摘要
肠道菌群在维持身体健康方面具有重要作用,肠道菌群的失调,可通过影响肠道稳态、肠道代谢、免疫功能等方面促进肿瘤尤其是肝胆胰肿瘤的发生、发展。因此,更好地了解肠道微生物群在肝胆胰肿瘤发展和进展中的作用,可能为肝胆胰恶性肿瘤患者开发新的预防和治疗策略提供机会。本文针对近几年肠道菌群在肝胆胰恶性肿瘤发展和进展的作用研究进行综述, 以期为今后研究提供参考。
人体内大概有10~100万亿个微生物,其所携带的遗传物质远超过人体基因,形成一个完整的微生态系统,而消化道则是人体内含微生物最多的场
HCC是世界范围内肿瘤致死原因第三位,由于早期症状不明显及缺乏有效早期诊断标记物,HCC患者在确诊时都处于中晚期阶段,预后很差。大量研
一项Meta分
肠道菌群还具有作为早期HCC检测生物标志物的潜
免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)是近期被批准作为HCC的一线或二线治疗药
CCA作为第二大常见的肝胆原发恶性肿瘤,约占消化系统肿瘤的3%,其主要起源于胆管上皮细胞,恶性程度高,近年来,CCA的发病率和病死率有明显上升趋
大量证
一项Meta分
胰腺癌作为一种恶性程度非常高的恶性肿瘤,只有约20%的患者在确诊时拥有手术机会,5年生存率不足10%。目前已知的胰腺癌危险因素包括吸烟、肥胖、慢性胰腺炎、2型糖尿病、遗传因素
既往认为胰腺组织是无菌的,而近年来研究发现正常胰腺组织和胰腺癌组织均有细菌存在。Nejman
研
肠道菌群除影响胰腺癌的发生发展外,还影响胰腺癌的治疗效果。研
肠道菌群作为机体的“乘客”,构成了一个非常复杂的微生态系统,能够影响全身的代谢、组织发育、炎症发生以及免疫功能等,影响肿瘤的发生发
大量研
此外,目前关于肠道菌群的研究还有一定的不足。首先样本采集大部分都是通过粪便,这并不能代表整个消化道的菌群检测,肠道固有黏膜层及小肠也拥有丰富的菌群数量和种类,并且时刻在动态变化,如何获得不同部位的肠道菌群样本具有一定的难度。另外由于目前的研究结果很多都基于动物实验或者某局部地区的患者样本采集分析,得到的结论也具有一定的局限性和争议性,仍需临床多中心大样本研究进一步证实。虽然现已认识到肠道菌群在肝胆胰肿瘤发生发展过程中的作用,但是对其作用机制仍不甚了解,如要将肠道菌群作为生物标记物和治疗靶点应用于临床,仍然任重道远。
作者贡献声明
陈平参与研究选题与设计,论文写作指导,对文章的知识性内容作批阅性审阅、指导;杨红梅参与研究选题与设计,论文初稿撰写,论文核修;冯子轩、徐孜旬参与论文核修,支持性贡献;王刚毅、吴欢、杨成晨、方睿参与引文收集整理。
利益冲突
所有作者均声明不存在利益冲突。
参考文献
Turnbaugh PJ, Ley RE, Hamady M, et al. The human microbiome project[J]. Nature, 2007, 449(7164):804-810. doi:10.1038/nature06244. [百度学术]
Bäckhed F, Ley RE, Sonnenburg JL, et al. Host-bacterial mutualism in the human intestine[J]. Science, 2005, 307(5717):1915-1920. doi:10.1126/science.1104816. [百度学术]
Helmink BA, Wadud Khan MA, Hermann A, et al. The microbiome, cancer, and cancer therapy[J]. Nat Med, 2019, 25(3):377-388. doi:10.1038/s41591-019-0377-7. [百度学术]
Rajagopala SV, Vashee S, Oldfield LM, et al. The Human Microbiome and Cancer[J]. Cancer Prev Res (Phila), 2017, 10(4):226-234. doi: 10.1158/1940-6207.CAPR-16-0249. [百度学术]
Galipeau HJ, Caminero A, Turpin W, et al. Novel fecal biomarkers that precede clinical diagnosis of ulcerative colitis[J]. Gastroenterology, 2021, 160(5):1532-1545. doi:10.1053/j.gastro.2020.12.004. [百度学术]
Schulz MD, Atay C, Heringer J, et al. High-fat-diet-mediated dysbiosis promotes intestinal carcinogenesis independently of obesity[J]. Nature, 2014, 514(7523):508-512. doi:10.1038/nature13398. [百度学术]
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. doi:10.1126/science.aan4236. [百度学术]
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. doi:10.1126/science.aan3706. [百度学术]
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. doi:10.1126/science.aad1329. [百度学术]
Choi H, Rao MC, Chang EB. Gut microbiota as a transducer of dietary cues to regulate host circadian rhythms and metabolism[J]. Nat Rev Gastroenterol Hepatol, 2021, 18(10):679-689. doi:10.1038/s41575-021-00452-2. [百度学术]
Mohd R, Chin SF, Shaharir SS, et al. Involvement of gut microbiota in SLE and lupus nephritis[J]. Biomedicines, 2023, 11(3):653. doi:10.3390/biomedicines11030653. [百度学术]
Yang C, Xu J, Xu X, et al. Characteristics of gut microbiota in patients with metabolic associated fatty liver disease[J]. Sci Rep, 2023, 13(1):9988. doi:10.1038/s41598-023-37163-4. [百度学术]
Jia W, Rajani C, Xu HX, et al. Gut microbiota alterations are distinct for primary colorectal cancer and hepatocellular carcinoma[J]. Protein Cell, 2021, 12(5):374-393. doi:10.1007/s13238-020-00748-0. [百度学术]
Yu LX, Schwabe RF. The gut microbiome and liver cancer: mechanisms and clinical translation[J]. Nat Rev Gastroenterol Hepatol, 2017, 14(9):527-539. doi:10.1038/nrgastro.2017.72. [百度学术]
Huang H, Ren Z, Gao X, et al. Integrated analysis of microbiome and host transcriptome reveals correlations between gut microbiota and clinical outcomes in HBV-related hepatocellular carcinoma[J]. Genome Med, 2020, 12(1):102. doi:10.1186/s13073-020-00796-5. [百度学术]
Luo W, Guo S, Zhou Y, et al. Hepatocellular carcinoma: how the gut microbiota contributes to pathogenesis, diagnosis, and therapy[J]. Front Microbiol, 2022, 13:873160. doi:10.3389/fmicb.2022.873160. [百度学术]
Schneider KM, Mohs A, Gui WF, et al. Imbalanced gut microbiota fuels hepatocellular carcinoma development by shaping the hepatic inflammatory microenvironment[J]. Nat Commun, 2022, 13(1):3964. doi:10.1038/s41467-022-31312-5. [百度学术]
Xuan SY, Xin YN, Chen AJ, et al. Association between the presence of H pylori in the liver and hepatocellular carcinoma: a meta-analysis[J]. World J Gastroenterol, 2008, 14(2):307-312. doi:10.3748/wjg.14.307. [百度学术]
Ren Z, Li A, Jiang J, et al. Gut microbiome analysis as a tool towards targeted non-invasive biomarkers for early hepatocellular carcinoma[J]. Gut, 2019, 68(6):1014-1023. doi:10.1136/gutjnl-2017-315084. [百度学术]
Grąt M, Wronka KM, Krasnodębski M, et al. Profile of gut microbiota associated with the presence of hepatocellular cancer in patients with liver cirrhosis[J]. Transplant Proc, 2016, 48(5):1687-1691. doi:10.1016/j.transproceed.2016.01.077. [百度学术]
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. doi:10.1016/j.ccr.2012.02.007. [百度学术]
Ponziani FR, Bhoori S, Castelli C, et al. Hepatocellular carcinoma is associated with gut microbiota profile and inflammation in nonalcoholic fatty liver disease[J]. Hepatology, 2019, 69(1):107-120. doi:10.1002/hep.30036. [百度学术]
Behary J, Amorim N, Jiang XT, et al. Gut microbiota impact on the peripheral immune response in non-alcoholic fatty liver disease related hepatocellular carcinoma[J]. Nat Commun, 2021, 12(1):187. doi:10.1038/s41467-020-20422-7. [百度学术]
Lapidot Y, Amir A, Nosenko R, et al. Alterations in the gut microbiome in the progression of cirrhosis to hepatocellular carcinoma[J]. mSystems, 2020, 5(3):e00153-e00120. doi:10.1128/mSystems.00153-20. [百度学术]
Zheng RP, Wang GQ, Pang ZQ, et al. Liver cirrhosis contributes to the disorder of gut microbiota in patients with hepatocellular carcinoma[J]. Cancer Med, 2020, 9(12):4232-4250. doi:10.1002/cam4.3045. [百度学术]
Demir T, Lee SS, Kaseb AO. Systemic therapy of liver cancer[J]. Adv Cancer Res, 2021, 149:257-294. doi:10.1016/bs.acr.2020.12.001. [百度学术]
Li L, Ye J. Characterization of gut microbiota in patients with primary hepatocellular carcinoma received immune checkpoint inhibitors: a Chinese population-based study[J]. Medicine, 2020, 99(37):e21788. doi:10.1097/MD.0000000000021788. [百度学术]
Zheng Y, Wang TT, Tu XX, 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. doi:10.1186/s40425-019-0650-9. [百度学术]
Peng Z, Cheng SY, Kou Y, et al. The gut microbiome is associated with clinical response to anti-PD-1/PD-L1 immunotherapy in gastrointestinal cancer[J]. Cancer Immunol Res, 2020, 8(10):1251-1261. doi:10.1158/2326-6066.CIR-19-1014. [百度学术]
Chung MW, Kim MJ, Won EJ, et al. Gut microbiome composition can predict the response to nivolumab in advanced hepatocellular carcinoma patients[J]. World J Gastroenterol, 2021, 27(42):7340-7349. doi:10.3748/wjg.v27.i42.7340. [百度学术]
Wu H, Zheng X, Pan T, et al. Dynamic microbiome and metabolome analyses reveal the interaction between gut microbiota and anti-PD-1 based immunotherapy in hepatocellular carcinoma[J]. Int J Cancer, 2022, 151(8):1321-1334. doi:10.1002/ijc.34118. [百度学术]
Lee PC, Wu CJ, Hung YW, et al. Gut microbiota and metabolites associate with outcomes of immune checkpoint inhibitor-treated unresectable hepatocellular carcinoma[J]. J Immunother Cancer, 2022, 10(6):e004779. doi:10.1136/jitc-2022-004779. [百度学术]
Ma C, Han MJ, Heinrich B, et al. Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells[J]. Science, 2018, 360(6391):eaan5931. doi:10.1126/science.aan5931. [百度学术]
Ponziani FR, de Luca A, Picca A, et al. Gut dysbiosis and fecal calprotectin predict response to immune checkpoint inhibitors in patients with hepatocellular carcinoma[J]. Hepatol Commun, 2022, 6(6):1492-1501. doi:10.1002/hep4.1905. [百度学术]
Khan SA, Thomas HC, Davidson BR, et al. Cholangiocarcinoma[J]. Lancet, 2005, 366(9493):1303-1314. doi:10.1016/s0140-6736(05)67530-7. [百度学术]
Ilyas SI, Gores GJ. Pathogenesis, diagnosis, and management of cholangiocarcinoma[J]. Gastroenterology, 2013, 145(6):1215-1229. doi:10.1053/j.gastro.2013.10.013. [百度学术]
Özdirik B, Müller T, Wree A, et al. The role of microbiota in primary sclerosing cholangitis and related biliary malignancies[J]. Int J Mol Sci, 2021, 22(13):6975. doi:10.3390/ijms22136975. [百度学术]
Liu L, Zhao Z, Hou X, et al. Effect of sphincter of Oddi dysfunction on the abundance of biliary microbiota (biliary microecology) in patients with common bile duct stones[J]. Front Cell Infect Microbiol, 2022, 12:1001441. doi:10.3389/fcimb.2022.1001441. [百度学术]
Shen HZ, Ye FQ, Xie L, et al. Metagenomic sequencing of bile from gallstone patients to identify different microbial community patterns and novel biliary bacteria[J]. Sci Rep, 2015, 5:17450. doi:10.1038/srep17450. [百度学术]
Sun L, Ke X, Guan A, et al. Intratumoural microbiome can predict the prognosis of hepatocellular carcinoma after surgery[J]. Clin Transl Med, 2023, 13(7):e1331. doi:10.1002/ctm2.1331. [百度学术]
Ketpueak T, Thiennimitr P, Apaijai N, et al. Association of chronic Opisthorchis infestation and microbiota alteration on tumorigenesis in cholangiocarcinoma[J]. Clin Transl Gastroenterol, 2020, 12(1):e00292. doi:10.14309/ctg.0000000000000292. [百度学术]
Saab M, Mestivier D, Sohrabi M, et al. Characterization of biliary microbiota dysbiosis in extrahepatic cholangiocarcinoma[J]. PLoS One, 2021, 16(3):e0247798. doi:10.1371/journal.pone.0247798. [百度学术]
Chen B, Fu SW, Lu L, et al. A preliminary study of biliary microbiota in patients with bile duct stones or distal cholangiocarcinoma[J]. Biomed Res Int, 2019, 2019:1092563. doi:10.1155/2019/1092563. [百度学术]
Treeriya R, Ho PN, Titapun A, et al. 1H NMR fecal metabolic phenotyping of periductal fibrosis- and cholangiocarcinoma-specific metabotypes defining perturbation in gut microbial-host co-metabolism[J]. PeerJ, 2023, 11:e15386. doi:10.7717/peerj.15386. [百度学术]
Zhou D, Wang JD, Weng MZ, et al. Infections of Helicobacter spp. in the biliary system are associated with biliary tract cancer: a meta-analysis[J]. Eur J Gastroenterol Hepatol, 2013, 25(4):447-454. doi:10.1097/MEG.0b013e32835c0362. [百度学术]
Avilés-Jiménez F, Guitron A, Segura-López F, et al. Microbiota studies in the bile duct strongly suggest a role for Helicobacter pylori in extrahepatic cholangiocarcinoma[J]. Clin Microbiol Infect, 2016, 22(2):178.e11-178.e22. doi:10.1016/j.cmi.2015.10.008. [百度学术]
Jia X, Lu S, Zeng Z, et al. Characterization of gut microbiota, bile acid metabolism, and cytokines in intrahepatic cholangiocarcinoma[J]. Hepatology, 2020, 71(3):893-906. doi:10.1002/hep.30852. [百度学术]
Zhang Q, Ma C, Duan Y, et al. Gut microbiome directs hepatocytes to recruit MDSCs and promote cholangiocarcinoma[J]. Cancer Discov, 2021, 11(5):1248-1267. doi:10.1158/2159-8290.CD-20-0304. [百度学术]
Jin S, Zhao R, Zhou C, et al. Feasibility and tolerability of sintilimab plus anlotinib as the second-line therapy for patients with advanced biliary tract cancers: an open-label, single-arm, phase Ⅱ clinical trial[J]. Int J Cancer, 2023, 152(8):1648-1658. doi:10.1002/ijc.34372. [百度学术]
Le Chatelier E, Nielsen T, Qin JJ, et al. Richness of human gut microbiome correlates with metabolic markers[J]. Nature, 2013, 500(7464):541-546. doi:10.1038/nature12506. [百度学术]
Liu R, Zhao R, Zhou X, et al. Conjugated bile acids promote cholangiocarcinoma cell invasive growth through activation of sphingosine 1-phosphate receptor 2[J]. Hepatology, 2014, 60(3):908-918. doi:10.1002/hep.27085. [百度学术]
Mizrahi JD, Surana R, Valle JW, et al. Pancreatic cancer[J]. Lancet, 2020, 395(10242):2008-2020. doi:10.1016/S0140-6736(20)30974-0. [百度学术]
Half E, Keren N, Reshef L, et al. Fecal microbiome signatures of pancreatic cancer patients[J]. Sci Rep, 2019, 9(1):16801. doi:10.1038/s41598-019-53041-4. [百度学术]
Bangolo AI, Trivedi C, Jani I, et al. Impact of gut microbiome in the development and treatment of pancreatic cancer: newer insights[J]. World J Gastroenterol, 2023, 29(25):3984-3998. doi:10.3748/wjg.v29.i25.3984. [百度学术]
Nejman D, Livyatan I, Fuks G, et al. The human tumor microbiome is composed of tumor type-specific intracellular bacteria[J]. Science, 2020, 368(6494):973-980. doi:10.1126/science.aay9189. [百度学术]
Jeong JY, Kim TB, Kim J, et al. Diversity in the extracellular vesicle-derived microbiome of tissues according to tumor progression in pancreatic cancer[J]. Cancers, 2020, 12(9):2346. doi:10.3390/cancers12092346. [百度学术]
Pushalkar S, Hundeyin M, Daley D, et al. The pancreatic cancer microbiome promotes oncogenesis by induction of innate and adaptive immune suppression[J]. Cancer Discov, 2018, 8(4):403-416. doi:10.1158/2159-8290.CD-17-1134. [百度学术]
Qin JJ, Li YR, Cai ZM, et al. A metagenome-wide association study of gut microbiota in type 2 diabetes[J]. Nature, 2012, 490(7418):55-60. doi:10.1038/nature11450. [百度学术]
Li JJ, Zhu MJ, Kashyap PC, et al. The role of microbiome in pancreatic cancer[J]. Cancer Metastasis Rev, 2021, 40(3):777-789. doi:10.1007/s10555-021-09982-2. [百度学术]
Matsukawa H, Iida N, Kitamura K, et al. Dysbiotic gut microbiota in pancreatic cancer patients form correlation networks with the oral microbiota and prognostic factors[J]. Am J Cancer Res, 2021, 11(6):3163-3175. [百度学术]
Ren Z, Jiang J, Xie H, et al. Gut microbial profile analysis by MiSeq sequencing of pancreatic carcinoma patients in China[J]. Oncotarget, 2017, 8(56):95176-95191. doi:10.18632/oncotarget.18820. [百度学术]
Kohi S, Macgregor-Das A, Dbouk M, et al. Alterations in the duodenal fluid microbiome of patients with pancreatic cancer[J]. Clin Gastroenterol Hepatol, 2022, 20(2):e196-e227. doi:10.1016/j.cgh.2020.11.006. [百度学术]
Geller LT, Barzily-Rokni 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. doi:10.1126/science.aah5043. [百度学术]
McAllister F, Khan MAW, Helmink B, et al. The tumor microbiome in pancreatic cancer: bacteria and beyond[J]. Cancer Cell, 2019, 36(6):577-579. doi:10.1016/j.ccell.2019.11.004. [百度学术]
Riquelme E, Zhang Y, Zhang L, et al. Tumor microbiome diversity and composition influence pancreatic cancer outcomes[J]. Cell, 2019, 178(4):795-806. doi:10.1016/j.cell.2019.07.008. [百度学术]
Lee YK, Mazmanian SK. Has the microbiota played a critical role in the evolution of the adaptive immune system?[J]. Science, 2010, 330(6012):1768-1773. doi:10.1126/science.1195568. [百度学术]
Poore GD, Kopylova E, Zhu QY, et al. Microbiome analyses of blood and tissues suggest cancer diagnostic approach[J]. Nature, 2020, 579(7800):567-574. doi:10.1038/s41586-020-2095-1. [百度学术]
Yatsunenko T, Rey FE, Manary MJ, et al. Human gut microbiome viewed across age and geography[J]. Nature, 2012, 486(7402):222-227. doi:10.1038/nature11053. [百度学术]