中文English
ISSN 1001-5256 (Print)
ISSN 2097-3497 (Online)
CN 22-1108/R

留言板

尊敬的读者、作者、审稿人, 关于本刊的投稿、审稿、编辑和出版的任何问题, 您可以本页添加留言。我们将尽快给您答复。谢谢您的支持!

姓名
邮箱
手机号码
标题
留言内容
验证码

胆汁酸-法尼醇核受体R-肠道微生态轴在肝衰竭发生及肝再生中的作用机制

陈研焰 蓝艳梅 王明刚 毛德文

引用本文:
Citation:

胆汁酸-法尼醇核受体R-肠道微生态轴在肝衰竭发生及肝再生中的作用机制

DOI: 10.3969/j.issn.1001-5256.2021.02.049
基金项目: 

国家自然科学基金 (81960841)

国家自然科学基金 (81774236)

国家自然科学基金 (81704021)

国家自然科学基金 (81760844)

广西自然科学基金创新研究团队项目 (2018GXNSFGA281002)

广西自然科学基金 (2017GXNSFBA198200)

广西自然科学基金 (2018GXNSFAA281047)

广西高校中青年教师基础能力提升项目 (2019KY0318)

广西高校中青年教师基础能力提升项目 (XP019012)

作者贡献声明:陈研焰负责资料分析,撰写论文;蓝艳梅、王明刚负责课题设计,收集数据,修改论文;毛德文负责拟定写作思路,指导撰写文章并最后定稿。
详细信息
    作者简介:

    陈研焰(1990—),女,主要从事中医药防治肝病研究

    通信作者:

    毛德文,mdwboshi2005@163.com

  • 中图分类号: R575

Mechanism of action of bile acid-farnesoid X receptor-intestinal microecological axis in the development of liver failure and liver regeneration

  • 摘要: 肝衰竭是常见的内科危重症,短时间内肝细胞大面积坏死而超过肝细胞再生能力导致该病病死率极高,促进有效肝再生是拮抗肝衰竭的关键。近年来发现胆汁酸、法尼醇核受体R、肠道微生态在肝衰竭和肝再生机制中发挥重要作用。现就胆汁酸、法尼醇核受体R、肠道微生态三者之间的相关性,及三者对肝衰竭和肝再生机制的作用方面进行综述,为临床肝衰竭的治疗提供新思路。

     

  • [1] 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. (in Chinese) 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
    [2] AMIN AA, AGARWAL B, JALAN R. Acute liver failure: Updates in pathogenesis and management[J]. Medicine (Abingdon), 2019, 47(12): 1-5.
    [3] MA Z, WU Y. Current status of liver failure treatment[J]. J Clin Hepatol, 2016, 32(9): 1668-1672. (in Chinese) DOI: 10.3969/j.issn.1001-5256.2016.09.007

    马臻, 乌云. 肝衰竭的治疗现状[J]. 临床肝胆病杂志, 2016, 32(9): 1668-1672. DOI: 10.3969/j.issn.1001-5256.2016.09.007
    [4] WANG XJ, ZHANG XP, NING Q. Immune-mediated liver failure[J]. J Clin Hepatol, 2014, 30(10): 984-991. (in Chinese) DOI: 10.3969/j.issn.1001-5256.2014.10.004

    王晓晶, 张小平, 宁琴. 肝衰竭的免疫发病机制[J]. 临床肝胆病杂志, 2014, 30(10): 984-991. DOI: 10.3969/j.issn.1001-5256.2014.10.004
    [5] MA H, PATTI ME. Bile acids, obesity, and the metabolic syndrome[J]. Best Pract Res Clin Gastroenterol, 2014, 28(4): 573-583. DOI: 10.1016/j.bpg.2014.07.004
    [6] MYANT NB, MITROPOULOS KA. Cholesterol 7 alpha-hydroxylase[J]. J Lipid Res, 1977, 18(2): 135-153. DOI: 10.1016/S0022-2275(20)41693-1
    [7] LI T, CHIANG JY. Bile acid signaling in metabolic disease and drug therapy[J]. Pharmacol Rev, 2014, 66(4): 948-983. DOI: 10.1124/pr.113.008201
    [8] SINAL CJ, TOHKIN M, MIYATA M, et al. Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis[J]. Cell, 2000, 102(6): 731-744. DOI: 10.1016/S0092-8674(00)00062-3
    [9] WANG H, CHEN J, HOLLISTER K, et al. Endogenous bile acids are ligands for the nuclear receptor FXR/BAR[J]. Mol Cell, 1999, 3(5): 543-553. DOI: 10.1016/S1097-2765(00)80348-2
    [10] YUAN L, BAMBHA K. Bile acid receptors and nonalcoholic fatty liver disease[J]. World J Hepatol, 2015, 7(28): 2811-2818. DOI: 10.4254/wjh.v7.i28.2811
    [11] MATSUBARA T, LI F, GONZALEZ FJ. FXR signaling in the enterohepatic system[J]. Mol Cell Endocrinol, 2013, 368(1-2): 17-29. DOI: 10.1016/j.mce.2012.05.004
    [12] HOLT JA, LUO G, BILLIN AN, et al. Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis[J]. Genes Dev, 2003, 17(13): 1581-1591. DOI: 10.1101/gad.1083503
    [13] KOELFAT K, VISSCHERS R, HODIN C, et al. FXR agonism protects against liver injury in a rat model of intestinal failure-associated liver disease[J]. J Clin Transl Res, 2018, 3(3): 318-327. https://www.zhangqiaokeyan.com/academic-journal-cn_clinical-translational-research_thesis/0201277661820.html
    [14] TANG L. Practice in the study of intestinal microecology in China[J]. Chin J Gastroenterol Hepatol, 2019, 28(3): 241-244. (in Chinese) DOI: 10.3969/j.issn.1006-5709.2019.03.001

    唐立. 中国肠道微生态学研究的实践[J]. 胃肠病学和肝病学杂志, 2019, 28(3): 241-244. DOI: 10.3969/j.issn.1006-5709.2019.03.001
    [15] NIE YF, HU J, YAN XH. Cross-talk between bile acids and intestinal microbiota in host metabolism and health[J]. J Zhejiang Univ Sci B, 2015, 16(6): 436-446. DOI: 10.1631/jzus.B1400327
    [16] VERBEKE L, FARRE R, VERBINNEN B, et al. The FXR agonist obeticholic acid prevents gut barrier dysfunction and bacterial translocation in cholestatic rats[J]. Am J Pathol, 2015, 185(2): 409-419. DOI: 10.1016/j.ajpath.2014.10.009
    [17] PAOLELLA G, MANDATO C, PIERRI L, et al. Gut-liver axis and probiotics: Their role in non-alcoholic fatty liver disease[J]. World J Gastroenterol, 2014, 20(42): 15518-15531. DOI: 10.3748/wjg.v20.i42.15518
    [18] ZHENG X, HUANG F, ZHAO A, et al. Bile acid is a significant host factor shaping the gut microbiome of diet-induced obese mice[J]. BMC Biol, 2017, 15(1): 120. DOI: 10.1186/s12915-017-0462-7
    [19] FRIEDMAN ES, LI Y, SHEN TD, et al. FXR-dependent modulation of the human small intestinal microbiome by the bile acid derivative obeticholic acid[J]. Gastroenterology, 2018, 155(6): 1741-1752. e5. DOI: 10.1053/j.gastro.2018.08.022
    [20] LI F, JIANG C, KRAUSZ KW, et al. Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity[J]. Nat Commun, 2013, 4: 2384. DOI: 10.1038/ncomms3384
    [21] ZHANG Y, LIMAYE PB, RENAUD HJ, et al. Effect of various antibiotics on modulation of intestinal microbiota and bile acid profile in mice[J]. Toxicol Appl Pharmacol, 2014, 277(2): 138-145. DOI: 10.1016/j.taap.2014.03.009
    [22] MISTRY RH, VERKADE HJ, TIETGE UJ. Reverse cholesterol transport is increased in germ-free mice-brief report[J]. Arterioscler Thromb Vasc Biol, 2017, 37(3): 419-422. DOI: 10.1161/ATVBAHA.116.308306
    [23] DEGIROLAMO C, RAINALDI S, BOVENGA F, et al. Microbiota modification with probiotics induces hepatic bile acid synthesis via downregulation of the Fxr-Fgf15 axis in mice[J]. Cell Rep, 2014, 7(1): 12-18. DOI: 10.1016/j.celrep.2014.02.032
    [24] YU YC, CHEN CW. Current status and research interests of the diagnosis and treatment of cholestatic liver disease[J]. J Clin Hepatol, 2019, 35(2): 241-246. (in Chinese) DOI: 10.3969/j.issn.1001-5256.2019.02.001

    于乐成, 陈成伟. 胆汁淤积性肝病的诊治现状及研究方向[J]. 临床肝胆病杂志, 2019, 35(2): 241-246. DOI: 10.3969/j.issn.1001-5256.2019.02.001
    [25] WANG XR, YAN BZ, YANG BS. The prognostic assessment of model for end-stage liver disease (MELD) and total bile acids in patients with subacute liver failure[J]. J Clin Hepatol, 2011, 27(6): 638-640. (in Chinese) DOI: 10.3969/j.issn.1001-5256.2011.06.023

    王晓韧, 颜炳柱, 杨宝山. 终末期肝病模型联合总胆汁酸对亚急性肝衰竭患者预后的评估[J]. 临床肝胆病杂志, 2011, 27(6): 638-640. DOI: 10.3969/j.issn.1001-5256.2011.06.023
    [26] MCMILLIN M, FRAMPTON G, QUINN M, et al. Bile acid signaling is involved in the neurological decline in a murine model of acute liver failure[J]. Am J Pathol, 2016, 186(2): 312-323. DOI: 10.1016/j.ajpath.2015.10.005
    [27] MODICA S, PETRUZZELLI M, BELLAFANTE E, et al. Selective activation of nuclear bile acid receptor FXR in the intestine protects mice against cholestasis[J]. Gastroenterology, 2012, 142(2): 355-365. e1-e4. DOI: 10.1053/j.gastro.2011.10.028
    [28] KONG B, ZHANG M, HUANG M, et al. FXR deficiency alters bile acid pool composition and exacerbates chronic alcohol induced liver injury[J]. Dig Liver Dis, 2019, 51(4): 570-576. DOI: 10.1016/j.dld.2018.12.026
    [29] LIAN F, WANG Y, XIAO Y, et al. Activated farnesoid X receptor attenuates apoptosis and liver injury in autoimmune hepatitis[J]. Mol Med Rep, 2015, 12(4): 5821-5827. DOI: 10.3892/mmr.2015.4159
    [30] ZHANG DG, ZHANG C, WANG JX, et al. Obeticholic acid protects against carbon tetrachloride-induced acute liver injury and inflammation[J]. Toxicol Appl Pharmacol, 2017, 314: 39-47. DOI: 10.1016/j.taap.2016.11.006
    [31] GAO FY, WANG XB. The role of intestinal endotoxemia in liver failure and its complications[J]. J Clin Hepatol, 2014, 30(8): 825-828. (in Chinese) DOI: 10.3969/j.issn.1001-5256.2014.08.036

    高方媛, 王宪波. 肠源性内毒素血症在肝衰竭发生发展中的作用[J]. 临床肝胆病杂志, 2014, 30(8): 825-828. DOI: 10.3969/j.issn.1001-5256.2014.08.036
    [32] BI MH, ZHANG SW, WANG BE, et al. Endotoxemia in rat hepatocyte mitochondria and its mechanism[J]. Chin J Appl Physiol, 2004, 20(1): 90-91, 97. (in Chinese) DOI: 10.3969/j.issn.1000-6834.2004.01.033

    毕铭华, 张淑文, 王宝恩, 等. 内毒素血症对大鼠肝细胞线粒体的损伤及其机制[J]. 中国应用生理学杂志, 2004, 20(1): 90-91, 97. DOI: 10.3969/j.issn.1000-6834.2004.01.033
    [33] ZHANG YC, BI YZ, FANG X, et al. Protective effect of probiotics in rats with acute- on-chronic liver failure and related mechanism[J]. J Clin Hepatol, 2019, 35(7): 1570-1575. (in Chinese) DOI: 10.3969/j.issn.1001-5256.2019.07.029

    张永超, 毕研贞, 方萧, 等. 益生菌对慢加急性肝衰竭大鼠模型的保护作用及其机制[J]. 临床肝胆病杂志, 2019, 35(7): 1570-1575. DOI: 10.3969/j.issn.1001-5256.2019.07.029
    [34] ZHOU Y, DU S, CHEN B. The theory of an intestinal microecological imbalance[J]. J Pathog Biol, 2019, 14(7): 867-870. (in Chinese) https://www.cnki.com.cn/Article/CJFDTOTAL-ZISC201907029.htm

    周月, 杜珊, 陈斌. 肠道微生态失衡理论的研究现状[J]. 中国病原生物学杂志, 2019, 14(7): 867-870. https://www.cnki.com.cn/Article/CJFDTOTAL-ZISC201907029.htm
    [35] DELZENNE NM, KNUDSEN C, BEAUMONT M, et al. Contribution of the gut microbiota to the regulation of host metabolism and energy balance: A focus on the gut-liver axis[J]. Proc Nutr Soc, 2019, 78(3): 319-328. DOI: 10.1017/S0029665118002756
    [36] ANTONIADES CG, BERRY PA, WENDON JA, et al. The importance of immune dysfunction in determining outcome in acute liver failure[J]. J Hepatol, 2008, 49(5): 845-861. DOI: 10.1016/j.jhep.2008.08.009
    [37] JIANG LN, ZHAO JM. Clinicopathological basis of liver failure[J]. J Clin Hepatol, 2019, 35(9): 1916-1919. (in Chinese) DOI: 10.3969/j.issn.1001-5256.2019.09.005

    蒋丽娜, 赵景民. 肝衰竭的临床病理基础[J]. 临床肝胆病杂志, 2019, 35(9): 1916-1919. DOI: 10.3969/j.issn.1001-5256.2019.09.005
    [38] MICHALOPOULOS GK. Liver regeneration after partial hepatectomy: Critical analysis of mechanistic dilemmas[J]. Am J Pathol, 2010, 176(1): 2-13. DOI: 10.2353/ajpath.2010.090675
    [39] DU HP, CHEN W, KONG FD, et al. Effect of bile acid on expression of farnesoid X receptor, interleukin-6 and recovery of liver function after hepatectomy in rats with cirrhosis of liver[J/CD]. Chin J Injury Repair and Wound Healing (Electronic Edition), 2018, 13(6): 450-454. (in Chinese)

    杜汉朋, 陈伟, 孔凡东, 等. 胆汁酸对肝硬化大鼠肝切除术后法尼酯X受体、白细胞介素-6的表达及肝功能恢复的影响[J/CD]. 中华损伤与修复杂志(电子版), 2018, 13(6): 450-454.
    [40] SUN SQ, QIU YD. Bile acid and farnesoid X receptor mediate liver regeneration[J/CD]. Chin J Exp Surg (Electronic Edition), 2017, 6(2): 147-149. (in Chinese)

    孙士全, 仇毓东. 胆汁酸与法尼酯X受体介导肝再生[J/CD]. 中华肝脏外科手术学电子杂志, 2017, 6(2): 147-149.
    [41] DING L, YANG Y, QU Y, et al. Bile acid promotes liver regeneration via farnesoid X receptor signaling pathways in rats[J]. Mol Med Rep, 2015, 11(6): 4431-4437. DOI: 10.3892/mmr.2015.3270
    [42] ZHANG L, HUANG X, MENG Z, et al. Significance and mechanism of CYP7a1 gene regulation during the acute phase of liver regeneration[J]. Mol Endocrinol, 2009, 23(2): 137-145. DOI: 10.1210/me.2008-0198
    [43] LU YM, YUAN SG, LIANG KW, et al. Relationship between farnesoid X receptor and liver regeneration of obstructive jaundice rats following partial hepatectomy with different biliary drainages[J]. Chin J Exp Surg, 2014, 31(2): 304-307. (in Chinese) DOI: 10.3760/cma.j.issn.1001-9030.2014.02.028

    鲁育民, 袁晟光, 梁科伟, 等. 法尼酯衍生物X受体与不同引流方式下梗阻性黄疸大鼠部分肝切除术后肝再生的关系[J]. 中华实验外科杂志, 2014, 31(2): 304-307. DOI: 10.3760/cma.j.issn.1001-9030.2014.02.028
    [44] CHEN WD, WANG YD, ZHANG L, et al. Farnesoid X receptor alleviates age-related proliferation defects in regenerating mouse livers by activating forkhead box m1b transcription[J]. Hepatology, 2010, 51(3): 953-962. http://med.wanfangdata.com.cn/Paper/Detail/PeriodicalPaper_PM19998409
    [45] KONG B, SUN R, HUANG M, et al. Fibroblast growth factor 15-dependent and bile acid-independent promotion of liver regeneration in mice[J]. Hepatology, 2018, 68(5): 1961-1976. DOI: 10.1002/hep.30041
    [46] LI J, GUO C, HE ZL, et al. Effect of fibroblast growth factor-15 on liver function and regeneration in rats with biliary obstruction by regulating bile acid metabolism[J]. J Hunan Normal Univ(Med Sci), 2019, 16(2): 3-7. (in Chinese) https://www.cnki.com.cn/Article/CJFDTOTAL-HNYG201902003.htm

    李佳, 郭超, 何自力, 等. FGF-15调节胆汁酸代谢对梗阻性黄疸大鼠肝功能及肝再生的影响[J]. 湖南师范大学学报(医学版), 2019, 16(2): 3-7. https://www.cnki.com.cn/Article/CJFDTOTAL-HNYG201902003.htm
    [47] XIE JF, FAN JY, YUAN SG. A study on exogenous bile acid for recovery of liver regeneration disorder caused by external biliary drain-age and its mechanism[J]. J Pract Med, 2018, 34(19): 3198-3202. (in Chinese) DOI: 10.3969/j.issn.1006-5725.2018.19.011

    谢经丰, 范基元, 袁晟光. 外源性胆汁酸恢复胆道外引流导致的肝再生障碍及其机制[J]. 实用医学杂志, 2018, 34(19): 3198-3202. DOI: 10.3969/j.issn.1006-5725.2018.19.011
    [48] SUI CQ, MA YH, ZHAO Y, et al. Progress in the study of the protective mechanism and agonists of FXR in liver diseases[J]. Tianjin Pharmacy, 2019, 31(1): 49-54. (in Chinese) https://www.cnki.com.cn/Article/CJFDTOTAL-TJYA201901018.htm

    隋常琪, 马宇衡, 赵岩, 等. FXR在肝脏疾病中的作用及其激动剂的研究进展[J]. 天津药学, 2019, 31(1): 49-54. https://www.cnki.com.cn/Article/CJFDTOTAL-TJYA201901018.htm
    [49] BAO Q, YU L, CHEN D, et al. Variation in the gut microbial community is associated with the progression of liver regeneration[J]. Hepatol Res, 2020, 50(1): 121-136. DOI: 10.1111/hepr.13424
    [50] WU X, SUN R, CHEN Y, et al. Oral ampicillin inhibits liver regeneration by breaking hepatic innate immune tolerance normally maintained by gut commensal bacteria[J]. Hepatology, 2015, 62(1): 253-264. DOI: 10.1002/hep.27791
    [51] LIU HX, ROCHA CS, DANDEKAR S, et al. Functional analysis of the relationship between intestinal microbiota and the expression of hepatic genes and pathways during the course of liver regeneration[J]. J Hepatol, 2016, 64(3): 641-650. DOI: 10.1016/j.jhep.2015.09.022
    [52] CHEN YJ, XU CP, MI JJ. Intestinal endotoxemia induced dynamic changes of IL-1β in plasma and residual liver tissue after partial hepatectomy in rats[J]. Int J Dig Dis, 2011, 31(3): 172-176. (in Chinese) DOI: 10.3969/j.issn.1673-534X.2011.03.015

    陈永静, 许翠萍, 米俊杰. 肝大部切除大鼠所致的IETM对血浆与肝组织IL-1β的影响[J]. 国际消化病杂志, 2011, 31(3): 172-176. DOI: 10.3969/j.issn.1673-534X.2011.03.015
    [53] REN QF, XU CP. Intestinal endotoxin-mediated liver injury affects the microenvironment of liver regeneration[J]. Chin Hepatol, 2018, 23(3): 263-266. (in Chinese) DOI: 10.3969/j.issn.1008-1704.2018.03.024

    任勤芳, 许翠萍. 肠源性内毒素介导肝损伤影响肝再生微环境[J]. 肝脏, 2018, 23(3): 263-266. DOI: 10.3969/j.issn.1008-1704.2018.03.024
    [54] LUO L, REEDY AR, JONES RM. Detecting reactive oxygen species generation and stem cell proliferation in the drosophila intestine[J]. Methods Mol Biol, 2016, 1422: 103-113. DOI: 10.1007%2F978-1-4939-3603-8_10
    [55] WANG J, CEN P, CHEN J, et al. Role of mesenchymal stem cells, their derived factors, and extracellular vesicles in liver failure[J]. Stem Cell Res Ther, 2017, 8(1): 137. DOI: 10.1186/s13287-017-0576-4
    [56] LI WW, BAO CY, LI YM. Effect of bone marrow mesenchymal stem cell transplantation on acute liver failure and its effect on IL-10 level[J]. Chin J Immunol, 2020, 36(7): 774-779. (in Chinese) DOI: 10.3969/j.issn.1000-484X.2020.07.002

    李文武, 鲍传裕, 李元明. 骨髓间充质干细胞移植在急性肝衰竭中的应用效果及对IL-10水平的影响研究[J]. 中国免疫学杂志, 2020, 36(7): 774-779. DOI: 10.3969/j.issn.1000-484X.2020.07.002
    [57] ZHANG RZ, WANG TS, LYU C, et al. The research progress of the mechanism of traditional Chinese medicine in the treatment of hepatic failure[J]. J Tradit Chin Med Univ Hunan, 2020, 40(2): 251-255. (in Chinese) https://www.cnki.com.cn/Article/CJFDTOTAL-HNZX202002027.htm

    张荣臻, 王挺帅, 吕超, 等. 中药治疗肝衰竭机制的研究进展[J]. 湖南中医药大学学报, 2020, 40(2): 251-255. https://www.cnki.com.cn/Article/CJFDTOTAL-HNZX202002027.htm
    [58] WANG XB, ZHANG Q, GAO FY. Prediction of acute -on - chronic liver failure and integrated traditional Chinese and Western medicine therapy[J]. J Clin Hepatol, 2020, 36(1): 19-25. (in Chinese) DOI: 10.3969/j.issn.1001-5256.2020.01.003

    王宪波, 张群, 高方媛. 慢加急性肝衰竭的预后评估及中西医结合治疗[J]. 临床肝胆病杂志, 2020, 36(1): 19-25. DOI: 10.3969/j.issn.1001-5256.2020.01.003
    [59] LYU C, MAO DW, QIN Q, et al. Effect of Wenyang Huayu Tuihuang Decoction in the treatment of hepatitis B-related chronic and acute liver failure[J]. China Med Herald, 2019, 16(30): 142-146. (in Chinese) https://www.cnki.com.cn/Article/CJFDTOTAL-YYCY201930031.htm

    吕超, 毛德文, 覃倩, 等. 温阳化瘀退黄方治疗乙型肝炎相关慢加急性肝衰竭的效果[J]. 中国医药导报, 2019, 16(30): 142-146. https://www.cnki.com.cn/Article/CJFDTOTAL-YYCY201930031.htm
  • 加载中
计量
  • 文章访问数:  471
  • HTML全文浏览量:  91
  • PDF下载量:  39
  • 被引次数: 0
出版历程
  • 收稿日期:  2020-07-16
  • 录用日期:  2020-08-17
  • 出版日期:  2021-02-20
  • 分享
  • 用微信扫码二维码

    分享至好友和朋友圈

目录

    /

    返回文章
    返回