肠道菌群对化疗药物抗肿瘤疗效的影响及其研究进展

马文兵, 卢晓云, 禚映辰, 郑巧伟, 封卫毅

中国药学杂志 ›› 2020, Vol. 55 ›› Issue (12) : 979-984.

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中国药学杂志 ›› 2020, Vol. 55 ›› Issue (12) : 979-984. DOI: 10.11669/cpj.2020.12.002
综述

肠道菌群对化疗药物抗肿瘤疗效的影响及其研究进展

  • 马文兵1,2, 卢晓云2, 禚映辰1, 郑巧伟1, 封卫毅1*
作者信息 +

Progress of Gut Microbiota in the Antineoplastic Efficacy of Chemotherapeutic Drugs

  • MA Wen-bing1,2, LU Xiao-yun2, ZHUO Ying-chen1, ZHENG Qiao-wei1, FENG Wei-yi1*
Author information +
文章历史 +

摘要

药物化疗依然是目前癌症最基础的治疗方法之一,然而不同患者对化疗药物的敏感性存在个体间的差异,有些甚至对药物化疗产生耐药,此类问题成为肿瘤临床治疗过程中的棘手问题。近年研究显示,肠道菌群可以通过多种机制调节宿主对化疗的反应,包括免疫相互作用、异质代谢和改变菌落结构,对新近兴起的免疫治疗及化疗药物的疗效发挥关键性的调节作用。笔者介绍临床上使用的传统化疗药物以及新型免疫治疗药物抗CTLA-4以及抗PD-1抗体对肠道菌群的影响,以及此种作用对化疗疗效的影响及其作用机制,以期为以肠道菌群为潜在靶点的癌症治疗提供依据和线索。

Abstract

Chemotherapeutic drugs play an important role in the treatment of cancer, but the individual differences of patients' sensitivity to chemotherapeutic drugs and the drug resistance of chemotherapeutic drugs have always been a thorny problem in clinical treatment. Recent studies have shown that gut microbiota plays a key role in regulating the efficacy of chemotherapeutic drugs. Gut microbiota can regulate host response to chemotherapy through a variety of mechanisms, including immune interaction, heterogeneous metabolism and changes in community structure. This paper introduces the effects of traditional chemotherapeutic drugs and new immunotherapeutic drugs, such as anti-CTLA-4 and anti-PD-1 antibodies, on gut microbiota, as well as their effects on chemotherapeutic efficacy and mechanism, in order to provide evidences and clues for cancer treatments targeting gut microbiota.

关键词

肠道菌群 / 肿瘤生长 / 化疗药物 / 免疫疗法 / 疗效

Key words

gut microbiota / tumor growth / chemotherapeutic drug / immunotherapy / effectiveness

引用本文

导出引用
马文兵, 卢晓云, 禚映辰, 郑巧伟, 封卫毅. 肠道菌群对化疗药物抗肿瘤疗效的影响及其研究进展[J]. 中国药学杂志, 2020, 55(12): 979-984 https://doi.org/10.11669/cpj.2020.12.002
MA Wen-bing, LU Xiao-yun, ZHUO Ying-chen, ZHENG Qiao-wei, FENG Wei-yi. Progress of Gut Microbiota in the Antineoplastic Efficacy of Chemotherapeutic Drugs[J]. Chinese Pharmaceutical Journal, 2020, 55(12): 979-984 https://doi.org/10.11669/cpj.2020.12.002
中图分类号: R969   

参考文献

[1] SENDER R, FUCHS S, MILO R. Revised estimates for the number of human and bacteria cells in the body[J]. PLoS Biol, 2016, 14(8): e1002533.
[2] JANDHYALA S M, et al. Role of the normal gut microbiota[J]. World J Gastroenterol, 2015, 21(29): 8787-8803.
[3] ROY S, TRINCHIERI G. Microbiota: a key orchestrator of cancer therapy[J]. Nat Rev Cancer, 2017, 17(5): 271-285.
[4] PANEBIANCO C, POTENZA A, ANDRIULLI A, et al. Exploring the microbiota to better understand gastrointestinal cancers physiology[J]. Clin Chem Lab Med, 2018, 56(9): 1400-1412.
[5] VON FRIELING J, FINK C, HAMM J, et al. Grow with the challenge-microbial effects on epithelial proliferation, carcinogenesis, and cancer therapy[J]. Front Microbiol, 2018, 9:2020.
[6] GORI S, INNO A, BELLUOMINI L, et al. Gut microbiota and cancer: how gut microbiota modulates activity, efficacy and toxicity of antitumoral therapy[J]. Crit Rev Oncol Hemat, 2019, 143: 139-147.
[7] REN D X, HUA Y, YU B Y, et al. Predictive biomarkers and mechanisms underlying resistance to PD1/PD-L1 blockade cancer immunotherapy[J]. Mol Cancer, 2020, 19(1): 19.
[8] ZITVOGEL L, GALLUZZI L, VIAUD S, et al. Cancer and the gut microbiota: an unexpected link[J]. Sci Transl Med, 2015,7(271):271ps1.
[9] ALEXANDER J L, WILSON I, TEARE J, et al. Gut microbiota modulation of chemotherapy efficacy and toxicity[J]. Nat Rev Gastroenterol Hepatol, 2017, 14(6): 356-365.
[10] VON B I, ADLERBERTH I,WOLD A, et al. Oral and intestinal microflora in 5-fluorouracil treated rats, translocation to cervical and mesenteric lymph nodes and effects of probiotic bacteria[J]. Oral Microbiol Immunol, 2003, 18(5): 278-284.
[11] NAM Y D, KIM H J, SEO J G, et al. Impact of pelvic radiotherapy on gut microbiota of gynecological cancer patients revealed by massive pyrosequencing[J]. PLoS One, 2013, 8(12): 82659.
[12] TAUR Y, JENQ R R,PERALES M A, et al. The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation[J]. Blood, 2014, 124(7): 1174-1182.
[13] POPE J L, TOMKOVICH S, YANG Y, et al. Microbiota as a mediator of cancer progression and therapy[J]. Transl Res, 2017, 179: 139-154.
[14] SHUI L, YANG X, LI J, et al. Gut microbiome as a potential factor for modulating resistance to cancer immunotherapy[J]. Front Immunol, 2020, 10:2989.
[15] SCOTT T A, QUINTANEIRO L M, NORVAISAS P, et al. Host-microbe co-metabolism dictates cancer drug efficacy in C. elegans[J]. Cell, 2017, 169(3): 442-456.
[16] GATTI L, ZUNINO F. Overview of tumor cell chemoresistance mechanisms[J]. Methods Mol Med, 2005, 111:127-148.
[17] VIAUD S, SACCHERI F, MIGNOT G, et al. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide[J]. Science, 2013, 342(6161): 971-976.
[18] DAILLERE R, VETIZOU M, WALDSCHMITT N, et al. Enterococcus hirae and Barnesiella intestinihominis facilitate cyclophosphamide-induced therapeutic immunomodulatory effects[J]. Immunity, 2016, 45(4): 931-943.
[19] CANTA A, POZZI E, CAROZZI V A. Mitochondrial dysfunction in chemotherapy-induced peripheral neuropathy (CIPN) [J]. Toxics, 2015, 3(2): 198-223.
[20] ZHOU H H, ZHANG L, ZHANG H X, et al. Tat-HA-NR2B9c attenuate oxaliplatin-induced neuropathic pain[J]. Exp Neurol, 2019, 311: 80-87.
[21] YEHIA R, SALEH S, ABHAR H E, et al. L-Carnosine protects against oxaliplatin-induced peripheral neuropathy in colorectal cancer patients: a perspective on targeting Nrf-2 and NF-kappa B pathways[J]. Toxicol Appl Pharmacol, 2019, 365: 41-50.
[22] GHISONI E, CASALONE V, GIANNONE G, et al. Role of mediterranean diet in preventing platinum based gastrointestinal toxicity in gynecolocological malignancies: a single institution experience[J]. World J Clin Oncol, 2019, 10(12):391-401.
[23] IIDA N, DZUTSEV A, STEWART C, et al. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment[J]. Science, 2013, 342(6161): 967-970.
[24] GUI Q F,LU H F,ZHANG C X, et al. Well-balanced commensal microbiota contributes to anti-cancer response in a lung cancer mouse model[J]. Genet Mol Res, 2015, 14(2): 5642-5651.
[25] WU C H, KO J L, LIAO J M, et al. D-methionine alleviates cisplatin-induced mucositis by restoring the gut microbiota structure and improving intestinal inflammation[J]. Ther Adv Med Oncol, 2019, 11:1758835918821021. DOI: 10.1177/1758835918821021.
[26] REN X X, LIU L, LIU P K, et al. Polysaccharide extracted from Enteromorpha ameliorates cisplastin-induced small intestine injury in mice[J]. J Funct Foods, 2018, 49: 154-161.
[27] WEXLER H M. Bacteroides: the good, the bad, and the nitty-gritty[J]. Clin Microbiol Rev, 2007, 20(4): 593-621.
[28] MOLINARO A, HOLST O, DILORENZO F, et al. Chemistry of lipid A: at the heart of innate immunity[J]. Chem Eur J, 2015, 21(2): 500-519.
[29] MAESHIMA N, FERNANDEZ R C. Recognition of lipid A variants by the TLR4-MD-2 receptor complex[J]. Front Cell Infect Microbiol, 2013, 3:3.
[30] HEUMANN D, ROGER T. Initial responses to endotoxins and Gram-negative bacteria[J]. Clin Chim Acta, 2002, 323(1-2): 59-72.
[31] STOJANOVSKA V, MCQUADE R M, FRASER S, et al. Oxaliplatin-induced changes in microbiota, TLR4+cells and enhanced HMGB1 expression in the murine colon[J]. PLoS One, 2018, 13(6):e0198359.
[32] MCQUADE R M, STOJANOVSKA V, BORNSTEIN J C, et al. Colorectal cancer chemotherapy: the evolution of treatment and new approaches[J]. Curr Med Chem, 2017, 24(15): 1537-1557.
[33] LEE J J, BEUMER J H, CHU E. Therapeutic drug monitoring of 5-fluorouracil[J]. Cancer Chemother Pharmacol, 2016, 78(3): 447-464.
[34] GONZALEZ V M, MARGARITA M S, VICENTE G, et al. Antitumor effect of 5-fluorouracil is enhanced by rosemary extract in both drug sensitive and resistant colon cancer cells[J]. Pharmacol Res, 2013, 72: 61-68.
[35] RIBEIRO R A, WANDERLEY C W S, WONG D V T, et al. Irinotecan- and 5-fluorouracil-induced intestinal mucositis: insights into pathogenesis and therapeutic perspectives[J]. Cancer Chemother Pharmacol, 2016, 78(5): 881-893.
[36] LEE C S, RYAN E J, DOHERTY G A. Gastro-intestinal toxicity of chemotherapeutics in colorectal cancer: the role of inflammation[J]. World J Gastroenterol, 2014, 20(14): 3751-3761.
[37] VAN SEBILLE Y Z A, GIBSON R J, WARDILL H R, et al. Highlight article: use of zebrafish to model chemotherapy and targeted therapy gastrointestinal toxicity[J]. Exp Biol Med, 2019, 244(14): 1178-1185.
[38] ZHANG S, YANG Y, WENG W, et al. Fusobacterium nucleatum promotes chemoresistance to 5-fluorouracil by upregulation of BIRC3 expression in colorectal cancer[J]. J Exp Clin Cancer Res, 2019,38(1):14.
[39] YUAN L, ZHANG S, LI H, et al. The influence of gut microbiota dysbiosis to the efficacy of 5-fluorouracil treatment on colorectal cancer[J]. Biomed Pharmacother, 2018, 108: 184-193.
[40] JUSTINO P F C, MELO L F M, NOGUEIRA A F, et al. Treatment with Saccharomyces boulardii reduces the inflammation and dysfunction of the gastrointestinal tract in 5-fluorouracil-induced intestinal mucositis in mice[J]. Br J Nutr, 2014, 111(9): 1611-1621.
[41] LI H L, LU L, WANG X S, et al. Alteration of gut microbiota and inflammatory cytokine/chemokine profiles in 5-fluorouracil induced intestinal mucositis[J]. Front Cell Infect Microbiol, 2017, 7:455.
[42] GARCIA G A.P, RITTER A D,SHRESTHA S, et al. Bacterial metabolism affects the C. elegans response to cancer chemotherapeutics[J]. Cell, 2017, 169(3): 431-441.
[43] STRINGER A M, GIBSON R J, LOGAN R M, et al. Gastrointestinal microflora and mucins may play a critical role in the development of 5-fluorouracil-induced gastrointestinal mucositis[J]. Exp Biol Med, 2009, 234(4): 430-441.
[44] GELLER L T, BARZIY R M, DANINO T, et al. Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine[J]. Science, 2017, 357(6356): 1156-1160.
[45] VOORDE J V, BALZARINI J, LIEKENS S. Mycoplasmas and cancer: focus on nucleoside metabolism[J]. Excli J, 2014, 13: 300-322.
[46] VANDE V J, SABUNCUOGLU S, NOPPEN S, et al. Nucleoside-catabolizing enzymes in mycoplasma-infected tumor cell cultures compromise the cytostatic activity of the anticancer drug gemcitabine[J]. J Biol Chem, 2014, 289(19): 13054-13065.
[47] HUANG S,LI J, WU J, et al. Mycoplasma infections and different human carcinomas[J]. World J Gastroenterol, 2001, 7(2): 266-269.
[48] LEHOURITIS P, CUMMINS J, STANTON M, et al. Local bacteria affect the efficacy of chemotherapeutic drugs[J]. Sci Rep, 2015, 5:14554.
[49] CHANG R, CHEN W, ZHOU T. Influence of gut microbiota regulation on pharmacokinetic characteristics[J]. Chin Pharm J (中国药学杂志), 2019, 54(15): 1211-1215.
[50] XU Y, VILLALONA C M. Irinotecan: mechanisms of tumor resistance and novel strategies for modulating its activity[J]. Ann Oncol, 2002, 13(12): 1841-1851.
[51] GUTHRIE L, SANCHIT G, JOHANNA D, et al. Human microbiome signatures of differential colorectal cancer drug metabolism[J]. Npj Biofilms Microbiomes, 2017, 3:27.
[52] LIN X B, DIELEMAN L, KETABI A, et al. Irinotecan (CPT-11) chemotherapy alters intestinal microbiota in tumour bearing rats[J]. PLoS One, 2012, 7(7): e39764.
[53] FORSGARD R A, MARRACHELLI V G, KORPELA K, et al. Chemotherapy-induced gastrointestinal toxicity is associated with changes in serum and urine metabolome and fecal microbiota in male Sprague-Dawley rats[J]. Cancer Chemother Pharmacol, 2017, 80(2): 317-332.
[54] VETIZOU M, PITT J, DAILLERE R, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota[J]. Science, 2015, 350(6264): 1079-1084.
[55] MATSON V, FESSLER J, BAO R, et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients[J]. Science, 2018, 359(6371): 104-108.
[56] BUCHBINDER E I, DESAI A. CTLA-4 and PD-1 pathways similarities, differences, and implications of their inhibition[J]. Am J Clin Oncol, 2016, 39(1): 98-106.
[57] GOUBET A G, DAILLERE R, ROBERTI M, et al. The impact of the intestinal microbiota in therapeutic responses against cancer[J]. C R Biologies, 2018, 341(5): 284-289.
[58] ALSAAB H O,SAU S, ALZHRANI R, et al. PD-1 and PD-L1 checkpoint signaling inhibition for cancer immunotherapy: mechanism, combinations, and clinical outcome[J]. Front Pharmacol, 2017,8:561.
[59] SIVAN A, CORRALES L, HUBERT N, et al. Commensal bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy[J]. Science, 2015, 350(6264): 1084-1089.
[60] ROUTY B, CHATELIER E L, DEROSA L, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors[J]. Science, 2018, 359(6371): 91-97.
[61] GOPALAKRISHNAN V, SPENCER C, NEZI L,et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients[J]. Science, 2018, 359(6371): 97-103.
[62] JOBIN C. Precision medicine using microbiota[J]. Science, 2018, 359(6371): 32-34.

基金

国家自然科学基金项目资助(81372379,81972814);西安交通大学第一附属医院院基金项目资助(2017MS-04)
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