肠道微生物群调节癌症治疗效果的研究进展
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摘要
系统生物学为发现肠道微生物群在人类健康几乎所有方面的作用提供了机会。现有证据支持肠道微生物群与化学治疗和新型靶向免疫治疗的药理作用密切相关的假设。肠道微生物群通过以下几个关键机制影响药物的治疗效果:代谢、免疫调节、易位、酶降解、多样性降低和生态变异。因此,肠道微生物群有望成为提高肿瘤治疗效果、降低肿瘤治疗不良反应的新靶点。越来越多的证据表明,癌症治疗扰乱宿主的免疫反应,导致免疫系统失调,进而影响治疗效果。肠道微生物通过调节药物疗效、影响抗癌作用和介导毒性,在肿瘤治疗中发挥重要作用。作者概述了肠道微生物群在癌症治疗中的调节作用,以及其在临床实践中提高化疗和免疫治疗效果的意义。
Systems biology provides an opportunity to discover the role that gut microbiota plays in almost all aspects of human health. Existing evidence supports the hypothesis that gut microbiota is closely related to the pharmacological effects of chemical therapy and novel targeted immunotherapy. Gut microbiota shapes the efficiency of drugs through several key mechanisms: metabolism, immunomodulation, translocation, enzymatic degradation, reduction of diversity, and ecological variability. Therefore, gut microbiota is expected to be a novel target to enhance the efficacy and reduce the toxicity and adverse effects of cancer therapy. There is growing evidence to show that cancer therapy perturbs the host immune response and results in dysbiosis of the immune system, which then influences the efficiency of the therapy. Studies suggest that gut microbes play a significant role in cancer therapy by modulating drug efficacy, abolishing the anticancer effect, and mediating toxicity. This review will outline the role of gut microbiota in modulating cancer therapy and the implications for improving the efficacy of chemotherapy and immunotherapy in clinical practice.
Systems biology provides an opportunity to discover the role that gut microbiota plays in almost all aspects of human health. Existing evidence supports the hypothesis that gut microbiota is closely related to the pharmacological effects of chemical therapy and novel targeted immunotherapy. Gut microbiota shapes the efficiency of drugs through several key mechanisms: metabolism, immunomodulation, translocation, enzymatic degradation, reduction of diversity, and ecological variability. Therefore, gut microbiota is expected to be a novel target to enhance the efficacy and reduce the toxicity and adverse effects of cancer therapy. There is growing evidence to show that cancer therapy perturbs the host immune response and results in dysbiosis of the immune system, which then influences the efficiency of the therapy. Studies suggest that gut microbes play a significant role in cancer therapy by modulating drug efficacy, abolishing the anticancer effect, and mediating toxicity. This review will outline the role of gut microbiota in modulating cancer therapy and the implications for improving the efficacy of chemotherapy and immunotherapy in clinical practice.
引文
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[24] U.S.National Library of Medicine.Explore 303,828 research studies in all 50 states and in 208 countries[DB/OL].[2019-04-25].https://clinicaltrials.gov.
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[2] Gagliani N,Hu B,Huber S,et al.The fire within:microbes inflame tumors[J].Cell,2014,157(4):776-783.
[3] Siegel RL,Miller KD,Jemal A.Cancer statistics,2018[J].CA Cancer J Clin,2018,68(1):7-30.
[4] Cryan JF,Dinan TG.Mind-altering microorganisms:the impact of the gut microbiota on brain and behaviour[J].Nat Rev Neurosci,2012,13(10):701-712.
[5] Zeevi D,Korem T,Zmora N,et al.Personalized nutrition by prediction of glycemic responses[J].Cell,2015,163(5):1079-1094.
[6] Bhatt AP,Redinbo MR,Bultman SJ.The role of the microbiome in cancer development and therapy[J].CA Cancer J Clin,2017,67(4):326-344.
[7] Sharma P,Allison JP.The future of immune checkpoint therapy[J].Science,2015,348(6230):56-61.
[8] Vétizou M,Pitt JM,Daillère R,et al.Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota[J].Science,2015,350(6264):1079-1084.
[9] Pitt JM,Vétizou M,Daillère R,et al.Resistance mechanisms to immune-checkpoint blockade in cancer:tumor-intrinsic and-extrinsic factors[J].Immunity,2016,44(6):1255-1269.
[10] Pitt JM,Vétizou M,Waldschmitt N,et al.Fine-tuning cancer immunotherapy:optimizing the gut microbiome[J].Cancer Res,2016,76(16):4602-4607.
[11] 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.
[12] 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.
[13] Lee H,Lee Y,Kim J,et al.Modulation of the gut microbiota by metformin improves metabolic profiles in aged obese mice[J].Gut Microbes,2018,9(2):155-165.
[14] Gopalakrishnan V,Spencer CN,Nezi L,et al.Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients[J].Science,2018,359(6371):97-103.
[15] Matson V,Fessler J,Bao RY,et al.The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients[J].Science,2018,359(6371):104-108.
[16] Cramer P,Bresalier RS.Gastrointestinal and hepatic complications of immune checkpoint inhibitors[J].Curr Gastroenterol Rep,2017,19(1):3.
[17] Dubin K,Callahan MK,Ren BY,et al.Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockade-induced colitis[J].Nat Commun,2016,7:10391.
[18] Pitt JM,Vétizou M,Gomperts Boneca I,et al.Enhancing the clinical coverage and anticancer efficacy of immune checkpoint blockade through manipulation of the gut microbiota[J].Oncoimmunology,2017,6(1):e1132137.
[19] Guiducci C,Vicari AP,Sangaletti S,et al.Redirecting in vivo elicited tumor infiltrating macrophages and dendritic cells towards tumor rejection[J].Cancer Res,2005,65(8):3437-3446.
[20] Stewart CA,Metheny H,Iida N,et al.Interferon-dependent IL-10 production by Tregs limits tumor Th17 inflammation[J].J Clin Invest,2013,123(11):4859-4874.
[21] Iida N,Dzutsev A,Stewart CA,et al.Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment[J].Science,2013,342(6161):967-970.
[22] 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.
[23] Daillère R,Vétizou M,Waldschmitt N,et al.Enterococcus hirae and barnesiella intestinihominis facilitate cyclophosphamide-induced therapeutic immunomodulatory effects[J].Immunity,2016,45(4):931-943.
[24] U.S.National Library of Medicine.Explore 303,828 research studies in all 50 states and in 208 countries[DB/OL].[2019-04-25].https://clinicaltrials.gov.
[25] Smith K,McCoy KD,Macpherson AJ.Use of axenic animals in studying the adaptation of mammals to their commensal intestinal microbiota[J].Semin Immunol,2007,19(2):59-69.