周 達(dá)，范建高

上海交通大學(xué)醫(yī)學(xué)院附屬新華醫(yī)院消化內(nèi)科，上海 200092

綜述

腸道菌群-SCFAs在代謝性疾病中的作用研究

周 達(dá)，范建高

上海交通大學(xué)醫(yī)學(xué)院附屬新華醫(yī)院消化內(nèi)科，上海 200092

腸道菌群被認(rèn)為是人類體內(nèi)不可或缺的“器官”，其代謝產(chǎn)物如短鏈脂肪酸(short-chain fatty acids，SCFAs)也被證實(shí)生物學(xué)作用顯著，尤其在機(jī)體代謝方面。本文就腸道菌群-SCFAs與代謝性疾病研究進(jìn)展作一闡述。

腸道菌群；短鏈脂肪酸；代謝

人類從出生腸道內(nèi)逐漸定植各種細(xì)菌，受飲食、環(huán)境等因素影響，直至兒童期趨于穩(wěn)定；菌群在腸道內(nèi)數(shù)量巨大(總數(shù)約1014)，種類豐富多達(dá)2 000余種，其基因總量更是人類的100～400倍；但是腸道菌群主要由厚壁菌門、擬桿菌門、放線菌門、變形菌門等組成，前兩者即達(dá)到總量90%以上[1]。腸道菌群與人類生長發(fā)育(尤其免疫與代謝)和疾病的發(fā)生、發(fā)展密切相關(guān)。

近年，腸道菌群與代謝及其機(jī)制被研究的越來越多，如腸道菌群失調(diào)可以促進(jìn)食物能量吸收，引起肥胖；可以調(diào)節(jié)腸道通透性，促進(jìn)脂多糖(lipopolysaccharide，LPS)甚至菌群移位入血，從而引發(fā)機(jī)體炎癥、免疫失衡；可以調(diào)節(jié)機(jī)體膽堿、膽汁酸代謝等[2]；甚至增加機(jī)體內(nèi)生性乙醇的產(chǎn)生，后者仍存在爭議[3]。這些機(jī)制與肥胖、2型糖尿病、非酒精性脂肪性肝病(nonalcoholic fatty liver disease，NAFLD)等慢性代謝性疾病發(fā)生、發(fā)展密切相關(guān)[4]。隨著研究的深入，焦點(diǎn)不光局限于腸道菌群本身，菌群代謝產(chǎn)物也被認(rèn)為是參與調(diào)節(jié)機(jī)體生命活動與代謝的重要物質(zhì)，如短鏈脂肪酸(short-chain fatty acids，SCFAs)[5]。

SCFAs是腸道菌群在體內(nèi)發(fā)酵纖維素產(chǎn)生，含不多于6個(gè)碳原子且溶于水的游離脂肪酸，主要包括甲、乙、丙、丁、戊酸(formic acid，acetic acid，propionic acid，butyric acid and valeric acid)，近端及遠(yuǎn)端結(jié)腸內(nèi)SCFAs濃度分別約120 mol/L和90 mol/L，其中最重要且相對較多(占總量95%)的是乙、丙、丁酸，三者比例大致為3∶1∶1[6]。它們與細(xì)胞的作用方式可以是彌散或者配體受體結(jié)合作用，如G蛋白偶聯(lián)受體(G protein coupled receptor，GPCR)[7]。

1 SCFAs調(diào)節(jié)炎癥免疫與代謝

慢性代謝性疾病發(fā)生、發(fā)展機(jī)制中，如肥胖、非酒精性脂肪性肝炎(non-alcoholic steatohepatitis，NASH)等，炎癥反應(yīng)尤為重要。SCFAs可通過抑制核轉(zhuǎn)錄因子κB(NF-κB)通路抑制炎癥細(xì)胞分泌白細(xì)胞介素2(IL-2)、白細(xì)胞介素6(IL-6)、腫瘤壞死因子α(TNF-α)等炎性因子[8-9]，后者與NASH的發(fā)生、發(fā)展密切相關(guān)；有研究發(fā)現(xiàn)在仔豬飼料中添加丁酸鈉，顯著降低了血清TNF-α和IL-6的水平，降低了腸道NF-κB的核內(nèi)功能，同時(shí)也改善了腸道菌群，抑制了有害細(xì)菌的生長[10]。此外，SCFAs可以通過調(diào)節(jié)機(jī)體免疫細(xì)胞間接控制炎癥反應(yīng)，丁酸鹽可以調(diào)節(jié)免疫細(xì)胞的活性，如中性粒細(xì)胞(neutrophils)、巨噬細(xì)胞(macrophages)、樹突狀細(xì)胞(dendritic cells，DCs)，可能通過細(xì)胞表面受體GPCR發(fā)揮作用[11-13]。淋巴細(xì)胞的免疫功能與代謝性疾病密不可分[2,14]，大量研究證實(shí)SCFAs可以體內(nèi)調(diào)節(jié)T淋巴細(xì)胞分化(Th1/Th2、Th17/Treg)、凋亡、分泌細(xì)胞因子如IL-2、IL-4、IL-5、IL-6、IL-10，進(jìn)入細(xì)胞后抑制組蛋白去乙?；?histone deacetylase，HDAC)發(fā)揮基因表達(dá)調(diào)控，由于T細(xì)胞低表達(dá)GPCR，因此是否通過表面受體仍存在爭議，可能僅是彌散作用導(dǎo)致[7,15]。

2 SCFAs調(diào)節(jié)腸道菌群、激素、屏障與代謝

SCFAs經(jīng)腸道菌群產(chǎn)生后首先被腸道上皮細(xì)胞利用，尤其是丁酸，作為腸上皮能量來源之一，調(diào)控腸上皮增殖、凋亡分化，促進(jìn)腸道分泌抗菌肽等提高腸道屏障保護(hù)性，同時(shí)也通過吸收入血，進(jìn)入肝臟、肌肉等調(diào)節(jié)整個(gè)機(jī)體能量代謝，如丙酸鹽就是一種很好的糖脂甚至蛋白合成前體，乙酸鹽則是膽固醇合成的一種基質(zhì)，同時(shí)乙酸可直接入血腦屏障作用下丘腦抑制食欲[5,16]。

SCFAs從多方面調(diào)節(jié)腸道功能，如腸道菌群、腸道通透性、腸道pH、腸道激素分泌、腸道蠕動等，其中丁酸被研究最多。機(jī)體內(nèi)，產(chǎn)丁酸菌主要存在于盲腸和結(jié)腸，主要屬于梭菌屬(Clostridium)、真桿菌屬(Eubacterium)和梭桿菌屬(Fusobacterium)，梭菌是革蘭氏陽性厭氧芽孢菌，丁酸梭菌(C.butyricum)、酪丁酸梭菌(C. tyrobutyricum)、丙酮丁醇梭菌(C.acetobutylicum)、巴斯德梭菌(C.pasteurianum)、拜氏梭菌(C. beijerinckii)等是產(chǎn)丁酸的代表[17]。大量動物學(xué)實(shí)驗(yàn)[18]證實(shí)丁酸可以改善腸道菌群，丁酸進(jìn)入細(xì)菌細(xì)胞后會分解為丁酸根離子和氫離子，而高濃度的氫離子會使大腸桿菌、沙門氏菌等有害菌大量死亡，乳酸桿菌等有益菌則由于其耐酸性而大量增殖。

有研究提示2型糖尿病患者體內(nèi)產(chǎn)丁酸鹽細(xì)菌如羅氏菌屬(Roseburia)、柔嫩梭菌群(Faecalibacterium prauznitzii)等，較健康對照者顯著減少[19-20]。在一項(xiàng)人體檢測試驗(yàn)中發(fā)現(xiàn)肥胖患者糞便中SCFAs總體較體質(zhì)量正常者升高(主要為丙酸升高顯著)且各種SCFAs比例發(fā)生變化，體質(zhì)量指數(shù)(body mass index，BMI)低者乙酸鹽比例相對升高[21]；在高脂誘導(dǎo)小鼠胰島素抵抗實(shí)驗(yàn)中，發(fā)現(xiàn)口服丁酸鈉可以提高胰島素敏感性，通過增強(qiáng)線粒體功能促進(jìn)能量消耗，促進(jìn)過氧化物酶體增殖物激活受體γ輔激活因子1α(PGC-1α)的表達(dá)，促進(jìn)脂肪酸氧化[22]。De Vadder等[23]通過動物學(xué)實(shí)驗(yàn)證實(shí)SCFAs可以激活腸道糖質(zhì)新生(intestinal gluconeogenesis，IGN)，而IGN在維持機(jī)體血糖正常水平及能量代謝平衡發(fā)揮至關(guān)重要的作用。這些作用可能與丁酸鹽顯著抑制組蛋白去乙?；?，提高組蛋白乙酰化水平有關(guān)，參與基因調(diào)控、免疫調(diào)節(jié)、細(xì)胞分化、氧化應(yīng)激、腸屏障功能調(diào)節(jié)、內(nèi)臟敏感度和腸道蠕動機(jī)制變化等活動，這些功能使丁酸成為維持腸道健康、維持機(jī)體代謝平衡的重要因素。

另有研究發(fā)現(xiàn)SCFAs通過與腸細(xì)胞表面受體GPCR41或GPCR43作用，促進(jìn)腸道激素分泌，如5-羥色胺(5-hydroxytryptamine，5-HT)、胰高血糖素樣肽(Glucagon-like peptide-1，GLP-1)和酪酪肽(PYY)等，5-HT是參與調(diào)節(jié)胃腸道運(yùn)動和分泌功能的重要神經(jīng)遞質(zhì),可以調(diào)節(jié)腸道通透性，促進(jìn)腸蠕動，減少機(jī)體對食物能量的吸收；GLP-1可以促進(jìn)機(jī)體胰島素分泌調(diào)節(jié)代謝；PYY可以提升飽腹感，減少食物攝入，調(diào)節(jié)腸道運(yùn)動減慢胃排空從而改善機(jī)體代謝[24-26]，同時(shí)GPR對機(jī)體能量脂質(zhì)代謝的調(diào)節(jié)依賴于腸道菌群，抑制腸道GPR激活可以減少食物能量吸收[26]。一項(xiàng)對超重人群研究發(fā)現(xiàn)丙酸鹽可以促進(jìn)人體腸道激素PYY及GLP-1分泌，提高胰島素敏感性，同時(shí)減少食物攝入，長期服用丙酸鹽可以控制體質(zhì)量增長，減少腹部脂肪的堆積，同時(shí)還發(fā)現(xiàn)那些合并NAFLD的超重者服用丙酸鹽后肝內(nèi)脂質(zhì)沉積減少[27]。SCFAs可以與脂肪細(xì)胞上的GPR43結(jié)合抑制脂解，從而降低小鼠血清脂質(zhì)及游離脂肪酸，敲除小鼠GPR43后效應(yīng)消失；同時(shí)促進(jìn)脂肪細(xì)胞分泌瘦素(Leptin)，瘦素是一典型代謝激素，促使機(jī)體減少攝食，增加能量釋放，抑制脂肪細(xì)胞的合成，進(jìn)而使體質(zhì)量減輕[28-29]；也有研究發(fā)現(xiàn)給予GPR43敲除小鼠高脂飲食，其血糖及體脂含量、肝內(nèi)脂質(zhì)沉積水平與對照組相比明顯改善，可以看出GPR缺陷保護(hù)高脂飲食誘導(dǎo)的一系列代謝異常，反映GFR在不同組織細(xì)胞的作用，尤其SCFAs與GPR的配體受體作用值得深究[30]。

上已談及腸道通透性的改變與機(jī)體代謝性疾病同樣密不可分，在肝臟中丁酸可以代謝成谷氨酸、谷氨酰胺和乙酰乙酸鹽，而后者是腸細(xì)胞的重要燃料，丁酸本身作為腸黏膜營養(yǎng)物質(zhì)之一，可以促進(jìn)腸細(xì)胞再生從而修復(fù)腸黏膜，調(diào)節(jié)正常腸細(xì)胞的增殖分化和凋亡，刺激腸道黏液素糖蛋白的合成，加強(qiáng)對黏膜層的保護(hù)作用；丁酸可以促進(jìn)腸道分泌胰高血糖素樣肽2(GLP-2)，GLP-2作為一種腸上皮特異性生長因子, 能促進(jìn)正常腸黏膜的生長及損傷腸上皮的修復(fù)，保護(hù)腸黏膜屏障[31]；丁酸鹽還能夠通過促進(jìn)細(xì)胞間緊密連接的裝配來發(fā)揮對腸道屏障功能的調(diào)節(jié)作用, 影響腸道通透性，減少有害物質(zhì)進(jìn)入血，如LPS等；上述作用機(jī)制與丁酸調(diào)節(jié)胞內(nèi)基因表達(dá)有關(guān)[18,32-33]。

隨著人類社會進(jìn)步，代謝性疾病的發(fā)病率呈現(xiàn)井噴，對人類健康構(gòu)成威脅。近年，對腸道菌群及其產(chǎn)物SCFAs的聚焦揭示其與機(jī)體生理病理狀態(tài)密切相關(guān)，與機(jī)體代謝的相互作用尤其值得深究，為需要進(jìn)一步研究代謝性疾病，如2型糖尿病、NAFLD、肥胖等提供新的診斷或治療靶點(diǎn)，進(jìn)一步闡明疾病發(fā)生、發(fā)展機(jī)制。

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(責(zé)任編輯：陳香宇)

Effects of intestinal microbiota-SCFAs in metabolic diseases

ZHOU Da, FAN Jian’gao

Department of Gastroenterology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China

Intestinal microbiota as a special “organ” plays a vital role in organisms, as well as its metabolic products, such as short-chain fatty acids (SCFAs), especially in metabolism. This paper reviewed the recent progress of intestinal microbiota-SCFAs in metabolic diseases.

Intestinal microbiota; Short-chain fatty acids; Metabolism

科技部973課題(2012CB517501)；國家自然基金(81070322、81270491、81470840)；上海市科委課題(0914090350、10411956300)；中國肝炎防治基金(XJS20120501)；上海市衛(wèi)生局百人計(jì)劃(XBR 2011007)

周達(dá)，博士研究生，研究方向：脂肪性肝病發(fā)病機(jī)制。E-mail：mubing2007@foxmail.com

范建高，教授，主任醫(yī)師，研究方向：脂肪性肝病、脂肪肝的遺傳與表現(xiàn)遺傳、代謝綜合征與肝病。E-mail：fanjiangao@gmail.com

10.3969/j.issn.1006-5709.2016.03.026

R574

A

1006-5709(2016)03-0330-03

2015-05-04