肠道菌群在肝癌发生发展及治疗中的作用研究进展

doi:10.3969/j.issn.1674-8115.2022.07.014

摘要/Abstract

摘要：

人体内存在众多的微生物群落，肠道菌群在人体微生物库中的占比高达80%。肠道菌群通过参与新陈代谢、免疫稳态等生理过程来调节机体的消化和免疫功能，还可影响癌症的发生并控制机体对癌症治疗药物的反应。肝癌是典型炎癌转化的肿瘤类型，发展规律常遵循肝炎?肝纤维化?肝硬化?肝癌这一过程。肠道菌群与门脉系统、胆管系统组成的双向肠肝交流体系通常称为肠?肝轴，越来越多的研究证据表明肠道菌群能通过与肠?肝轴的交互循环作用参与肝癌发生发展的各个环节。鉴于在肝癌早期中的特异性变化，肠道菌群如今被视为肝癌早期诊断的新靶点。免疫治疗是针对中晚期肝癌的新兴治疗方式，通过益生菌、合理使用抗生素、粪便移植等方式调节肠道菌群可显著提高宿主的抗肿瘤免疫反应。在肝癌化疗、中药辅助、饮食模式等非免疫治疗的过程中，重塑肠道菌群稳态在延缓肿瘤进展、改善肝癌治疗预后效果及维持机体健康等方面具有重要的潜在价值。由于肠道菌群在肝癌的发生发展及治疗过程中发挥重要作用，因此该文综述了肠道菌群在肝炎?肝纤维化?肝硬化?肝癌过程中的相关研究，并论述了其作为肝癌预防、诊断及治疗靶点的巨大潜力。

关键词: 肠道菌群, 肝癌, 免疫治疗

Abstract:

The gut microbiota, as one of the microfloras existing in human body, is accounted for approximately 80% in human microbiome. Gut microbiota regulates digestive and immune functions through participating in physiological processes such as metabolism and immune homeostasis, meanwhile impacts the occurrence of cancer and controls the body response to cancer treatment drugs. Hepatocellular carcinoma (HCC) is a typical type of inflammatory cancer, the development of which follows the process of hepatitis, liver fibrosis, liver cirrhosis and HCC. The bidirectional communication system composed of gut microbiota, portal vein system and bile duct system, is usually called the enteric-liver axis. More and more research evidences show that gut microbiota can participate in the occurrence and development of HCC via the interaction cycle with the enteric-liver axis. In view of the specific transformation of gut microbiota in the early stage of HCC, it is usually regarded as a new target for the early diagnosis of HCC. Immunotherapy is an emerging treatment for advanced HCC. It is reported that regulating gut microbiota through probiotics, rational application of antibiotics, fecal transplantation and other methods can significantly improve the anti-tumor immune response of host. In the non-immunotherapy process of HCC chemotherapy, traditional Chinese medicine-assisted therapy and dietary pattern, remodeling gut microbiota homeostasis has potential value in postponing tumor progression, improving the prognosis of HCC treatment and maintaining body health. Since gut microbiota plays a crucial role in the occurrence, development and treatment of HCC, this review summarizes the studies of gut microbiota in the process of hepatitis, liver fibrosis, cirrhosis and HCC, and discusses its great potential as a target for the prevention, diagnosis and treatment of HCC.

Key words: gut microbiota, hepatocellular carcinoma, immunotherapy

中图分类号:

R730.1

卢雨, 王昊, 巴乾. 肠道菌群在肝癌发生发展及治疗中的作用研究进展[J]. 上海交通大学学报（医学版）, 2022, 42(7): 939-944.

LU Yu, WANG Hao, BA Qian. Role of gut microbiota in hepatocellular carcinoma: cancer occurrence, progresses and treatments[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022, 42(7): 939-944.

参考文献 47

1	VILLANUEVA A. Hepatocellular carcinoma[J]. N Engl J Med, 2019, 380(15): 1450-1462.
2	FRIEDMAN S L, NEUSCHWANDER-TETRI B A, RINELLA M, et al. Mechanisms of NAFLD development and therapeutic strategies[J]. Nat Med, 2018, 24(7): 908-922.
3	SONBOL M B, RIAZ I B, NAQVI S A A, et al. Systemic therapy and sequencing options in advanced hepatocellular carcinoma: a systematic review and network meta-analysis[J]. JAMA Oncol, 2020, 6(12): e204930.
4	WOODHOUSE C A, PATEL V C, SINGANAYAGAM A, et al. Review article: the gut microbiome as a therapeutic target in the pathogenesis and treatment of chronic liver disease[J]. Aliment Pharmacol Ther, 2018, 47(2): 192-202.
5	BENSON A K. The gut microbiome: an emerging complex trait[J]. Nat Genet, 2016, 48(11): 1301-1302.
6	SONG M Y, CHAN A T, SUN J. Influence of the gut microbiome, diet, and environment on risk of colorectal cancer[J]. Gastroenterology, 2020, 158(2): 322-340.
7	SUEZ J, ZMORA N, SEGAL E, et al. The pros, cons, and many unknowns of probiotics[J]. Nat Med, 2019, 25(5): 716-729.
8	DUBINKINA V B, TYAKHT A V, ODINTSOVA V Y, et al. Links of gut microbiota composition with alcohol dependence syndrome and alcoholic liver disease[J]. Microbiome, 2017, 5(1): 141.
9	FAN Y, PEDERSEN O. Gut microbiota in human metabolic health and disease[J]. Nat Rev Microbiol, 2021, 19(1): 55-71.
10	LI J, SUNG C Y, 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.
11	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.
12	BAJAJ J S. Alcohol, liver disease and the gut microbiota[J]. Nat Rev Gastroenterol Hepatol, 2019, 16(4): 235-246.
13	EL-SERAG H B. Hepatocellular carcinoma[J]. N Engl J Med, 2011, 365(12): 1118-1127.
14	SCHWABE R F, GRETEN T F. Gut microbiome in HCC: mechanisms, diagnosis and therapy[J]. J Hepatol, 2020, 72(2): 230-238.
15	TRIPATHI A, DEBELIUS J, BRENNER D A, et al. Publisher Correction: the gut-liver axis and the intersection with the microbiome[J]. Nat Rev Gastroenterol Hepatol, 2018, 15(12): 785.
16	YU L X, SCHWABE R F. The gut microbiome and liver cancer: mechanisms and clinical translation[J]. Nat Rev Gastroenterol Hepatol, 2017, 14(9): 527-539.
17	DAPITO D H, MENCIN A, GWAK G Y, et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4[J]. Cancer Cell, 2012, 21(4): 504-516.
18	BOURSIER J, MUELLER O, BARRET M, et al. The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota[J]. Hepatology, 2016, 63(3): 764-775.
19	SEKI E, DE MINICIS S, OSTERREICHER C H, et al. TLR4 enhances TGF-β signaling and hepatic fibrosis[J]. Nat Med, 2007, 13(11): 1324-1332.
20	ISAYAMA F, HINES I N, KREMER M, et al. LPS signaling enhances hepatic fibrogenesis caused by experimental cholestasis in mice[J]. Am J Physiol Gastrointest Liver Physiol, 2006, 290(6): G1318-G1328.
21	TAN C C, LING Z X, HUANG Y, et al. Dysbiosis of intestinal microbiota associated with inflammation involved in the progression of acute pancreatitis[J]. Pancreas, 2015, 44(6): 868-875.
22	OIKONOMOU T, PAPATHEODORIDIS G V, SAMARKOS M, et al. Clinical impact of microbiome in patients with decompensated cirrhosis[J]. World J Gastroenterol, 2018, 24(34): 3813-3820.
23	MONTE M J, MARIN J J G, ANTELO A, et al. Bile acids: chemistry, physiology, and pathophysiology[J]. World J Gastroenterol, 2009, 15(7): 804-816.
24	XIE G X, WANG X N, HUANG F J, et al. Dysregulated hepatic bile acids collaboratively promote liver carcinogenesis[J]. Int J Cancer, 2016, 139(8): 1764-1775.
25	GADALETA R M, VAN ERPECUM K J, OLDENBURG B, et al. Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease[J]. Gut, 2011, 60(4): 463-472.
26	LOO T M, KAMACHI F, WATANABE Y, et al. Gut microbiota promotes obesity-associated liver cancer through PGE2-mediated suppression of antitumor immunity[J]. Cancer Discov, 2017, 7(5): 522-538.
27	ZHANG X, COKER O O, CHU E S, et al. Dietary cholesterol drives fatty liver-associated liver cancer by modulating gut microbiota and metabolites[J]. Gut, 2021, 70(4): 761-774.
28	REN Z G, LI A, JIANG J W, et al. Gut microbiome analysis as a tool towards targeted non-invasive biomarkers for early hepatocellular carcinoma[J]. Gut, 2019, 68(6): 1014-1023.
29	DEPOMMIER C, EVERARD A, DRUART C, et al. Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study[J]. Nat Med, 2019, 25(7): 1096-1103.
30	ZHANG L, DING J, LI H Y, et al. Immunotherapy for advanced hepatocellular carcinoma, where are we? [J]. Biochim Biophys Acta Rev Cancer, 2020, 1874(2): 188441.
31	LIU Z Y, LIN Y, ZHANG J Y, et al. Molecular targeted and immune checkpoint therapy for advanced hepatocellular carcinoma[J]. J Exp Clin Cancer Res, 2019, 38(1): 447.
32	TEMRAZ S, NASSAR F, KREIDIEH F, et al. Hepatocellular carcinoma immunotherapy and the potential influence of gut microbiome[J]. Int J Mol Sci, 2021, 22(15): 7800.
33	KOLODZIEJCZYK A A, ZHENG D P, SHIBOLET O, et al. The role of the microbiome in NAFLD and NASH[J]. EMBO Mol Med, 2019, 11(2): e9302.
34	ZHENG Y, WANG T T, TU X X, et al. Gut microbiome affects the response to anti-PD-1 immunotherapy in patients with hepatocellular carcinoma[J]. J Immunother Cancer, 2019, 7(1): 193.
35	CHANG C J, LIN T L, TSAI Y L, et al. Next generation probiotics in disease amelioration[J]. J Food Drug Anal, 2019, 27(3): 615-622.
36	HAN J J, ZHANG S Y, XU Y, et al. Beneficial effect of antibiotics and microbial metabolites on expanded Vδ2Vγ9 T cells in hepatocellular carcinoma immunotherapy[J]. Front Immunol, 2020, 11: 1380.
37	ROUTY B, LE CHATELIER E, DEROSA L, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors[J]. Science, 2018, 359(6371): 91-97.
38	SMITS L P, BOUTER K E C, DE VOS W M, et al. Therapeutic potential of fecal microbiota transplantation[J]. Gastroenterology, 2013, 145(5): 946-953.
39	OO K M, LWIN A A, KYAW Y Y, et al. Safety and long-term effect of the probiotic FK-23 in patients with hepatitis C virus infection[J]. Biosci Microbiota Food Health, 2016, 35(3): 123-128.
40	LEE D K, KANG J Y, SHIN H S, et al. Antiviral activity of Bifidobacterium adolescentis SPM0212 against Hepatitis B virus[J]. Arch Pharm Res, 2013, 36(12): 1525-1532.
41	LIU Y H, LIU Q, HESKETH J, et al. Protective effects of selenium-glutathione-enriched probiotics on CCl4-induced liver fibrosis[J]. J Nutr Biochem, 2018, 58: 138-149.
42	WU R H, MEI X T, YE Y B, et al. Zn(II)-curcumin solid dispersion impairs hepatocellular carcinoma growth and enhances chemotherapy by modulating gut microbiota-mediated zinc homeostasis[J]. Pharmacol Res, 2019, 150: 104454.
43	FU H Y, LIU X, JIN L, et al. Safflower yellow reduces DEN-induced hepatocellular carcinoma by enhancing liver immune infiltration through promotion of collagen degradation and modulation of gut microbiota[J]. Food Funct, 2021, 12(21): 10632-10643.
44	REN Z G, CHEN X M, HONG L J, et al. Nanoparticle conjugation of ginsenoside Rg3 inhibits hepatocellular carcinoma development and metastasis[J]. Small, 2020, 16(2): e1905233.
45	WANG W, XU A L, LI Z C, et al. Combination of probiotics and Salvia miltiorrhiza polysaccharide alleviates hepatic steatosis via gut microbiota modulation and insulin resistance improvement in high fat-induced NAFLD mice[J]. Diabetes Metab J, 2020, 44(2): 336-348.
46	LE BASTARD Q, CHAPELET G, JAVAUDIN F, et al. The effects of inulin on gut microbial composition: a systematic review of evidence from human studies[J]. Eur J Clin Microbiol Infect Dis, 2020, 39(3): 403-413.
47	KOLODZIEJCZYK A A, ZHENG D P, ELINAV E. Diet-microbiota interactions and personalized nutrition[J]. Nat Rev Microbiol, 2019, 17(12): 742-753.

[1]	胡哲轩, 张欣, 沃璐璐, 李静池, 王娇, 周佽想, 赵倩. TRMT61A在肝癌细胞中的功能及其机制研究[J]. 上海交通大学学报（医学版）, 2022, 42(6): 742-750.
[2]	李静威, 王俐文, 蒋玲曦, 詹茜, 陈皓, 沈柏用. 胰腺癌免疫抑制性肿瘤微环境研究综述[J]. 上海交通大学学报(医学版), 2021, 41(8): 1103-1108.
[3]	凌徐心仪, 张瑶, 钟华. 非小细胞肺癌免疫治疗获益人群筛选的研究进展[J]. 上海交通大学学报(医学版), 2021, 41(8): 1114-1119.
[4]	马韵芳, 潘丽娜, 李圳, 高蓓莉, 胡家安, 徐志红. 司美替尼下调KRAS G12V突变型非小细胞肺癌细胞PD-L1水平的探索性研究[J]. 上海交通大学学报(医学版), 2021, 41(6): 741-748.
[5]	袁瑞雪, 傅迎美, 禹顺英. 辅助性T细胞17和调节性T细胞在抑郁症中的作用机制研究进展[J]. 上海交通大学学报(医学版), 2021, 41(10): 1384-1388.
[6]	何春明，尹航，郑佳杰，唐健，傅于捷，赵晓菁. 肺癌免疫治疗：免疫抑制细胞和肺内免疫[J]. 上海交通大学学报(医学版), 2020, 40(8): 1137-1142.
[7]	刘洁，仇晓春. 乳腺肿瘤干细胞研究热点及趋势分析[J]. 上海交通大学学报(医学版), 2020, 40(7): 881-888.
[8]	戴飞，魏瑾瑾，汤欣玥，陈峥，蔺林. 舌下含服免疫治疗对效应性T细胞和调节性T细胞功能的影响[J]. 上海交通大学学报(医学版), 2020, 40(5): 626-632.
[9]	周铖1，孙鹏飞2，尹继瑶3，王阳阳1，肖海娟4, 5. 粪菌移植治疗炎症性肠病的研究进展[J]. 上海交通大学学报（医学版）, 2020, 40(2): 267-.
[10]	贺明，魏倩，张颖婷. 铁死亡相关机制与其在肝脏相关疾病中作用的研究进展[J]. 上海交通大学学报(医学版), 2020, 40(11): 1519-1523.
[11]	储维薇，徐洁颖，李尚，翟君钰，杜艳芝. 脱氢表雄酮诱导的多囊卵巢综合征模型大鼠的肠道菌群研究[J]. 上海交通大学学报（医学版）, 2019, 39(9): 975-.
[12]	王蕾蕾1，陶晔璇2. 妊娠期糖尿病孕妇与健康孕妇的肠道菌群差异[J]. 上海交通大学学报（医学版）, 2019, 39(11): 1300-.
[13]	宋月红，江海峰，彭素芳，赵敏. 肠道菌群在抑郁症、焦虑症及物质使用障碍中的作用[J]. 上海交通大学学报（医学版）, 2019, 39(10): 1199-.
[14]	张昕雨 1，张璟2，朱小强 1，曹颖颖 1，陈豪燕 1. 基于宏基因组学分析构建诊断大肠癌的肠道菌群标签[J]. 上海交通大学学报（医学版）, 2018, 38(9): 1019-.
[15]	王磊 1，焦先婷 1，魏真真 1，刘斌 3，刘晓艳 3，余晓丹 1, 2. 孕前和孕期维生素 D缺乏对子代大鼠肠道菌群及抗菌肽 cathelicidin的影响[J]. 上海交通大学学报（医学版）, 2018, 38(8): 874-.