劉晨晨， 李 穩(wěn)， 王凌云

濟(jì)寧市第一人民醫(yī)院消化內(nèi)科，山東 濟(jì)寧 272111

腸道菌群與非酒精性脂肪性肝病關(guān)系的研究進(jìn)展

劉晨晨， 李 穩(wěn)， 王凌云

濟(jì)寧市第一人民醫(yī)院消化內(nèi)科，山東 濟(jì)寧 272111

非酒精性脂肪性肝病(non-alcoholic fatty liver disease，NAFLD)是西方國(guó)家及一些亞洲國(guó)家中常見的慢性肝臟疾病，目前在世界范圍內(nèi)的發(fā)病率逐漸上升。NAFLD包括單純性脂肪肝、非酒精性脂肪性肝炎(non-alcoholic steatohepatitis, NASH)、NASH相關(guān)性肝硬化及肝癌等一系列疾病。NASH進(jìn)展為肝硬化、肝癌的風(fēng)險(xiǎn)大，預(yù)后差，是世界范圍內(nèi)沉重的醫(yī)療負(fù)擔(dān)。NAFLD是由多種因素引起的疾病，除了環(huán)境因素及遺傳因素外，近年來(lái)不斷有證據(jù)提示，腸道菌群在NAFLD的發(fā)生、發(fā)展過(guò)程中起一定作用，本文就腸道菌群與NAFLD關(guān)系的研究進(jìn)展作一概述。

腸道菌群；非酒精性脂肪性肝?。灰葝u素抵抗

非酒精性脂肪性肝病(non-alcoholic fatty liver disease，NAFLD)是西方國(guó)家及一些亞洲國(guó)家中常見的慢性肝病，在西方國(guó)家普通人群中的發(fā)生率是25%，肥胖患者中30%～100%，2型糖尿病患者中10%～75%[1-2]。NAFLD包括單純性脂肪肝、非酒精性脂肪性肝炎(non-alcoholic steatohepatitis, NASH)、NASH相關(guān)性肝硬化及肝癌等[3]。目前NAFLD發(fā)病機(jī)制尚不明確，近年來(lái)不斷有研究[4]提示，腸道菌群在NAFLD發(fā)生、發(fā)展過(guò)程起重要作用，本文就腸道菌群與NAFLD關(guān)系的研究進(jìn)展作一概述。

1 NAFLD臨床特點(diǎn)

85%的NAFLD患者只合并脂肪變性，病情進(jìn)展緩慢，其中10%～15%將會(huì)進(jìn)展成為NASH，在一部分患者中最終會(huì)進(jìn)展為肝硬化，甚至肝功能衰竭、肝癌等[4]。NAFLD合并糖尿病患者出現(xiàn)肝硬化、死亡等風(fēng)險(xiǎn)較單純NAFLD患者明顯增大[5]。NASH肝臟病理改變以肝臟小葉和門脈的炎癥為主，以中性粒細(xì)胞、單核細(xì)胞、淋巴細(xì)胞浸潤(rùn)為特征，伴隨不同程度的纖維化、肝細(xì)胞死亡、病理性血管增生等。多次打擊學(xué)說(shuō)認(rèn)為，NAFLD進(jìn)展為NASH經(jīng)歷了多次打擊，第一次打擊引起胰島素抵抗(insulin resistance, IR)，進(jìn)而肝臟中脂肪堆積，使得肝細(xì)胞更易受多種其他因素的影響，第二次打擊導(dǎo)致脂質(zhì)過(guò)氧化、炎癥因子產(chǎn)量增加，誘導(dǎo)NAFLD進(jìn)展為NASH，其他打擊包括遺傳因素、氧化應(yīng)激、Kupffer細(xì)胞中TLR-4介導(dǎo)的信號(hào)通路等[6]；近年研究[7-9]認(rèn)為,腸道菌群紊亂也是一種打擊因素，可以影響固有免疫或促進(jìn)內(nèi)源性乙醇產(chǎn)生而影響機(jī)體。

2 腸道菌群與NAFLD

人類腸腔中寄居著數(shù)萬(wàn)億的微生物，包括細(xì)菌、古細(xì)菌、病毒、真菌，其中擬桿菌門和厚壁桿菌門是主導(dǎo)的門類[10]。研究[11]顯示，腸道菌群紊亂可以加重NAFLD，誘發(fā)小腸菌群過(guò)度生長(zhǎng)，造成腸道黏膜通透性增加。應(yīng)用qPCR的研究[10]顯示，與單純NAFLD患者相比，NASH患者腸道菌群中擬桿菌群數(shù)量減少。應(yīng)用測(cè)序技術(shù)[12]顯示，與健康個(gè)體相比，NASH患者中厚壁桿菌數(shù)量減少，而擬桿菌數(shù)量增加；研究[13]顯示，家族性NAFLD患者中毛螺桿菌、乳桿菌數(shù)量增加；研究[14]表明，腸道菌群紊亂可以影響營(yíng)養(yǎng)物質(zhì)吸收、患者食欲、宿主基因表達(dá)及免疫反應(yīng)等，進(jìn)而影響NAFLD。研究[15]顯示，與健康對(duì)照組相比，NAFLD患者中糞便菌群在門水平的豐度降低，擬桿菌門數(shù)量增多20%，而厚壁菌門數(shù)量減少24%；NAFLD患者中革蘭陰性桿菌數(shù)目更多，小腸菌群失調(diào)與非肥胖NAFLD有明顯的相關(guān)性，并能加重NAFLD。研究[16]顯示，NAFLD患者的腸道菌群紊亂不依賴于肥胖因素，主要與擬桿菌門、變形桿菌門數(shù)目的變化及小腸菌群過(guò)度生長(zhǎng)有關(guān)。

2.1腸道菌群與內(nèi)毒素血癥腸道菌群中革蘭陰性菌的LPS是產(chǎn)生內(nèi)毒素血癥的重要部分，LPS和腸源性產(chǎn)物如肽聚糖在門脈血流中含量增加會(huì)引起肝臟中內(nèi)毒素介導(dǎo)因子增加，進(jìn)而促進(jìn)單純性NAFLD向NASH進(jìn)展。研究[13]顯示，腸道菌群構(gòu)成的改變與NAFLD密切相關(guān)，Mouzaki等[10]發(fā)現(xiàn),與健康成人相比，肥胖NASH患者中擬桿菌數(shù)量明顯減少，而在單純NAFLD患者中變化差異無(wú)統(tǒng)計(jì)學(xué)意義。Brun等[17]研究認(rèn)為，腸道通透性增加引起的內(nèi)毒素血癥是引起NAFLD的起始因素，而腸道菌群在其病理過(guò)程中起重要作用。

2.2腸道菌群與膽汁酸膽汁酸作為重要信號(hào)傳導(dǎo)分子，在脂質(zhì)溶解及吸收過(guò)程中起關(guān)鍵作用[18]。膽汁酸可以調(diào)節(jié)肝細(xì)胞中葡萄糖及脂質(zhì)代謝、炎癥反應(yīng)、激活多種核因子受體而調(diào)節(jié)自身合成[19]。膽汁酸由膽固醇合成，并在肝臟中加工完善，膽汁酸在腸道由腸內(nèi)菌群進(jìn)一步修飾并重吸收。腸道菌群可以通過(guò)改變膽汁酸的代謝而影響膽汁酸的產(chǎn)量[20]。膽汁酸對(duì)細(xì)菌細(xì)胞膜有降解作用，進(jìn)而可以對(duì)腸道菌群起一定的抗菌作用，從而改變腸道菌群的構(gòu)成[21]。

2.3腸道菌群與IRNAFLD患者中IR明顯增加，促進(jìn)肝臟中游離脂肪酸的堆積，進(jìn)而加重NAFLD[22]。研究[23]提示，腸道菌群與IR具有相關(guān)性，革蘭陰性菌細(xì)胞壁成分中的LPS可通過(guò)TLR-4受體依賴途徑或非依賴途徑激活炎癥反應(yīng)鏈，引起TNF-α、IL-6、iNO、NF-κB等炎癥因子的抑制因子表達(dá)增加，進(jìn)而導(dǎo)致IR。在小鼠中應(yīng)用益生菌或抗TNF-α抗體等調(diào)節(jié)腸道菌群可以降低炎癥因子水平、改善IR狀態(tài)并且降低肝臟炎癥水平[24]。

2.4腸道菌群與內(nèi)源性乙醇生理狀態(tài)下人體可以產(chǎn)生少量?jī)?nèi)源性乙醇，內(nèi)源性乙醇在肝臟被乙醇脫氫酶有效降解[25]。研究[16]顯示，NASH患者腸道中產(chǎn)乙醇的埃希菌屬增加，可以明顯升高血清乙醇水平；NASH患者中乙醇代謝酶明顯增多[25]，Zhu等[12]研究顯示，腸源性內(nèi)源性乙醇和NASH密切相關(guān)；另有研究[16]顯示，兒童NAFLD患者中變形桿菌和普氏菌屬數(shù)量增加，內(nèi)源性乙醇產(chǎn)量增高。NASH患者中產(chǎn)乙醇細(xì)菌的增多會(huì)升高循環(huán)血液中乙醇水平[26]，內(nèi)生乙醇可引起氧化應(yīng)激并增大腸道通透性，使肝臟中乙醇及其代謝產(chǎn)物增多，進(jìn)而加重肝臟炎癥反應(yīng)、促進(jìn)NAFLD疾病進(jìn)展。

3 高胰島素血癥、TNF-α信號(hào)通路與NAFLD

一些有毒性脂質(zhì)如游離飽和脂肪酸、游離膽固醇、神經(jīng)酰胺及其他鞘脂類在肝細(xì)胞中的異常堆積可以激活細(xì)胞應(yīng)激反應(yīng)等多種信號(hào)通路，最終引起細(xì)胞死亡，這種作用被稱為脂毒性，脂毒性是NAFLD進(jìn)展過(guò)程中的關(guān)鍵事件；脂毒性可以促進(jìn)肝臟局部及全身的IR，進(jìn)而導(dǎo)致高胰島素血癥[27]。高胰島素血癥可引起胰島素生長(zhǎng)因子(IGF-1)表達(dá)增加，IGF-1具有重要的促增殖和抗凋亡活性[28]。動(dòng)物實(shí)驗(yàn)[29]結(jié)果顯示，TLR-4介導(dǎo)了NAFLD進(jìn)展至NASH的過(guò)程，TLR-4受體分子可通過(guò)誘發(fā)活性氧依賴的X結(jié)合蛋白1(XBP-1)而在Kupffer細(xì)胞介導(dǎo)NASH中有一定作用。IL-6可以激活信號(hào)傳導(dǎo)分子STAT-3，具有促進(jìn)增殖和抗凋亡作用[30]，飲食因素和肥胖因素均可以通過(guò)促進(jìn)IL-6和TNF-α表達(dá)而促進(jìn)肝臟炎癥和腫瘤的發(fā)生、發(fā)展。

4 肝臟固有免疫與NAFLD

肝臟是抵御腸道來(lái)源病原菌的第一道屏障，70%的肝臟血流來(lái)自腸道靜脈回流血液，食物抗原、內(nèi)毒素(脂多糖、鞭毛蛋白等)、細(xì)菌產(chǎn)物等首先由肝臟代謝解毒[31]，再進(jìn)入循環(huán)血液。多種肝臟細(xì)胞如Kupffer細(xì)胞、竇狀隙內(nèi)皮細(xì)胞、膽管上皮細(xì)胞、肝細(xì)胞可以表達(dá)固有免疫受體分子，能夠識(shí)別多種細(xì)菌產(chǎn)物病原識(shí)別受體；肝臟中富含的固有免疫細(xì)胞如巨噬細(xì)胞、淋巴細(xì)胞、自然殺傷細(xì)胞、樹突樣細(xì)胞等可以通過(guò)模式識(shí)別受體識(shí)別攜帶特定病原菌模式分子的外源性分子。受體分子與細(xì)菌產(chǎn)物之間的相互作用引起炎癥小體等多種炎癥信號(hào)通路的激活。在小鼠中，炎癥小體缺失會(huì)引起擬桿菌數(shù)量增加及厚壁桿菌數(shù)量減少，同時(shí)引起肝臟的脂肪變及炎癥反應(yīng)[32]。與健康對(duì)照組相比，NASH患者中厚壁桿菌門中的疣微菌科數(shù)量減少[16]；與肥胖患者、健康個(gè)體相比，NASH患者中埃希菌屬數(shù)量增加[12，16]。在炎癥小體基因敲除的小鼠中觀察到腸道菌群病理性改變，門脈血中LPS和細(xì)菌DNA含量增加、肝臟中TNF-α表達(dá)增強(qiáng)，進(jìn)而促進(jìn)肝臟脂肪變和炎癥[32]。在小鼠中的研究顯示，Kupffer細(xì)胞中TLR4在介導(dǎo)單純NAFLD進(jìn)展至NASH中起一定作用[29]，而TLR-4缺失時(shí)可減少NASH發(fā)生[33]。以上結(jié)果顯示，炎癥小體功能受損可以引起腸道菌群的改變并增加肝臟中促炎因子，加速NAFLD向NASH進(jìn)展。Toll樣受體(Toll-like receptors, TLRs)在固有免疫過(guò)程中起關(guān)鍵作用，是生物體中結(jié)構(gòu)上高度保守的轉(zhuǎn)膜蛋白。TLR-5在腸道黏膜中表達(dá)，可被細(xì)菌鞭毛蛋白激活；TLR-5敲除的小鼠出現(xiàn)攝食過(guò)量、IR、高脂血癥、肥胖、腸道菌群紊亂等改變，將這種小鼠中的腸道菌群移植至正常小鼠后，正常小鼠中出現(xiàn)代謝綜合征[34]。

5 細(xì)胞外囊與NAFLD

細(xì)胞外囊(extracellular vesicles, EVs)是細(xì)胞間有效的信號(hào)分子，可轉(zhuǎn)運(yùn)多種具有生物活性分子到靶標(biāo)細(xì)胞中，在多種生理及病理過(guò)程中起一定作用[35-38]。EVs可以釋放多種生物活性分子，EVs包括外夾體、核外顆粒體、凋亡小體三類。研究[39]顯示，在NASH患者血液中具有脂毒性的飽和游離脂肪酸進(jìn)入肝臟后可以產(chǎn)生并釋放大量EVs，這些EVs可作用于多種靶細(xì)胞而促進(jìn)NAFLD進(jìn)展。Ibrahim研究探討了脂毒性介導(dǎo)的肝細(xì)胞源性EVs在NASH疾病中的作用，結(jié)果顯示，混合譜系激酶3(mixed lineage kinase 3，MLK3)介導(dǎo)了肥胖患者肝源性EVs的釋放，EVs中攜帶趨化因子配體10，是一種潛在肝細(xì)胞源性巨噬細(xì)胞化學(xué)引誘劑，而使用MLK3抑制劑后引起趨化因子配體10數(shù)量顯著增加[40]。最近的一項(xiàng)研究顯示，分化成熟的脂肪酸在受到軟脂酸刺激時(shí)會(huì)引起大量EVs釋放，這些EVs可引起巨噬細(xì)胞的遷移，而軟脂酸可通過(guò)激活Caspase-3而引起EVs釋放，進(jìn)而可以作為一種化學(xué)趨化劑[41]。脂肪細(xì)胞源性的EVs作為一種新的信號(hào)分子，連接了脂肪應(yīng)激與巨噬細(xì)胞招募，EVs介導(dǎo)的細(xì)胞間信號(hào)傳導(dǎo)是多種因素引起疾病如NASH的中心環(huán)節(jié)。

綜上所述，人類和動(dòng)物中的研究均顯示，腸道菌群紊亂與NAFLD密切相關(guān)，腸道菌群紊亂可能通過(guò)引起內(nèi)毒素血癥、誘發(fā)IR、增加內(nèi)源性乙醇產(chǎn)量、影響膽汁酸代謝及機(jī)體免疫反應(yīng)等在NAFLD病理過(guò)程中起一定作用，但是否具有因果關(guān)系，及具體的機(jī)制仍需要進(jìn)一步闡明；闡明這一機(jī)制將為NALFD的防治提供新的思路和靶點(diǎn)。

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《胃腸病學(xué)和肝病學(xué)雜志》編輯部

Relationshipbetweengutmicrobiotaandnon-alcoholicfattyliverdisease

LIU Chenchen, LI Wen, WANG Lingyun

Department of Gastroenterology, Ji’ning First People’s Hospital, Ji’ning 272111, China

Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease in Western countries and some Asian countries, and currently the incidence of NAFLD continues to increase worldwide. NAFLD encompasses a pathologic spectrum of disease, from relatively benign accumulation of lipid (steatosis) to progressive non-alcoholic steatohepatitis (NASH) associated with inflammation, fibrosis, necrosis and hepatocellular carcinoma. Without an effective available treatment, the prognosis of NASH is poor due to the high risk of progressive liver diseases such as cirrhosis and carcinoma, making it a great burden in health worldwide. NAFLD is a multifactorial disease, apart from environmental and genetical factors, recent studies suggest that gut microbiota might be implicated in the pathogenesis of NAFLD. Here, the relationship between gut microbiota and NAFLD was reviewed.

Gut microbiota; Non-alcoholic fatty liver disease; Insulin resistance

R575.5

A

1006-5709(2017)10-1103-04

2017-04-25

10.3969/j.issn.1006-5709.2017.10.008

劉晨晨，碩士研究生，研究方向：胃腸道微生態(tài)。E-mail：njliucc@163.com

李穩(wěn)，博士研究生，研究方向：慢性肝病的基礎(chǔ)與臨床。E-mail：jnlwen@163.com