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    腸道菌群及其代謝產物在非酒精性脂肪性肝病發(fā)生發(fā)展及治療中的作用

    2023-04-29 00:44:03李永強唐文娟周永健
    臨床肝膽病雜志 2023年8期
    關鍵詞:膽汁酸益生菌菌群

    李永強 唐文娟 周永健

    摘要:非酒精性脂肪性肝?。∟AFLD)是全世界最為常見的慢性肝病。肝臟與腸道之間有著緊密的結構及功能關系即“腸-肝軸”,其中腸道菌群可通過菌群易位、內源性乙醇的產生、膽汁酸和膽堿代謝的調節(jié)異常、內毒素血癥等參與NAFLD的發(fā)生、發(fā)展。本文主要關注腸道菌群及代謝產物在NAFLD發(fā)生、發(fā)展及治療中的作用進展。關鍵詞:非酒精性脂肪性肝病; 胃腸道微生物組; 治療學基金項目:國家自然科學基金(82170585, 81970507); 廣州市醫(yī)學重點學科(2021-2023); 廣州市科技計劃項目(SL2022A03J01100); 廣東省自然科學基金(2021A1515011290)

    Role of intestinal microbiota and metabolites in the development, progression, and treatment of nonalcoholic fatty liver disease

    LI Yongqiang, TANG Wenjuan, ZHOU Yongjian. (Department of Gastroenterology, Guangzhou First Peoples Hospital & The Second Affiliated Hospital of South China University of Technology;Guangzhou Digestive Disease Center,? Guangzhou 510180, China)

    Corresponding author:ZHOU Yongjian, eyzhouyongjian@scut.edu.cn (ORCID:0000-0003-1721-7639)

    Abstract:Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease around the world. There is a close structural and functional relationship between the liver and the intestine, namely “the gut-liver axis”, in which intestinal microbiota can participate in the development and progression of NAFLD through microbial translocation, production of endogenous ethanol, abnormal regulation of bile acid metabolism and choline metabolism, and endotoxemia. This article reviews the role of intestinal microbiota and metabolites in the development, progression, and treatment of NAFLD.

    Key words:Non-alcoholic Fatty Liver Disease; Gastrointestinal Microbiome; Therapeutics

    Research funding:National Natural Science Foundation of China (NSFC)(82170585, 81970507); The Project of Key Medical Discipline in Guangzhou(2021-2023); Guangzhou Planned Project of Science and Technology(SL2022A03J01100); National Natural Science Foundation of Guangdong Province (2021A1515011290)

    非酒精性脂肪性肝病(NAFLD)是在排除病毒感染、酒精過量及其他因素,以肝脂肪異常堆積為特征的肝病,包括肝臟單純脂肪變性、非酒精性脂肪性肝炎(NASH)、肝纖維化、肝硬化,并可能發(fā)展為肝細胞癌和肝衰竭。隨著生活節(jié)奏、飲食習慣改變等因素,NAFLD發(fā)病率高達25%[1],已成為全球最常見的慢性肝病。NAFLD是與向心性肥胖、胰島素抵抗、高血壓、高血脂、高血糖等代謝綜合征有關的肝病[2]。當前NAFLD的發(fā)病機制尚未完全明確,“多因素共同打擊”假說逐漸取代“二次打擊”假說理論成為NAFLD發(fā)病機制的主要理論。除了脂肪堆積、脂質氧化應激、胰島素抵抗外,腸道菌群及代謝物、腸道屏障功能異常也密切參與了NAFLD的發(fā)生、發(fā)展[3]。

    肝臟與腸道之間有著緊密的結構及功能關系,即“腸-肝軸”,兩者通過膽道、門靜脈、體循環(huán)進行聯(lián)系,肝臟通過膽道系統(tǒng)將分泌的膽汁酸及其他生物活性物質釋放到腸道中。肝臟的75%血供來自門靜脈,成為第一個通過門靜脈血液暴露于腸道菌群及代謝產物的器官。正常的腸道屏障能夠阻止腸腔內微生物及代謝產物或毒素轉移至腸腔外,腸道屏障的破壞或能引起腸道微生物的易位,過度活化免疫系統(tǒng),引發(fā)或促進肝臟炎癥的發(fā)生發(fā)展。因而NAFLD的發(fā)生發(fā)展可影響腸道菌群穩(wěn)態(tài),腸道菌群及代謝產物異常等也可影響NAFLD的發(fā)生發(fā)展。本文主要關注NAFLD的腸道菌群及代謝產物失衡和相關治療的進展。

    1腸道菌群失衡是NAFLD發(fā)生、發(fā)展的重要因素

    人體腸道菌群主要以擬桿菌門、厚壁菌門、變形桿菌門、放線菌門為主,占腸道菌群的90%,其中擬桿菌門、厚壁菌門占主導地位[4]。腸道菌群與人體代謝、免疫和疾病的調節(jié)有關,其與NAFLD的發(fā)生發(fā)展有著密切聯(lián)系,腸道中存在物理、生化、免疫等多種屏障限制腸道微生物及代謝物的易位。長期不健康飲食習慣(如高糖高脂飲食、暴飲暴食)可引起腸道微生物群的生態(tài)失調,進而導致屏障功能損傷和免疫穩(wěn)態(tài)的紊亂。一方面,由腸道菌群及其代謝產物誘導的免疫細胞的過度激活可能導致進一步的肝損傷、炎癥和纖維化,從而加速NAFLD的發(fā)展,另一方面,來自腸道細菌的代謝物如短鏈脂肪酸 (SCFA)、膽汁酸等改善肝組織中的炎癥反應、氧化損傷、脂肪變性。與健康者相比,NAFLD患者腸道菌群多樣性顯著下降,腸道菌群組成存在顯著改變[5],主要為革蘭陰性菌(包括擬桿菌、變形桿菌、腸桿菌)豐度顯著增加,而厚壁菌門細菌尤其是產SCFA的細菌如乳酸桿菌、瘤胃球菌等的豐度顯著減少[5]。腸道菌群或是NAFLD發(fā)生發(fā)展病理過程的關鍵因素。

    2腸道菌群來源的代謝產物影響NAFLD的發(fā)生、發(fā)展2.1膽汁酸膽汁酸由肝臟合成,經膽管分泌到腸道,以促進膳食脂肪、膽固醇和脂溶性維生素的乳化及吸收,其后膽汁酸到達回腸末端,被膽汁酸轉運蛋白介導的活性攝取機制重吸收。膽汁酸可通過法尼醇X受體(FXR)和G蛋白偶聯(lián)膽汁酸受體5(TGR5,也稱GPBAR1)活化信號通路,在維持肝葡萄糖、脂質和能量代謝的調節(jié)中發(fā)揮重要作用[6-7]。FXR主要由初級膽汁酸激活,而TGR5主要由次級膽汁酸激活[8-9]。FXR活化刺激過氧化物酶體增殖物激活受體α(PPARα)的表達和活化,誘導成纖維細胞生長因子21的表達和分泌。成纖維細胞生長因子21通過絲裂原活化蛋白激酶,激活哺乳動物雷帕霉素復合物1靶點,增強脂肪細胞中的葡萄糖攝取,并通過調節(jié)脂肪生成的主要轉錄調節(jié)因子PPARγ的活性,促進脂肪組織中的脂肪酸氧化[10-12]。FXR還上調肝糖原合成,調節(jié)胰高血糖素樣肽1的表達,增加與NAFLD密切相關的胰島素敏感性[8]。研究[13]顯示,F(xiàn)XR激動劑藥物奧貝膽酸可防止腸道屏障破壞,抑制NASH的發(fā)展,為其用于預防或治療NASH提供了證據(jù)。除了FXR外,TGR5在肝臟組織中的Kupffer細胞和內皮細胞中表達,可調節(jié)肝臟炎癥和葡萄糖代謝,具有改善胰島素敏感性的功能。TGR5通過抑制巨噬細胞中NF-κB信號傳導和細胞因子生成來減輕炎癥反應[14]。

    腸道菌群中的膽汁酸水解酶催化膽汁酸解耦連反應是膽汁酸代謝的重要通路反應。腸道中多個細菌種類可使初級膽汁酸解耦連,包括梭狀芽胞桿菌、乳酸菌、雙歧桿菌、真桿菌、埃希氏菌和擬桿菌[15],腸道菌群通過將初級膽汁酸代謝為次級膽汁酸,影響膽汁酸池的穩(wěn)態(tài),后者參與調節(jié)NAFLD形成過程中的脂質和能量代謝途徑[16]。腸道菌群失衡影響膽汁酸代謝,腸道菌群與膽汁酸之間的相互作用為NAFLD的腸道菌群靶向治療提供了基礎證據(jù)。

    2.2SCFASCFA是一組由5個或以下的碳原子組成的飽和脂肪酸,主要通過腸道微生物發(fā)酵可溶性膳食纖維和不易消化的碳水化合物產生。其中丁酸、丙酸和乙酸在腸道中含量最高[17],乙酸和丙酸主要由腸道中擬桿菌門產生,丁酸主要由厚壁菌門產生[18]。SCFA作用于G蛋白偶聯(lián)受體GPR41和GPR43,這些受體廣泛分布在腸道內分泌L細胞、白色脂肪組織、骨骼肌和肝臟中,其中L細胞釋放胰高血糖素樣肽1,通過直接作用于肝細胞,激活脂肪酸β-氧化和胰島素敏感性相關的基因來參與NAFLD發(fā)生發(fā)展[19-20]。此外,SCFA通過抑制組蛋白脫乙酰酶和GPR43通路在Treg細胞分化發(fā)揮免疫調節(jié)作用,通過減少T淋巴細胞、中性粒細胞、巨噬細胞、單核細胞等多種免疫細胞的遷移和增殖,減少多種促炎細胞因子(腫瘤壞死因子-α、單核細胞趨化蛋白-1等)的表達,上調抗炎細胞因子前列腺素E2,發(fā)揮抗炎作用[21]。另外丁酸鹽可通過AMPK(腺苷酸活化蛋白激酶)激活,促進緊密連接的組裝及腸道屏障的形成,改善腸道菌群失調來減輕高脂肪飲食誘發(fā)的脂肪性肝炎[22]。

    2.3脂多糖(LPS)LPS又稱為內毒素,是革蘭陰性菌的外膜主要成分。肝細胞中廣泛表達的Toll樣受體4(TLR4)是LPS和多種游離脂肪酸的模式識別受體[23],通過門靜脈系統(tǒng)進入肝臟的LPS誘導的TLR4活化誘導Kupffer細胞分泌炎性細胞因子(例如IL-6、IL-1β和TNF-α)和趨化因子,刺激星狀細胞,導致肝臟炎癥和纖維化[24-25],此外,增加的LPS可能通過肌球蛋白輕鏈激酶的TLR-14依賴性上調以及IRAK-4(IL-1R相關激酶4)的活化損害腸道屏障功能,導致腸道通透性增加。據(jù)報道[26],在NAFLD患者和實驗動物中均可見血清LPS水平升高,降低血漿LPS水平可改善肝脂肪變性,提示LPS引發(fā)的慢性低度炎癥可能是NAFLD進展的重要因素。

    2.4腸道菌群來源的內源性乙醇研究[27]顯示,NAFLD患兒的血乙醇水平顯著高于健康兒童,與血液中胰島素、瘦素和甘油三酯水平呈正相關,不飲酒的NASH患者腸道菌群組成改變引起生態(tài)失調會增加血液中乙醇水平,提示腸道微生物發(fā)酵可產生內源性乙醇[28]。臨床前和臨床研究已確認大腸桿菌、腸桿菌科和肺炎克雷伯菌為產乙醇細菌,在NAFLD患者和小鼠中含量相對較高[28]。乙醇可增加細胞色素P450 2E1(CYP2E1)的mRNA和蛋白表達,導致自由基的釋放,引起線粒體功能障礙,引發(fā)肝損傷[29]。內源性乙醇抑制三羧酸循環(huán)并增加乙酸鹽水平,促進肝細胞中甘油三酯的積累[30]。乙醇的代謝產物乙醛參與削弱腸道緊密連接蛋白[31],與腸道中抗菌肽表達下調有關[32],并增加腸道屏障通透性,導致腸道屏障功能損傷,增加腸道菌群的易位。總之,腸道微生物群的調節(jié)會產生各種改變的代謝物,最終導致肝臟炎癥和NAFLD的發(fā)生發(fā)展。

    2.5膽堿膽堿是一種人體必需的磷脂,主要通過飲食攝入及肝臟合成,是細胞膜磷脂的重要組成之一,其參與肝臟中的低密度脂蛋白合成等脂質代謝過程、膽汁和膽固醇的肝腸循環(huán)過程,并在肝臟脂質轉運中起著重要作用[33]。而膽堿缺乏將抑制極低密度脂蛋白合成和分泌,導致肝臟甘油三酯蓄積和肝脂肪變性,從而引起肥胖[34]。腸道菌群可將膽堿轉化為三甲胺(TMA),后者經肝臟單加氧酶氧化形成三甲胺N-氧化物(TMAO),被認為是早期代謝綜合征的新型生物標志物[35]。研究[36]顯示,腸道菌群將膽堿轉化為TMA會降低宿主的膽堿生物利用度,并模仿膽堿缺乏狀態(tài),導致代謝紊亂。據(jù)報道[37],NAFLD患者血液中TMAO水平升高,TMAO調節(jié)葡萄糖代謝并通過增加血清炎性細胞因子C-C基序趨化因子2水平誘導胰島素抵抗,引起脂肪組織炎癥及血糖異常。

    3靶向腸道菌群對NAFLD的潛在防治作用

    目前,越來越多的證據(jù)表明腸道菌群及其代謝產物的變化影響著NAFLD的發(fā)生、發(fā)展。多項研究提示靶向腸道菌群如益生菌、益生元、合生元以及腸道菌群移植等在NAFLD的防治中具有較好的前景。

    3.1益生菌乳酸桿菌、雙歧桿菌是最常用的益生菌[38]。動物研究[39]顯示,乳桿菌可通過激活AMPK通路磷酸化ACC,阻斷SREBP-1/Fas信號通路,抑制脂肪的重新生成,增加脂肪酸氧化,以緩解NAFLD進展。同樣,補充混合益生菌制劑可改善腸道上皮通透性,維持緊密連接蛋白,減輕炎癥,并降低肝臟甘油三酯濃度[40]。在臨床研究中,Alisi等[41]發(fā)現(xiàn)補充4個月的VSL#3(含副干酪乳桿菌、植物乳桿菌、嗜酸乳桿菌、德氏乳桿菌、長雙歧桿菌、嬰兒雙歧桿菌、短雙歧桿菌、唾液鏈球菌)改善了NAFLD肥胖兒童的肝功能,增加了胰高血糖素樣肽/活性胰高血糖素樣肽水平。Sepideh等[42]認為補充多菌株益生菌可改善NAFLD患者胰島素敏感性和肝臟炎癥。此外,益生菌與藥物(如NASH治療中的二甲雙胍和NAFLD治療中的他汀類藥物)聯(lián)合使用比單獨使用更能改善肝臟炎癥、降低膽固醇水平[43-44]。以上研究提示益生菌單獨使用或與其他藥物聯(lián)合使用在NAFLD治療中顯示了良好的臨床應用潛力。

    3.2益生元益生元是宿主微生物選擇性利用的一種基質,有益于宿主健康[38]。作為益生元中的膳食低聚果糖,除了利于有益菌種(雙歧桿菌屬)的繁殖,還可通過PPARα刺激脂肪酸氧化減少肝臟甘油三酯的積累,并通過抑制SREBP-2依賴性膽固醇合成,減少膽固醇蓄積[45]。益生元還可增加內源性促腸胰高血糖素衍生肽的產生,改善腸道屏障中緊密連接完整性,降低肥胖相關的腸道通透性[46]。異麥芽低聚糖與番茄紅素(抗氧化劑)的聯(lián)合治療可防止體質量增加,增強脂肪組織脂肪動員,并改善高脂飲食誘導的NAFLD小鼠的胰島素抵抗,減少代謝內毒素血癥,提示抗氧化劑和益生元的聯(lián)合使用在NAFLD治療中可能帶來更大的益處。

    3.3合生元合生元是益生菌、益生元的組合,通過選擇性刺激一種或有限數(shù)量的促進健康的細菌的生長和/或激活其代謝[38]。研究[47]顯示,含副干酪乳桿菌B21060阿拉伯半乳聚糖和低聚果糖的合生素可增加核PPAR及其靶基因的表達,有效降低與高脂攝入有關的肝損傷。Malaguarnera等[48]認為合生元(長雙歧桿菌和低聚果糖)與生活方式干預相結合在降低NASH患者血清腫瘤壞死因子、C反應蛋白、內毒素和轉氨酶水平,改善HOMA-IR和NASH活性指數(shù)的程度優(yōu)于單獨生活方式干預。目前仍需更多研究驗證益生菌、益生元、合生元在預防和治療NAFLD中的效果。

    3.4腸道菌群移植(fecal microbiota transplantation,F(xiàn)MT)FMT是近年來較為新穎的治療方法,是將健康人糞便中的功能腸道菌群移植到患者腸道內,重建新的腸道菌群,實現(xiàn)腸道及腸外疾病的治療?,F(xiàn)FMT已成功用于難治性和復發(fā)性艱難梭菌患者的治療,也有較多應用于治療炎癥性腸病和腸易激綜合征。FMT可通過改善肝內脂質積累、血清促炎細胞因子水平來減輕高脂飲食誘導NASH小鼠模型的肝臟炎癥[49]。研究[50]顯示FMT可以通過改善腸道微生物群失調來減少肝臟中的脂肪堆積,減輕脂肪肝,且認為FMT對瘦NAFLD患者的腸道微生物群重建效果優(yōu)于肥胖的NAFLD患者。

    4小結和展望

    腸道菌群及代謝物在NAFLD發(fā)生、發(fā)展中扮演著重要的角色。靶向腸道菌群如益生菌、益生元、合生元、腸道菌群移植治療在動物試驗中獲得積極的療效,相關臨床研究也逐漸得到關注。鑒于腸道菌群容易受到多種因素影響,不同地區(qū)、飲食,不同患者腸道菌群亦存在差異,腸道微生物群靶向治療對NAFLD的臨床療效仍需通過大規(guī)模和組織良好的隨機對照試驗研究來證實。

    利益沖突聲明:本文不存在任何利益沖突。作者貢獻聲明:李永強負責論文的擬定及撰寫;唐文娟負責論文的修改;周永健參與修改論文并最后定稿。

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    收稿日期:2023-05-04;錄用日期:2023-06-04

    本文編輯:林姣

    引證本文:LI YQ, TANG WJ, ZHOU YJ.? Role of intestinal microbiota and metabolites in the development, progression, and treatment of nonalcoholic fatty liver disease[J]. J Clin Hepatol, 2023, 39(8): 1805-1810.

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