肠道菌群-脂多糖-Toll样受体4轴与肝细胞癌的关系

黄蓉; 倪加加; 高毅

doi:10.3969/j.issn.1001-5256.2018.06.041

肠道菌群-脂多糖-Toll样受体4轴与肝细胞癌的关系

DOI: 10.3969/j.issn.1001-5256.2018.06.041

南方医科大学珠江医院肝胆二科

基金项目:

国家自然科学基金(81470875)；

详细信息

中图分类号: R735.7
计量
- 文章访问数: 1564
- HTML全文浏览量: 18
- PDF下载量: 329
- 被引次数: 34
出版历程
- 收稿日期: 2017-12-11
- 出版日期: 2018-06-20

The association between the intestinal microbiota-lipopolysaccharide-Toll-like receptor 4 axis and hepatocellular carcinoma

Department of Hepatobiliary Surgery II, Zhujiang Hospital, Southern Medical University

Research funding:

摘要

摘要: 肝细胞癌是各种慢性肝病终末期的主要并发症,研究表明肝病患者普遍存在肠道屏障破坏和肠道菌群紊乱,导致肠道细菌移位,发生内毒素血症。Toll样受体4是肝内一种模式识别受体,能够结合内毒素中的活性成分——脂多糖,通过胞内一系列信号转导途径导致免疫炎症反应,最终促进肝纤维化和肿瘤发生。综述了肠道菌群-脂多糖-Toll样受体4轴与肝细胞癌发病机制相关研究进展。
- 癌,肝细胞 /
- 肠杆菌科 /
- 脂多糖类 /
- Toll样受体4 /
- 综述
Abstract: Hepatocellular carcinoma is the major complication of various end-stage chronic liver diseases. Studies have shown that intestinal barrier injury and intestinal flora disturbance are commonly seen in patients with liver diseases, which may cause intestinal bacterial translocation and endotoxemia. Toll-like receptor 4 (TLR4) is a pattern recognition receptor in the liver and can bind to lipopolysaccharide (LPS) , the active ingredient of endotoxin, result in immune inflammatory response via various signal transduction pathways, and finally promote hepatic fibrosis and tumorigenesis. This article reviews the intestinal microbiota-LPS-TLR4 axis and the pathogenesis of hepatocellular carcinoma.
- carcinoma, hepatocellular /
- enterobacteriaceae /
- lipopolysaccharides /
- Toll-like receptor 4 /
- review

HTML全文

参考文献(41)

[1]LUO J, JIN F.Recent advances in understanding the impact of intestinal microbiota on host behavior[J].Chin Sci Bull, 2014, 59 (22) :2169-2190. (in Chinese) 罗佳, 金锋.肠道菌群影响宿主行为的研究进展[J].科学通报, 2014, 59 (22) :2169-2190.

[2]YU LX, SCHWABE RF.The gut microbiome and liver cancer:mechanisms and clinical translation[J].Nat Rev Gastroenterol Hepatol, 2017, 14 (9) :527-539.

[3]KIZILTAS S.Toll-like receptors in pathophysiology of liver diseases[J].World J Hepatol, 2016, 8 (32) :1354-1369.

[4]WEI XP, GAO X, MA YJ.Relationship between small intestinal bacterial overgrowth and severity of with hepatitis B cirrhosis[J].J Clin Hepatol, 2016, 32 (4) :716-719. (in Chinese) 魏新朋, 高晓, 马英杰.乙型肝炎肝硬化患者小肠细菌过度生长与疾病严重程度的相关性[J].临床肝胆病杂志, 2016, 32 (4) :716-719.

[5]BENTEN D, WIEST R.Gut microbiome and intestinal barrier failure——the"Achilles heel"in hepatology?[J].J Hepatol, 2012, 56 (6) :1221-1223.

[6]WU ZW, XU KJ, LI LJ, et al.Investigation of intestinal bacterial translocation in 78 patients with cirrhosis after liver transplantation[J].Chin J Surg, 2006, 44 (21) :1456-1459. (in Chinese) 吴仲文, 徐凯进, 李兰娟, 等.78例肝硬化患者肠道细菌易位及其相关性研究[J].中华外科杂志, 2006, 44 (21) :1456-1459.

[7]RACANELLI V, REHERMANN B.The liver as an immunological organ[J].Hepatology, 2006, 43 (2 Suppl 1) :s54-s62.

[8]TAKEDA K, KAISHO T, AKIRA S.Toll-like receptors[J].Annu Rev Immunol, 2003, 21 (1) :335-376.

[9]DAPITO DH, MENCIN A, GWAK GY, et al.Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4[J].Cancer Cell, 2012, 21 (4) :504-516.

[10]YOON HY, YI HY.Liver cirrhosis mortality in the United States, 1970-2007 surveillance report#88:NIAAA homepage 2010[EB/OL].http://pubs.niaaa.nih.gov/publications/surveillance88/Cirr07.htm, 2017-12-7.

[11]REHM J, MATHERS C, POPOVA S, et al.Global burden of disease and injury and economic cost attributable to alcohol use and alcohol-use disorders[J].Lancet, 2009, 373 (9682) :2223-2233.

[12]SANYAL AJ, YOON SK, LENCIONI R.The etiology of hepatocellular carcinoma and consequences for treatment[J].Oncologist, 2010, 15 (Suppl 4) :14-22.

[13]LIPPAI D, BALA S, CATALANO D, et al.Micro-RNA-155deficiency prevents alcohol-induced serum endotoxin increase and small bowel inflammation in mice[J].Alcohol Clin Exp Res, 2014, 38 (8) :2217-2224.

[14]PRADERE JP, TROEGER JS, DAPITO DH, et al.Toll-like receptor 4 and hepatic fibrogenesis[J].Semin Liver Dis, 2010, 30 (3) :232-244.

[15]SZABO G.Gut-liver axis in alcoholic liver disease[J].Gastroenterology, 2015, 148 (1) :30-36.

[16]UESUGI T, FROH M, ARTEEL GE, et al.Toll-like receptor 4 is involved in the mechanism of early alcohol-induced liver injury in mice[J].Hepatology, 2001, 34 (1) :101-108.

[17]ADACHI Y, MOORE LE, BRADFORD BU, et al.Antibiotics prevent liver injury in rats following long-term exposure to ethanol[J].Gastroenterology, 1995, 108 (1) :218-224.

[18]FAN JG, FARRELL GC.Epidemiology of non-alcoholic fatty liver disease in China[J].J Hepatol, 2009, 50 (1) :204-210.

[19]MICHELOTTI GA, MACHADO MV, DIEHL AM.NAFLD, NASH and liver cancer[J].Nat Rev Gastroenterol Hepatol, 2013, 10 (11) :656.

[20]STREBA LA, VERE CC, ROGOVEANU I, et al.Nonalcoholic fatty liver disease, metabolic risk factors, and hepatocellular carcinoma:An open question[J].World J Gastroenterol, 2015, 21 (14) :4103-4110.

[21]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.

[22]SPRUSS A, KANURI G, WAGNERBERGER S, et al.Toll-like receptor 4 is involved in the development of fructose-induced hepatic steatosis in mice[J].Hepatology, 2009, 50 (4) :1094-1104.

[23]PAPPO I, BERCOVIER H, BERRY EM, et al.Polymyxin B reduces total parenteral nutrition-associated hepatic steatosis by its antibacterial activity and by blocking deleterious effects of lipopolysaccharide[J].JPEN J Parenter Enteral Nutr, 1992, 16 (6) :529-532.

[24]PAPPO I, BECOVIER H, BERRY EM, et al.Polymyxin B reduces cecal flora, TNF production and hepatic steatosis during total parenteral nutrition in the rat[J].J Surg Res, 1991, 51 (2) :106-112.

[25]DRENICK EJ, FISLER J, JOHNSON D.Hepatic steatosis after intestinal bypass——prevention and reversal by metronidazole, irrespective of protein-calorie malnutrition[J].Gastroenterology, 1982, 82 (3) :535-548.

[26]MIELE L, VALENZA V, LA TORRE G, et al.Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease[J].Hepatology, 2009, 49 (6) :1877-1887.

[27]BROERING R, LU M, SCHLAAK JF.Role of Toll-like receptors in liver health and disease[J].Clin Sci (Lond) , 2011, 121 (10) :415-426.

[28]SOARES JB, PIMENTEL-NUNES P, RONCON-ALBUQUERQUE R, et al.The role of lipopolysaccharide/toll-like receptor 4 signaling in chronic liver diseases[J].Hepatol Int, 2010, 4 (4) :659-672.

[29]KAO JH, CHEN DS.Global control of hepatitis B virus infection[J].Lancet Infect Dis, 2002, 2 (7) :395-403.

[30]CHEN DS.Fighting against viral hepatitis:Lessons from Taiwan[J].Hepatology, 2011, 54 (2) :381-392.

[31]CHEN MM, ZHENG JS, LIU YY, et al.Changes of intestinal microbiota in patients with chronic hepatitis B and liver cirrhosis[J].Acta Univ Med Anhui, 2015, 50 (5) :648-652. (in Chinese) 陈萌萌, 郑吉顺, 刘艳艳, 等.慢性乙型肝炎以及肝硬化患者肠道微生物研究[J].安徽医科大学学报, 2015, 50 (5) :648-652.

[32]LI LJ, WU ZW, MA WH, et al.Changes in intestinal microflora in patients with chronic severe hepatitis[J].Chin Med J, 2001, 114 (8) :86-89. (in Chinese) 李兰娟, 吴仲文, 马伟杭, 等.慢性重型肝炎患者肠道菌群变化及其作用的研究 (英文) [J].中华医学杂志, 2001, 114 (8) :86-89.

[33]DOLGANIUC A, NORKINA O, KODYS K, et al.Viral and host factors induce macrophage activation and loss of toll-like receptor tolerance in chronic HCV infection[J].Gastroenterology, 2007, 133 (5) :1627-1636.

[34] JIANG FM, LI XF, CHENG SQ, et al.Clinical significance of expression of TLR3 and TLR4 in liver tissue of patients with chronic hepatitis B[J].Int J Virol, 2017, 24 (3) :209-212. (in Chinese) 蒋福明, 李秀芬, 程书权, 等.慢性乙型肝炎患者肝组织Toll样受体3、4表达及其临床意义[J].国际病毒学杂志, 2017, 24 (3) :209-212.

[35]SOARES JB, PIMENTEL-NUNES P, AFONSO L, et al.Increased hepatic expression of TLR2 and TLR4 in the hepatic inflammation-fibrosis-carcinoma sequence[J].Innate Immun, 2012, 18 (5) :700-708.

[36]TORRE LA, BRAY F, SIEGEL RL, et al.Global cancer statistics, 2012[J].CA Cancer J Clin, 2015, 65 (2) :87-108.

[37]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.

[38]JING YY, HAN ZP, SUN K, et al.Toll-like receptor 4 signaling promotes epithelial-mesenchymal transition in human hepatocellular carcinoma induced by lipopolysaccharide[J].BMC Med, 2012, 10:98.

[39]MACHIDA K, TSUKAMOTO H, MKRTCHYAN H, et al.Tolllike receptor 4 mediates synergism between alcohol and HCV in hepatic oncogenesis involving stem cell marker Nanog[J].Proc Natl Acad Sci U S A, 2009, 106 (5) :1548-1553.

[40]ZHANG HL, YU LX, YANG W, et al.Profound impact of gut homeostasis on chemically-induced pro-tumorigenic inflammation and hepatocarcinogenesis in rats[J].J Hepatol, 2012, 57 (4) :803-812.

[41]LI J, SUNG CY, LEE N, et al.Probiotics modulated gut microbiota suppresses hepatocellular carcinoma growth in mice[J].Proc Natl Acad Sci U S A, 2016, 113 (9) :e1306-e1315.

施引文献

期刊类型引用(30)

1.	汪淑佳，俞黎. 多学科团队诊疗模式下的PDCA循环管理在梗阻性黄疸患者围术期护理中的应用效果分析. 中国社区医师. 2025(02): 96-98 . 百度学术
2.	易衡，何芬，王曦，冯谦，唐杰，卿小琼，孙菲菲，陈重. 超声引导下PTCD治疗晚期MOJ疗效及预后因素分析. 武汉大学学报(医学版). 2024(07): 814-819 . 百度学术
3.	李鸿. 老年晚期恶性梗阻性黄疸患者实时超声弹性成像定量分析对PTCD预后的预测价值. 昆明医科大学学报. 2023(01): 122-127 . 百度学术
4.	李鸿. 老年晚期恶性梗阻性黄疸患者实时超声弹性成像定量分析对PTCD预后的评估价值. 昆明医科大学学报. 2023(02): 150-155 . 百度学术
5.	梁亚丽，李馨，夏俊杰. 胰腺癌梗阻性黄疸患者经皮穿刺胆管引流术后发生胰腺炎的危险因素分析. 实用癌症杂志. 2023(08): 1321-1324 . 百度学术
6.	杨立新，刘茜，周晶晶，唐亚丹，傅鹏，戴峰，白淑芬. 不同方法PTCD应用于梗阻性黄疸治疗中的体会. 现代医用影像学. 2023(12): 2229-2231+2235 . 百度学术
7.	华建军. 超声引导下经皮肝穿刺胆管引流术治疗对阻塞性黄疸病人胆红素水平与肝功能的影响研究. 贵州医药. 2022(02): 226-227 . 百度学术
8.	黄道琼，沈小叶，刘骏，刘月娥，陈瑜. 回授法在经皮肝穿刺胆管引流术后的应用. 介入放射学杂志. 2022(03): 294-297 . 百度学术
9.	彭赵宏，张德志，施万印，赵本胜，熊壮，汪名权，宋文，陶龙香，刘斌，张帅，程翔. ~(125)I粒子支架治疗恶性梗阻性黄疸支架通畅时间的影响因素分析. 安徽医科大学学报. 2022(04): 645-649 . 百度学术
10.	王玮，陈熙，罗丹，李启祥，尹合坤. 不同姑息性引流术对低位恶性梗阻性黄疸的近远期疗效及安全性分析. 当代医学. 2022(19): 39-42 . 百度学术
11.	买买提·瓦司力，高旭升，司俊杰，徐峰. 经皮肝穿引流和支架植入在恶性梗阻性黄疸患者治疗的疗效评价. 新疆医学. 2022(07): 770-772+809 . 百度学术
12.	王颖. 彩超引导经皮穿刺肝胆管引流术治疗梗阻性黄疸的临床研究. 中国医疗器械信息. 2022(15): 123-125 . 百度学术
13.	宋飞，向盈盈，车佳音，李红阳，徐文勇，魏凌潇，黄明. 胆道~(125)I粒子支架与金属裸支架治疗Bismuth Corlette Ⅲ型胆管癌合并梗阻性黄疸的临床对比. 昆明医科大学学报. 2022(11): 85-89 . 百度学术
14.	冉庆. ERCP联合PTCD胆总管支架置入胆管引流治疗恶性梗阻性黄疸的临床价值. 医学食疗与健康. 2021(04): 86-87 . 百度学术
15.	王锦程，余佩和，苏松，李波. 经内镜鼻胆管引流术与经内镜胆道支架置入术在低位恶性梗阻性黄疸术前胆道引流效果比较的Meta分析. 临床肝胆病杂志. 2021(04): 863-867 . 本站查看
16.	马博，周军，周京涛，李建刚，王俊. 胆道支架植入治疗恶性梗阻性黄疸术后并发症的发生因素分析. 现代生物医学进展. 2021(07): 1283-1286 . 百度学术
17.	张建松，侯森，崔虎啸. 超声引导下经皮肝穿刺胆道引流联合胆管复合支架置入术治疗晚期肝外胆管癌的效果. 癌症进展. 2021(09): 931-934 . 百度学术
18.	张华安，周晓芳，蒋易君，张淏嘉. NRS-2002联合炎症反应标志物预测恶性梗阻性黄疸患者预后的Nomogram模型构建. 山东医药. 2021(16): 35-40 . 百度学术
19.	石书伟，王劲. 经皮肝穿刺胆道引流联合金属支架植入术对恶性梗阻性黄疸的影响. 黑龙江医学. 2021(15): 1608-1609 . 百度学术
20.	宋英茜，陶冶. 梗阻性黄疸经皮肝穿刺胆道引流术后胆道感染的病原菌特点及其危险因素分析. 中国实用乡村医生杂志. 2021(02): 33-36 . 百度学术
21.	张志强，韩涛，崔钢，王奕，蔡恒烈，廖骞. 右肝管入路单通道横跨左右肝管引流治疗汇管区恶性梗阻性黄疸的临床研究. 中国普通外科杂志. 2021(12): 1503-1508 . 百度学术
22.	傅建英. 内镜介入治疗急性梗阻性黄疸的疗效及对患者炎症因子的影响. 中外医疗. 2021(33): 57-60 . 百度学术
23.	李蔚，王锡斌，崔卫东，杨青，刘会苗，杨金雨，王锡斌. 超声引导下经皮经肝胆管穿刺引流术治疗急性梗阻性化脓性胆管炎患者疗效分析. 实用肝脏病杂志. 2020(03): 447-450 . 百度学术
24.	李磊. 胆道支架联合经皮肝穿刺胆管引流术对晚期恶性梗阻性黄疸的临床应用价值. 名医. 2020(08): 85-86 . 百度学术
25.	张蓓，答秀维，张乐. 经皮肝穿刺胆道外引流治疗恶性梗阻性黄疸疗效及对患者细胞免疫功能、血清直接胆红素、超敏C反应蛋白水平的影响. 陕西医学杂志. 2020(10): 1249-1252 . 百度学术
26.	朱超，刘会春，胡小四，庞青，陈邦邦，李传涛. 胆道双支架联合~(125)I粒子腔内照射治疗恶性肝门部胆道梗阻的疗效分析. 介入放射学杂志. 2020(11): 1100-1104 . 百度学术
27.	姜磊，都晓英，孙医学，张大坤，周凯，徐建中，陈芳芳. PTBS术治疗恶性梗阻性黄疸的临床价值及预后因素分析. 蚌埠医学院学报. 2019(09): 1202-1205+1209 . 百度学术
28.	江新华. 64层螺旋CT3D成像与MRCP成像技术对胆道梗阻性疾病的诊断价值. 江西医药. 2019(11): 1336-1340 . 百度学术
29.	吴子鑫，吴申伟. 经皮肝穿刺胆道支架植入治疗对恶性梗阻性黄疸患者肝功能指标、炎症指标的影响. 齐齐哈尔医学院学报. 2019(24): 3098-3099 . 百度学术
30.	武飞. 经皮肝穿刺胆管引流术与Roux-en-Y胆肠吻合术治疗恶性梗阻性黄疸患者的对比研究. 中国药物与临床. 2019(23): 4098-4100 . 百度学术