粪菌移植在慢性肝病治疗中的应用

徐洪凯; 汪春付; 张野; 连建奇

doi:10.3969/j.issn.1001-5256.2023.09.031

粪菌移植在慢性肝病治疗中的应用

DOI: 10.3969/j.issn.1001-5256.2023.09.031

空军军医大学第二附属医院传染科，西安 710038

基金项目:

陕西省重点研发计划 (2022SF－186)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：徐洪凯负责撰写论文；汪春付、张野负责修改论文；连建奇负责拟定写作思路，指导撰写文章并最后定稿。

详细信息

通信作者:
连建奇， lianjq@fmmu.edu.cn （ORCID： 0000－0002－5549－7590）

计量
- 文章访问数: 390
- HTML全文浏览量: 134
- PDF下载量: 39
- 被引次数: 0
出版历程
- 收稿日期: 2022-11-21
- 录用日期: 2023-01-02
- 出版日期: 2023-09-19

Role of fecal microbiota transplantation in chronic liver diseases

Department of Infectious Diseases，The Second Affiliated Hospital of Air Force Medical University，Xi’an 710038，China

Research funding:

Shaanxi Province Key Research and Development Plan (2022SF－186)

More Information

Corresponding author: LIAN Jianqi， lianjq@fmmu.edu.cn （ORCID： 0000－0002－5549－7590）

摘要

摘要: 肠道菌群失调与慢性肝病的发生、发展及预后有着密切关系，而慢性肝病可加重肠道菌群失调，两者相互作用，相互影响。粪菌移植（FMT）通过移植健康捐献者的粪便菌群直接重建患者的肠道菌群并维持动态平衡，以达到目标治疗效果。近年来FMT作为重建肠道菌群的核心方法和肝脏疾病治疗方案的重要突破点得到了大量基础研究和临床试验的证实。本文就FMT在慢性肝病中的基础研究、临床研究及前景展望进行综述。
- 肝疾病 /
- 粪便微生物群移植 /
- 胃肠道微生物组
Abstract: Gut microbiota dysbiosis is closely associated with the development， progression， and prognosis of chronic liver diseases， while chronic liver diseases can aggravate gut microbiota dysbiosis， and the two interact with and influence each other. Through transplantation of fecal flora from healthy donors， fecal microbiota transplantation （FMT） directly reconstructs the intestinal flora of patients and maintains homeostasis， thereby achieving targeted therapeutic outcomes. In recent years， many basic research studies and clinical trials have proved FMT as a core therapeutic strategy for reconstructing intestinal flora and an important breakthrough point in treatment regimens for liver diseases. This article reviews the basic research， clinical studies， and future prospect of FMT in chronic liver diseases.
- Liver Diseases /
- Fecal Microbiota Transplantation /
- Gastrointestinal Microbiome

HTML全文

表 1 各类慢性肝病经过FMT治疗后肠道菌群的变化

Table 1. Changes of intestinal flora after FMT treatment for various chronic liver diseases

疾病种类	第一作者，发表年份	类型	治疗/处理过程	菌群变化
非酒精代谢相关性疾病	叶毅，2019^［14］	临床试验	将非酒精代谢相关性疾病患者随机分为观察组和对照组，观察组行FMT和保肝药物治疗，对照组仅行保肝药物治疗	治疗3个月和6个月后观察组肠杆菌、葡萄球菌和肠球菌显著低于对照组，而双歧杆菌、拟杆菌、乳酸杆菌、普氏菌和普雷沃菌显著高于对照组
非酒精代谢相关性疾病	ZHOU D，2017^［54］	动物实验	将小鼠随机分为对照组、高脂饮食组和高脂饮食+FMT组。高脂食物喂养8周，FMT治疗8周。检测小鼠肠道微生物区系结构、盲肠内容物丁酸浓度、肝脏病理及肝内脂质和细胞因子	FMT组小鼠与高脂饮食组小鼠比较，菌群紊乱得到纠正，克里斯滕森菌科（属于厚壁菌门）和乳酸菌丰度增加，丁酸浓度上升
非酒精代谢相关性疾病	WITJES JJ， 2020^［55］	临床试验	将肝脂肪变性患者分为2组，每8周进行3次FMT，1组为异体供者，1组为自体供者，24周后对两组受试者的粪便菌群进行分析	异体供者组与瘤胃球菌、真细菌、粪杆菌和普氏菌有关的细菌的粪便微生物群丰度增加
酒精性肝病	PHILIPS CA， 2017^［19］	临床试验	对8例不符合皮质类固醇治疗条件的SAH男性患者进行FMT治疗，同期仅接受常规治疗的SAH患者为对照组，分别在6个月和1年后进行微生物群落分析	与常规治疗的SAH患者相比，FMT治疗的患者变形杆菌及肺炎克雷伯杆菌明显减少，放线杆菌、绒毛肠球菌、长双歧杆菌及埃氏巨噬菌数量上升
酒精性肝病	PHILIPS CA，2018^［20］	回顾性研究	对比了51例SAH患者的类固醇、营养疗法、己酮可可碱和FMT的治疗效果	FMT治疗8天后变形杆菌数量下降，厚壁菌门数量上升，FMT后30～90天梭状芽孢杆菌和拟杆菌增多，放线杆菌稳定，γ－变形杆菌减少，并新出现丹毒杆菌
肝硬化	BAJAJ JS，2019^［56］	临床试验	将15例患有肝性脑病的肝硬化患者随机分为2组，1组口服15粒FMT胶囊，1组服用安慰剂胶囊	FMT后30天与治疗前相比，十二指肠黏膜菌群多样性增加，十二指肠瘤胃球菌科和双歧杆菌科升高，面纱藻科降低。FMT组在第30天与安慰剂组相比，腊肠菌科和里肯内拉科数量升高
肝衰竭	高安，2021^［40］	动物实验	将40只小鼠分为正常组、模型组、粪菌移植组（选取正常组小鼠粪便作为粪菌供体）、模型小鼠粪菌移植组（选取模型组小鼠粪便作为粪菌供体），每组10只	与正常组小鼠相比，模型组小鼠疣微菌门，阿克曼菌属、Erysipelatoclostridium显著上升，Dubosiella、Duncaniella显著下降；模型小鼠粪菌移植组Faecalibaculum显著上升，Patescibacteria、脱铁杆菌门、Muribaculum、Candidatus－Saccharimonas、理研菌属、Odoribacter、Mucispirillum、Lachnospiraceae－unclassified显著下降。粪菌移植组小鼠Paramuribaculum、嗜胆菌属显著上升，厚壁菌门、Rikenella、Absiella显著下降
肝衰竭	LIU YM，2021^［41］	动物实验	选取20只小鼠，平均分为对照组、急性肝损伤模型组、FMT组、布拉酵母菌灌胃供体粪菌移植组，FMT组小鼠注射D－半乳糖胺后48 h口服粪便上清液100 mL，每24 h给予FMT 1次，共7次	经过FMT治疗后ALF小鼠的乳杆菌科、普氏菌科、S24－7、臭杆菌科和立克内菌科等菌群的比例恢复正常

下载: 导出CSV

参考文献(57)

[1]	LAGIER JC, KHELAIFIA S, ALOU MT, et al. Culture of previously uncultured members of the human gut microbiota by culturomics[J]. Nat Microbiol, 2016, 1: 16203. DOI: 10.1038/nmicrobiol.2016.203.
[2]	ALBILLOS A, DE GOTTARDI A, RESCIGNO M. The gut－liver axis in liver disease: Pathophysiological basis for therapy[J]. J Hepatol, 2020, 72( 3): 558－ 577. DOI: 10.1016/j.jhep.2019.10.003.
[3]	ZHANG FM, CUI BT, HE XX, et al. Microbiota transplantation: Concept, methodology and strategy for its modernization[J]. Protein Cell, 2018, 9( 5): 462－ 473. DOI: 10.1007/s13238－018－0541－8.
[4]	OOIJEVAAR RE, TERVEER EM, VERSPAGET HW, et al. Clinical application and potential of fecal microbiota transplantation[J]. Annu Rev Med, 2019, 70: 335－ 351. DOI: 10.1146/annurev－med－111717－122956.
[5]	CAMMAROTA G, IANIRO G, TILG H, et al. European consensus conference on faecal microbiota transplantation in clinical practice[J]. Gut, 2017, 66( 4): 569－ 580. DOI: 10.1136/gutjnl－2016－313017.
[6]	WANG Y, ZHANG S, BORODY TJ, et al. Encyclopedia of fecal microbiota transplantation: A review of effectiveness in the treatment of 85 diseases[J]. Chin Med J, 2022, 135( 16): 1927－ 1939. DOI: 10.1097/CM9.0000000000002339.
[7]	ARON－WISNEWSKY J, VIGLIOTTI C, WITJES J, et al. Gut microbiota and human NAFLD: Disentangling microbial signatures from metabolic disorders[J]. Nat Rev Gastroenterol Hepatol, 2020, 17( 5): 279－ 297. DOI: 10.1038/s41575－020－0269－9.
[8]	DE MUNCK TJI, XU P, VERWIJS HJA, et al. Intestinal permeability in human nonalcoholic fatty liver disease: A systematic review and meta－analysis[J]. Liver Int, 2020, 40( 12): 2906－ 2916. DOI: 10.1111/liv.14696.
[9]	ZHANG J. Progress in the relationship between gut microbiota and children non－alcoholic fatty liver disease[J]. Int J Pediatr, 2020, 47( 8): 522－ 527. DOI: 10.3760/cma.j.issn.1673－4408.2020.08.002. 张晶. 肠道微生物与儿童非酒精性脂肪性肝病关系的研究进展[J]. 国际儿科学杂志, 2020, 47( 8): 522－ 527. DOI: 10.3760/cma.j.issn.1673－4408.2020.08.002.
[10]	LONG XX, LIU D, LI HT, et al. Research progress of intestinal flora in nonalcoholic fatty liver disease[J]. Shanghai Med J, 2021, 44( 11): 867－ 872. DOI: 10.19842/j.cnki.issn.0253－9934.2021.11.017. 龙晓雪, 刘丹, 李华婷, 等. 肠道菌群在非酒精性脂肪性肝病中的研究进展[J]. 上海医学, 2021, 44( 11): 867－ 872. DOI: 10.19842/j.cnki.issn.0253－9934.2021.11.017.
[11]	TAN XY, LIU Y, LONG JG, et al. Trimethylamine N－oxide aggravates liver steatosis through modulation of bile acid metabolism and inhibition of farnesoid X receptor signaling in nonalcoholic fatty liver disease[J]. Mol Nutr Food Res, 2019, 63( 17): e1900257. DOI: 10.1002/mnfr.201900257.
[12]	ABENAVOLI L, MAURIZI V, RINNINELLA E, et al. Fecal microbiota transplantation in NAFLD treatment[J]. Medicina, 2022, 58( 11): 1559. DOI: 10.3390/medicina58111559.
[13]	LIANG FF, LU XJ, DENG ZL, et al. Effect of washed microbiota transplantation on patients with dyslipidemia in South China[J]. Front Endocrinol(Lausanne), 2022, 13: 827107. DOI: 10.3389/fendo.2022.827107. eCollection 2022.
[14]	YE Y, ZHENG L, ZHENG ED, et al. Changes of intestinal flora in patients with nonalcoholic fatty liver disease and therapeutic effect of fecal bacteria transplantation[J]. Chin J Integr Tradit West Med Dig, 2019, 27( 10): 758－ 763. DOI: 10.3969/j.issn.1671－038X.2019.10.09. 叶毅, 郑亮, 郑恩典, 等. 非酒精性脂肪性肝病的肠道菌群变化及粪菌移植治疗作用研究[J]. 中国中西医结合消化杂志, 2019, 27( 10): 758－ 763. DOI: 10.3969/j.issn.1671－038X.2019.10.09.
[15]	BAJAJ JS. Alcohol, liver disease and the gut microbiota[J]. Nat Rev Gastroenterol Hepatol, 2019, 16( 4): 235－ 246. DOI: 10.1038/s41575－018－0099－1.
[16]	BAJAJ JS, HEUMAN DM, HYLEMON PB, et al. Altered profile of human gut microbiome is associated with cirrhosis and its complications[J]. J Hepatol, 2014, 60( 5): 940－ 947. DOI: 10.1016/j.jhep.2013.12.019.
[17]	LECLERCQ S, MATAMOROS S, CANI PD, et al. Intestinal permeability, gut－bacterial dysbiosis, and behavioral markers of alcohol－dependence severity[J]. Proc Natl Acad Sci U S A, 2014, 111( 42): E4485－E4493. DOI: 10.1073/pnas.1415174111.
[18]	YAN AW, FOUTS DE, BRANDL J, et al. Enteric dysbiosis associated with a mouse model of alcoholic liver disease[J]. Hepatology, 2011, 53( 1): 96－ 105. DOI: 10.1002/hep.24018.
[19]	PHILIPS CA, PANDE A, SHASTHRY SM, et al. Healthy donor fecal microbiota transplantation in steroid－ineligible severe alcoholic hepatitis: A pilot study[J]. Clin Gastroenterol Hepatol, 2017, 15( 4): 600－ 602. DOI: 10.1016/j.cgh.2016.10.029.
[20]	PHILIPS CA, PHADKE N, GANESAN K, et al. Corticosteroids, nutrition, pentoxifylline, or fecal microbiota transplantation for severe alcoholic hepatitis[J]. Indian J Gastroenterol, 2018, 37( 3): 215－ 225. DOI: 10.1007/s12664－018－0859－4.
[21]	WEN H, SHI YL. Correlation between liver function and intestinal flora in patients with hepatitis B virus infected liver cirrhosis[J]. Henan Med Res, 2022, 31( 9): 1651－ 1654. 闻慧, 史玉领. 乙型肝炎病毒感染肝硬化患者肝功能与肠道菌群的相关性[J]. 河南医学研究, 2022, 31( 9): 1651－ 1654.
[22]	XING LK, DENG YD, YAO LQ, et al. Changes of intestinal flora in patients with hepatitis B liver cirrhosis[J]. J Pract Hepatol, 2020, 23( 2): 256－ 259. DOI: 10.3969/j.issn.1672－5069.2020.02.027. 邢乐康, 邓永东, 姚立琼, 等. 乙型肝炎肝硬化患者肠道菌群变化研究[J]. 实用肝脏病杂志, 2020, 23( 2): 256－ 259. DOI: 10.3969/j.issn.1672－5069.2020.02.027.
[23]	LU HF, WU ZW, XU W, et al. Intestinal microbiota was assessed in cirrhotic patients with hepatitis B virus infection[J]. Microb Ecol, 2011, 61( 3): 693－ 703. DOI: 10.1007/s00248－010－9801－8.
[24]	LI YG, YU ZJ, LI A, et al. Gut microbiota alteration and modulation in hepatitis B virus－related fibrosis and complications: Molecular mechanisms and therapeutic inventions[J]. World J Gastroenterol, 2022, 28( 28): 3555－ 3572. DOI: 10.3748/wjg.v28.i28.3555.
[25]	CHOU HH, CHIEN WH, WU LL, et al. Age－related immune clearance of hepatitis B virus infection requires the establishment of gut microbiota[J]. Proc Natl Acad Sci U S A, 2015, 112( 7): 2175－ 2180. DOI: 10.1073/pnas.1424775112.
[26]	WANG JZ, ZHOU X, LI XR, et al. Fecal microbiota transplantation alters the outcome of hepatitis B virus infection in mice[J]. Front Cell Infect Microbiol, 2022, 12: 844132. DOI: 10.3389/fcimb.2022.844132.
[27]	REN YD, YE ZS, YANG LZ, et al. Fecal microbiota transplantation induces hepatitis B virus e－antigen(HBeAg) clearance in patients with positive HBeAg after long－term antiviral therapy[J]. Hepatology, 2017, 65( 5): 1765－ 1768. DOI: 10.1002/hep.29008.
[28]	MADSEN M, KIMER N, BENDTSEN F, et al. Fecal microbiota transplantation in hepatic encephalopathy: A systematic review[J]. Scand J Gastroenterol, 2021, 56( 5): 560－ 569. DOI: 10.1080/00365521.2021.1899277.
[29]	AHMAD J, KUMAR M, SARIN SK, et al. PS－163－Faecal microbiota transplantation with tenofovir is superior to tenofovir alone in improving clinical outcomes in acute－on－chronic liver failure due to hepatitis B: An open label randomized controlled trial(NCT02689245)[J]. J Hepatol, 2019, 70( 1): e102. DOI: 10.1016/S0618－8278(19)30181－1.
[30]	SARANGI AN, GOEL A, SINGH A, et al. Faecal bacterial microbiota in patients with cirrhosis and the effect of lactulose administration[J]. BMC Gastroenterol, 2017, 17( 1): 1－ 12. DOI: 10.1186/s12876－017－0683－9.
[31]	ARAB JP, MARTIN－MATEOS RM, SHAH VH. Gut－liver axis, cirrhosis and portal hypertension: The chicken and the egg[J]. Hepatol Int, 2018, 12( Suppl 1): 24－ 33. DOI: 10.1007/s12072－017－9798－x.
[32]	WANG WW, ZHANG Y, HUANG XB, et al. Fecal microbiota transplantation prevents hepatic encephalopathy in rats with carbon tetrachloride－induced acute hepatic dysfunction[J]. World J Gastroenterol, 2017, 23( 38): 6983－ 6994. DOI: 10.3748/wjg.v23.i38.6983.
[33]	CHENG YW, ALHAFFAR D, SAHA S, et al. Fecal microbiota transplantation is safe and effective in patients with Clostridioidesdifficile infection and cirrhosis[J]. Clin Gastroenterol Hepatol, 2021, 19( 8): 1627－ 1634. DOI: 10.1016/j.cgh.2020.06.051.
[34]	DHIMAN RK, ROY A, PREMKUMAR M, et al. Single session fecal microbiota transplantation in decompensated cirrhosis: an initial experience of clinical endpoints[C]// The Liver Meeting Digital Experience™. AASLD, 2020.
[35]	WOODHOUSE C, EDWARDS L, MULLISH BH, et al. Results of the PROFIT trial, a PROspective randomised placebo－controlled feasibility trial of faecal mIcrobiota transplantation in advanced cirrhosis[J]. J Hepatol, 2020, 73: S77－S 78. DOI: 10.1016/S0168－8278(20)30687－5.
[36]	Liver Failure and Artificial Liver Group, Chinese Society of Infectious Diseases, Chinese Medical Association; Severe Liver Disease and Artificial Liver Group, Chinese Society of Hepatology, Chinese Medical Association. Guideline for diagnosis and treatment of liver failure(2018)[J]. J Clin Hepatol, 2019, 35( 1): 38－ 44. DOI: 10.3969/j.issn.1001－5256.2019.01.007. 中华医学会感染病学分会肝衰竭与人工肝学组, 中华医学会肝病学分会重型肝病与人工肝学组. 肝衰竭诊治指南(2018年版)[J]. 临床肝胆病杂志, 2019, 35( 1): 38－ 44. DOI: 10.3969/j.issn.1001－5256.2019.01.007.
[37]	WANG FC, LI ZY, ZHANG WJ, et al. The significance of gut microbiota in acute－on－chronic liver failure[J]. J Clin Hepatol, 2022, 38( 7): 1667－ 1670. DOI: 10.3969/j.issn.1001－5256.2022.07.040. 王富春, 李子怡, 张万洁, 等. 肠道菌群在慢加急性肝衰竭中的意义[J]. 临床肝胆病杂志, 2022, 38( 7): 1667－ 1670. DOI: 10.3969/j.issn.1001－5256.2022.07.040.
[38]	CHEN MX, WANG SY. Role of intestinal dysbacteriosis in the pathogenesis of acute－on－chronic hepatitis B liver failure[J]. J Clin Hepatol, 2019, 35( 3): 665－ 668. DOI: 10.3969/j.issn.1001－5256.2019.03.048. 陈木兴, 王少扬. 肠道菌群失调在乙型肝炎相关慢加急性肝衰竭发病机制中的作用[J]. 临床肝胆病杂志, 2019, 35( 3): 665－ 668. DOI: 10.3969/j.issn.1001－5256.2019.03.048.
[39]	LIAO W, TANG Y, FAN WH, et al. Analysis of gut microbiota imbalance and its influencing factors in patients with chronic acute liver failure[J]. Trauma and Crit Medicine, 2021, 9( 5): 394－ 396. DOI: 10.16048/j.issn.2095－5561.2021.05.17. 廖威, 唐艳, 范文瀚, 等. 慢加急性肝衰竭患者肠道菌群失调情况及影响因素分析[J]. 创伤与急危重病医学, 2021, 9( 5): 394－ 396. DOI: 10.16048/j.issn.2095－5561.2021.05.17.
[40]	GAO A, XU YJ, LU SW, et al. Effect of fecal microbiota transplantation on intestinal flora in mice with acute－on－chronic liver failure[J]. J Clin Hepatol, 2021, 37( 6): 1379－ 1385. DOI: 10.3969/j.issn.1001－5256.2021.06.031. 高安, 徐玉静, 陆圣威, 等. 粪菌移植对慢加急性肝衰竭小鼠模型肠道菌群的影响[J]. 临床肝胆病杂志, 2021, 37( 6): 1379－ 1385. DOI: 10.3969/j.issn.1001－5256.2021.06.031.
[41]	LIU YM, FAN LD, CHENG Z, et al. Fecal transplantation alleviates acute liver injury in mice through regulating Treg/Th17 cytokines balance[J]. Sci Rep, 2021, 11( 1): 1611. DOI: 10.1038/s41598－021－81263－y.
[42]	SHARMA A, ROY A, PREMKUMAR M, et al. Fecal microbiota transplantation in alcohol－associated acute－on－chronic liver failure: An open－label clinical trial[J]. Hepatol Int, 2022, 16( 2): 433－ 446. DOI: 10.1007/s12072－022－10312－z.
[43]	LEI ZL, HUANG Y. Advances in research on intestinal flora imbalance in the development and prevention of liver cancer[J]. Anti Tumor Pharm, 2020, 10( 1): 16－ 20. DOI: 10.3969/j.issn.2095－1264.2020.01.04. 雷中利, 黄燕. 肠道菌群失调在肝癌发生、‍发展和预防、‍治疗中的研究进展[J]. 肿瘤药学, 2020, 10( 1): 16－ 20. DOI: 10.3969/j.issn.2095－1264.2020.01.04.
[44]	DENG HD, FAN XL. The role of intestinal microbiota in tumor occurrence, development and immunotherapy: A review[J]. Chin J Biotechnol, 2022, 38( 6): 2105－ 2119. DOI: 10.13345/j.cjb.210711. 邓寒丹, 范兴丽. 肠道菌群在肿瘤发生发展及免疫治疗中作用的研究进展[J]. 生物工程学报, 2022, 38( 6): 2105－ 2119. DOI: 10.13345/j.cjb.210711.
[45]	ZHENG W, ZHANG YH, ZHAO Y. Role of intestinal microflora in the pathogenesis of hepatocellular carcinoma[J]. J Clin Hepatol, 2019, 35( 7): 1613－ 1615. DOI: 10.3969/j.issn.1001－5256.2019.07.041. 郑微, 张永宏, 赵艳. 肠道微生物群在肝细胞癌发病机制中的作用[J]. 临床肝胆病杂志, 2019, 35( 7): 1613－ 1615. DOI: 10.3969/j.issn.1001－5256.2019.07.041.
[46]	FEDIRKO V, TRAN HQ, GEWIRTZ AT, et al. Exposure to bacterial products lipopolysaccharide and flagellin and hepatocellular carcinoma: A nested case－control study[J]. BMC Med, 2017, 15( 1): 72. DOI: 10.1186/s12916－017－0830－8.
[47]	XIE GX, WANG XN, HUANG FJ, et al. Dysregulated hepatic bile acids collaboratively promote liver carcinogenesis[J]. Int J Cancer, 2016, 139( 8): 1764－ 1775. DOI: 10.1002/ijc.30219.
[48]	HUANG R, NI JJ, GAO Y. The association between the intestinal microbiota－lipopolysaccharide－Toll－like receptor 4 axis and hepatocellularcarcinoma[J]. J Clin Hepatol, 2018, 34( 6): 1325－ 1328. DOI: 10.3969/j.issn.1001－5256.2018.06.041. 黄蓉, 倪加加, 高毅. 肠道菌群－脂多糖－Toll样受体4轴与肝细胞癌的关系[J]. 临床肝胆病杂志, 2018, 34( 6): 1325－ 1328. DOI: 10.3969/j.issn.1001－5256.2018.06.041.
[49]	AFFO S, YU LX, SCHWABE RF. The role of cancer－associated fibroblasts and fibrosis in liver cancer[J]. Annu Rev Pathol, 2017, 12: 153－ 186. DOI: 10.1146/annurev－pathol－052016－100322.
[50]	YU LX, YAN HX, LIU Q, et al. Endotoxin accumulation prevents carcinogen－induced apoptosis and promotes liver tumorigenesis in rodents[J]. Hepatology, 2010, 52( 4): 1322－ 1333. DOI: 10.1002/hep.23845.
[51]	NI JJ, HUANG R, ZHOU HF, et al. Analysis of the relationship between the degree of dysbiosis in gut microbiota and prognosis at different stages of primary hepatocellular carcinoma[J]. Front Microbiol, 2019, 10: 1458. DOI: 10.3389/fmicb.2019.01458.
[52]	ZHENG W, ZHAO P, ZHANG YH, et al. Metagenomic analysis on characteristics of intestinal flora of patients with primary liver cancer[J/CD]. Chin J Exp Clin Infect Dis(Electronic Edition), 2021, 15( 3): 149－ 157. DOI: 10.3877/cma.j.issn.1674－1358.2021.03.002. 郑微, 赵鹏, 张永宏, 等. 宏基因组测序技术分析原发性肝癌患者肠道菌群特征[J/CD]. 中华实验和临床感染病杂志(电子版), 2021, 15( 3): 149－ 157. DOI: 10.3877/cma.j.issn.1674－1358.2021.03.002.
[53]	BARUCH EN, YOUNGSTER I, BEN－BETZALEL G, et al. Fecal microbiota transplant promotes response in immunotherapy－refractory melanoma patients[J]. Science, 2021, 371( 6529): 602－ 609. DOI: 10.1126/science.abb5920.
[54]	ZHOU D, PAN Q, SHEN F, et al. Total fecal microbiota transplantation alleviates high－fat diet－induced steatohepatitis in mice via beneficial regulation of gut microbiota[J]. Sci Rep, 2017, 7( 1): 1529. DOI: 10.1038/s41598－017－01751－y.
[55]	WITJES JJ, SMITS LP, PEKMEZ CT, et al. Donor fecal microbiota transplantation alters gut microbiota and metabolites in obese individuals with steatohepatitis[J]. Hepatol Commun, 2020, 4( 11): 1578－ 1590. DOI: 10.1002/hep4.1601.
[56]	BAJAJ JS, SALZMAN NH, ACHARYA C, et al. Fecal microbial transplant capsules are safe in hepatic encephalopathy: A phase 1, randomized, placebo－controlled trial[J]. Hepatology, 2019, 70( 5): 1690－ 1703. DOI: 10.1002/hep.30690.
[57]	DEFILIPP Z, BLOOM PP, TORRES SOTO M, et al. Drug－resistant E. coli bacteremia transmitted by fecal microbiota transplant[J]. N Engl J Med, 2019, 381( 21): 2043－ 2050. DOI: 10.1056/NEJMoa1910437.