿主腸道損傷和全身炎癥[46]。腸黏膜表面的分泌型IgA(secretory immunoglobulin A,SIgA)也能與共生菌[陰溝腸桿菌(E.cloacae)或野生型大腸桿菌(wild-typeE.coli)]特異性結(jié)合，防止其穿透上皮屏障[54]。就此而言，宿主腸道免疫系統(tǒng)對共生菌有一種制約作用，在正常情況下限制共生菌進(jìn)入腸道上皮細(xì)胞，避免微生物對腸道的過度刺激，維持腸道微生物與宿主正常的共生關(guān)系。

3.2 影響共生菌群的組成和功能

免疫因子IgA能通過對腸道菌群組成和功能的調(diào)控來維持宿主和微生物之間的共生關(guān)系。研究發(fā)現(xiàn)，小鼠體內(nèi)活化誘導(dǎo)胞嘧啶核苷脫氨酶(activation-induced cytidine deaminase,AICD)的缺失或突變可導(dǎo)致腸道IgA的應(yīng)答缺陷，使細(xì)菌數(shù)量擴(kuò)增(尤其是厭氧菌)，從而引起腸道菌群的組成發(fā)生改變[55]。抑制性協(xié)同受體程序性死亡蛋白-1(inhibitory co-receptor programmed death-1)的缺失能降低了IgA與細(xì)菌的結(jié)合能力，導(dǎo)致小鼠腸道菌群結(jié)構(gòu)的改變，與野生型小鼠相比其共生菌的數(shù)量如雙歧桿菌屬(Bifidobacterium)和多型擬桿菌屬(Bacteroides)等的細(xì)菌數(shù)量無明顯變化，而腸桿菌科(Enterobacteriaceae)的細(xì)菌數(shù)量則增加近400倍[56]，暗示這種菌群結(jié)構(gòu)的改變可促進(jìn)某些條件性病原菌的增殖，使其從豐度較低的常駐菌轉(zhuǎn)變?yōu)閷λ拗饔泻χ虏【?。除了改變?xì)菌群落結(jié)構(gòu)外，一項在小鼠上的試驗發(fā)現(xiàn)，IgA與共生菌多形擬桿菌(Bacteroidesthetaiotaomicron)結(jié)合后能影響其基因表達(dá)，導(dǎo)致編碼亞硝酸鹽還原酶的操縱子(BT1414～1418)、參與一氧化氮代謝的基因(BT0687)和編碼細(xì)胞色素D泛醇氧化酶亞基的操縱子(與細(xì)菌的耐氧性有關(guān))表達(dá)量顯著上升[57]。ILC3s的功能缺陷時，IL-22分泌量減少，導(dǎo)致SFB異常擴(kuò)增，使腸道Th17細(xì)胞免疫應(yīng)答增加[58]。

此外，某些免疫基因的缺失也可能影響腸道菌群結(jié)構(gòu)，如轉(zhuǎn)錄因子T-bet(由Tbx21基因編碼)能夠調(diào)控參與先天性和適應(yīng)性免疫反應(yīng)的細(xì)胞的炎癥應(yīng)答，小鼠缺失Tbx21基因可導(dǎo)致腸道內(nèi)潛在致病菌克雷白氏桿菌(Klebsiellapneumoniae)、奇異變形桿菌(Proteusmirabilis)和幽門螺旋桿菌(Helicobactertyphlonius)累積，易患潰瘍性結(jié)腸炎[59]。上皮細(xì)胞NLRP6炎性體缺陷小鼠的炎性因子白細(xì)胞介素-18(IL-18)產(chǎn)量減少，菌群結(jié)構(gòu)發(fā)生改變，普雷沃氏菌科(Prevotellaceae)細(xì)菌的數(shù)量大幅增加[60]。

上述研究均說明了腸道免疫系統(tǒng)能通過各種途徑調(diào)節(jié)共生菌在宿主腸道中的分布、組成和功能，但目前只對少數(shù)免疫細(xì)胞和因子與共生菌的關(guān)系做了初步研究，更多的免疫細(xì)胞因子對宿主腸道微生物的影響及其具體機(jī)制還有待進(jìn)一步探索。

4 小 結(jié)

大量研究初步揭示了單胃動物腸道菌群與宿主腸道免疫系統(tǒng)之間的復(fù)雜互作關(guān)系，這種互作機(jī)制保障了腸道內(nèi)環(huán)境的穩(wěn)定。然而，研究尚需深入，很多問題仍不清楚，如消化道中的其他共生微生物(如真菌、病毒)是否與腸道免疫系統(tǒng)間也存在互作？具體機(jī)制是什么？與細(xì)菌-宿主免疫系統(tǒng)互作有無異同？腸道微生物與宿主免疫系統(tǒng)之間的互作是否也遵循“腸-腦-腸”軸這一經(jīng)典規(guī)則？從營養(yǎng)學(xué)角度出發(fā)，探究能否通過營養(yǎng)調(diào)控手段來改善腸道菌群結(jié)構(gòu)，甚至靶向調(diào)控某一類或幾類特殊菌群，達(dá)到提高動物機(jī)體免疫力的效果，將是動物營養(yǎng)學(xué)研究的全新領(lǐng)域，相關(guān)研究結(jié)果將為豐富動物抗病營養(yǎng)學(xué)理論提供基礎(chǔ)數(shù)據(jù)。

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*Corresponding author, associate professor, E-mail: luoluo212@126.com

(責(zé)任編輯 菅景穎)

Interaction between Intestinal Microflora and Intestinal Immune System of Host and Its Possible Mechanisms in Monogastric Animals

LI Jiayan CHEN Daiwen YU Bing HE Jun YU Jie MAO Xiangbing LUO Junqiu ZHENG Ping HUANG Zhiqing LUO Yuheng*

(KeyLaboratoryforAnimalDisease-ResistanceNutritionofMinistryofEdcation,InstituteofAnimalNutrition,SichuanAgriculturalUniversity,Ya’an625014,China)

The intestinal tract of monogastirc animals harbors large amount of microorganisms with complex species. The intestinal microbes and their metabolites coevolve with the intestinal immune system of host. These microbes and their metabolites play an important role in maintaining hosts’ intestinal homeostasis. Accumulating evidences indicated that normal microflora could promote the development of immune system and regulate the maintaining of immunologic function of host, as well as co-resist the proliferation and invasion of various pathogens. In contrast, the intestinal immune system of host exhibits restrictive and regulatory roles to symbiotic microflora, for examples, immune tolerance to normal flora, or immunological rejection to pathogens. The breakdown of this homeostasis causes the occurrence of gastrointestinal diseases of host. Here, we reviewed the interaction between intestinal microflora and the intestinal immune system of host. Based on the results of existing studies, the possible mechanisms were also systemically summarized.[ChineseJournalofAnimalNutrition, 2017, 29(7)：2252-2260]

monogastric animals; intestinal microflora; intestinal immune system; immunocytes; underlying mechanism

10.3969/j.issn.1006-267x.2017.07.006

2016-12-30

國家自然科學(xué)基金項目(3167131062)

李佳彥(1994—)，女，湖南婁底人，碩士研究生，從事豬的營養(yǎng)研究。E-mail: ljy1367206340@163.com

*通信作者:羅玉衡，副研究員，碩士生導(dǎo)師，E-mail: luoluo212@126.com

S852.6

A

1006-267X(2017)07-2252-09