The association between the intestinal microbiota-lipopolysaccharide-Toll-like receptor 4 axis and hepatocellular carcinoma
-
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。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.
-
Key words:
- carcinoma, hepatocellular /
- enterobacteriaceae /
- lipopolysaccharides /
- Toll-like receptor 4 /
- review
-
[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.
本文二维码
计量
- 文章访问数: 1485
- HTML全文浏览量: 16
- PDF下载量: 327
- 被引次数: 0