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Clinical Studies

Potential influence of the microbiome environment in patients with biliary tract cancer and implications for therapy

Abstract

Biliary tract cancers, including intra- and extra-hepatic cholangiocarcinoma as well as gallbladder cancer, are associated with poor prognosis and the majority of patients present with advanced-stage, non-resectable disease at diagnosis. Biliary tract cancer may develop through an accumulation of genetic and epigenetic alterations and can be influenced by microbial exposure. Furthermore, the liver and biliary tract are exposed to the gastrointestinal microbiome through the gut–liver axis. The availability of next-generation sequencing technology has led to an increase in studies investigating the relationship between microbiota and human disease. In particular, the interplay between the microbiome, the tumour micro-environment and response to systemic therapy is a prospering area of interest. Given the poor outcomes for patients with biliary tract cancer, this emerging field of research, through which new biomarkers may be identified, offers potential as a tool for early diagnosis, prognostication or even as a future therapeutic target. This review summarises the available evidence on the microbiome environment in patients with biliary tract cancer, including a discussion around confounding factors, implications for therapy and proposed future directions.

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Fig. 1: Microbial metabolism of bile acids and the enterohepatic circulation [28,29,30,31].
Fig. 2: Flow diagram describing identification of studies reporting on the microbiome environment in biliary tract cancer.

References

  1. Nakeeb A, Pitt HA, Sohn TA, Coleman JA, Abrams RA, Piantadosi S, et al. Cholangiocarcinoma: a spectrum of intrahepatic, perihilar, and distal tumors. Ann Surg. 1996;224:463–75.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  2. Banales JM, Cardinale V, Carpino G, Marzioni M, Andersen JB, Invernizzi P, et al. Expert consensus document: cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA). Nat Rev Gastroenterol Hepatol. 2016;13:261–80.

    PubMed  Article  Google Scholar 

  3. Patel T. Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the United States. Hepatology. 2001;33:1353–7.

    CAS  PubMed  Article  Google Scholar 

  4. Taylor-Robinson SD, Toledano MB, Arora S, Keegan TJ, Hargreaves S, Beck A, et al. Increase in mortality rates from intrahepatic cholangiocarcinoma in England and Wales 1968–1998. Gut. 2001;48:816–20.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. Rahib L, Wehner MR, Matrisian LM, Nead KT. Estimated projection of US cancer incidence and death to 2040. JAMA Netw Open. 2021;4:e214708.

    PubMed  PubMed Central  Article  Google Scholar 

  6. Forner A, Vidili G, Rengo M, Bujanda L, Ponz-Sarvisé M, Lamarca A. Clinical presentation, diagnosis and staging of cholangiocarcinoma. Liver Int. 2019;39:98–107.

    PubMed  Article  Google Scholar 

  7. Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362:1273–81.

    CAS  PubMed  Article  Google Scholar 

  8. Lamarca A, Palmer DH, Wasan HS, Ross PJ, Ma YT, Arora A, et al. Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial. Lancet Oncol. 2021;22:690–701.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. Valle JW, Kelley RK, Nervi B, Oh DY, Zhu AX. Biliary tract cancer. Lancet. 2021;397:428–44.

    CAS  PubMed  Article  Google Scholar 

  10. Sithithaworn P, Yongvanit P, Duenngai K, Kiatsopit N, Pairojkul C. Roles of liver fluke infection as risk factor for cholangiocarcinoma. J Hepatobiliary Pancreat Sci. 2014;21:301–8.

    PubMed  Article  Google Scholar 

  11. Clements O, Eliahoo J, Kim JU, Taylor-Robinson SD, Khan SA. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma: A systematic review and meta-analysis. J Hepatol. 2019;72:95–103.

    PubMed  Article  Google Scholar 

  12. Hsing AW, Bai Y, Andreotti G, Rashid A, Deng J, Chen J, et al. Family history of gallstones and the risk of biliary tract cancer and gallstones: A population-based study in Shanghai, China. Int J Cancer. 2007;121:832–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. Lewis JT, Talwalkar JA, Rosen CB, Smyrk TC, Abraham SC. Prevalence and risk factors for gallbladder neoplasia in patients with primary sclerosing cholangitis: Evidence for a metaplasia-dysplasia-carcinoma sequence. Am J Surg Pathol. 2007;31:907–13.

    PubMed  Article  Google Scholar 

  14. Kamisawa T, Kaneko K, Itoi T, Ando H. Pancreaticobiliary maljunction and congenital biliary dilatation. Lancet Gastroenterol Hepatol. 2017;2:610–8.

    PubMed  Article  Google Scholar 

  15. Li ZM, Wu ZX, Han B, Mao YQ, Chen HL, Han SF, et al. The association between BMI and gallbladder cancer risk: a meta-analysis. Oncotarget. 2016;7:43669–79.

    PubMed  PubMed Central  Article  Google Scholar 

  16. Nakamura H, Arai Y, Totoki Y, Shirota T, Elzawahry A, Kato M, et al. Genomic spectra of biliary tract cancer. Nat Genet. 2015;47:1003–10.

    CAS  PubMed  Article  Google Scholar 

  17. Sender R, Fuchs S, Milo R. Revised estimates for the number of human and bacteria cells in the body. PLoS Biol. 2016;14:e1002533.

  18. Honda K, Littman DR. The microbiota in adaptive immune homeostasis and disease. Nature. 2016;535:75–84.

    CAS  PubMed  Article  Google Scholar 

  19. Fukuda S, Toh H, Hase K, Oshima K, Nakanishi Y, Yoshimura K, et al. Bifidobacteria can protect from enteropathogenic infection through production of acetate. Nature. 2011;469:543–9.

    CAS  PubMed  Article  Google Scholar 

  20. Tremaroli V, Bäckhed F. Functional interactions between the gut microbiota and host metabolism. Nature. 2012;489:242–9.

    CAS  PubMed  Article  Google Scholar 

  21. Gao R, Wang Z, Li H, Cao Z, Gao Z, Chen H, et al. Gut microbiota dysbiosis signature is associated with the colorectal carcinogenesis sequence and improves the diagnosis of colorectal lesions. J Gastroenterol Hepatol. 2020;35:2109–21.

    PubMed  Article  Google Scholar 

  22. Chen J, Domingue JC, Sears CL. Microbiota dysbiosis in select human cancers: evidence of association and causality. Semin Immunol. 2017;32:25–34.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. Le Chatelier E, Nielsen T, Qin J, Prifti E, Hildebrand F, Falony G, et al. Richness of human gut microbiome correlates with metabolic markers. Nature. 2013;500:541–6.

    PubMed  Article  CAS  Google Scholar 

  24. Bäckhed F, Ding H, Wang T, Hooper LV, Gou YK, Nagy A, et al. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci USA. 2004;101:15718–23.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  25. Ma HQ, Yu TT, Zhao XJ, Zhang Y, Zhang HJ. Fecal microbial dysbiosis in Chinese patients with inflammatory bowel disease. World J Gastroenterol. 2018;24:1464–77.

    PubMed  PubMed Central  Article  Google Scholar 

  26. Wu SC, Cao ZS, Chang KM, Juang JL. Intestinal microbial dysbiosis aggravates the progression of Alzheimer’s disease in Drosophila. Nat Commun. 2017;8:24.

  27. Keshavarzian A, Green SJ, Engen PA, Voigt RM, Naqib A, Forsyth CB, et al. Colonic bacterial composition in Parkinson’s disease. Mov Disord. 2015;30:1351–60.

    CAS  PubMed  Article  Google Scholar 

  28. Tripathi A, Debelius J, Brenner DA, Karin M, Loomba R, Schnabl B, et al. The gut-liver axis and the intersection with the microbiome. Nat Rev Gastroenterol Hepatol. 2018;15:397–411.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. De Aguiar Vallim TQ, Tarling EJ, Edwards PA. Pleiotropic roles of bile acids in metabolism. Cell Metab. 2013;17:657–69.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  30. Ridlon JM, Harris SC, Bhowmik S, Kang DJ, Hylemon PB. Consequences of bile salt biotransformations by intestinal bacteria. Gut Microbes. 2016;7:22–39.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. Wahlström A, Sayin SI, Marschall H-U, Bäckhed F. Intestinal Crosstalk between Bile Acids and Microbiota and Its Impact on Host Metabolism. Cell Metab. 2016;24:41–50.

    PubMed  Article  CAS  Google Scholar 

  32. Albillos A, de Gottardi A, Rescigno M. The gut-liver axis in liver disease: pathophysiological basis for therapy. J Hepatol. 2020;72:558–77.

    CAS  PubMed  Article  Google Scholar 

  33. Ma C, Han M, Heinrich B, Fu Q, Zhang Q, Sandhu M, et al. Gut microbiome–mediated bile acid metabolism regulates liver cancer via NKT cells. Science. 2018;360:eaan5931.

  34. Scheufele F, Aichinger L, Jäger C, Demir IE, Schorn S, Sargut M, et al. Effect of preoperative biliary drainage on bacterial flora in bile of patients with periampullary cancer. Br J Surg. 2017;104:e182–e188.

    CAS  PubMed  Article  Google Scholar 

  35. Scheufele F, Schorn S, Demir IE, Sargut M, Tieftrunk E, Calavrezos L, et al. Preoperative biliary stenting versus operation first in jaundiced patients due to malignant lesions in the pancreatic head: a meta-analysis of current literature. Surg (U S). 2017;161:939–50.

    Google Scholar 

  36. Shrader HR, Miller AM, Tomanek-Chalkley A, McCarthy A, Coleman KL, Ear PH, et al. Effect of bacterial contamination in bile on pancreatic cancer cell survival. Surg (U S). 2021;169:617–22.

    Google Scholar 

  37. Molinero N, Ruiz L, Milani C, Gutiérrez-Díaz I, Sánchez B, Mangifesta M, et al. The human gallbladder microbiome is related to the physiological state and the biliary metabolic profile. Microbiome. 2019;7:1–17.

    Article  Google Scholar 

  38. Saab M, Mestivier D, Sohrabi M, Rodriguez C, Khonsari MR, Faraji A, et al. Characterization of biliary microbiota dysbiosis in extrahepatic cholangiocarcinoma. PLoS ONE. 2021;16:e0247798.

  39. Xiao M, Gao Y, Wang Y. Helicobacter species infection may be associated with cholangiocarcinoma: a meta‐analysis. Int J Clin Pr. 2014;68:262–70.

    CAS  Article  Google Scholar 

  40. Zhou D, Wang JD, Weng MZ, Zhang Y, Wang XF, Gong W, et al. Infections of Helicobacter spp. in the biliary system are associated with biliary tract cancer: A meta-analysis. Eur J Gastroenterol Hepatol. 2013;25:447–54.

    PubMed  Article  Google Scholar 

  41. Segura-López FK, Avilés-Jiménez F, Güitrón-Cantú A, Valdéz-Salazar HA, León-Carballo S, Guerrero-Pérez L, et al. Infection with Helicobacter bilis but not Helicobacter hepaticus was Associated with Extrahepatic Cholangiocarcinoma. Helicobacter. 2015;20:223–30.

    PubMed  Article  CAS  Google Scholar 

  42. Avilés-Jiménez F, Guitron A, Segura-López F, Méndez-Tenorio A, Iwai S, Hernández-Guerrero A, et al. Microbiota studies in the bile duct strongly suggest a role for Helicobacter pylori in extrahepatic cholangiocarcinoma. Clin Microbiol Infect. 2016;22:178.

    PubMed  Article  Google Scholar 

  43. Murphy G, Michel A, Taylor PR, Albanes D, Weinstein SJ, Virtamo J, et al. Association of seropositivity to Helicobacter species and biliary tract cancer in the ATBC study. Hepatology. 2014;60:1963–71.

    CAS  PubMed  Article  Google Scholar 

  44. Nagaraja V, Eslick GD. Systematic review with meta-analysis: the relationship between chronic Salmonella typhi carrier status and gall‐bladder cancer. Aliment Pharm Ther. 2014;39:745–50.

    CAS  Article  Google Scholar 

  45. Koshiol J, Wozniak A, Cook P, Adaniel C, Acevedo J, Azócar L, et al. Salmonella enterica serovar Typhi and gallbladder cancer: a case-control study and meta-analysis. Cancer Med. 2016;5:3310–25.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. Serra N, Di Carlo P, Gulotta G, d’Arpa F, Giammanco A, Colomba C, et al. Bactibilia in women affected with diseases of the biliary tract and pancreas. A STROBE guidelines-adherent cross-sectional study in Southern Italy. J Med Microbiol. 2018;67:1090–5.

    CAS  PubMed  Article  Google Scholar 

  47. Di Carlo P, Serra N, D’arpa F, Agrusa A, Gulotta G, Fasciana T, et al. The microbiota of the bilio-pancreatic system: a cohort, STROBE-compliant study. Infect Drug Resist. 2019;12:1513–27.

    PubMed  PubMed Central  Article  Google Scholar 

  48. Tsuchiya Y, Loza E, Villa-Gomez G, Trujillo CC, Baez S, Asai T, et al. Metagenomics of microbial communities in gallbladder bile from patients with gallbladder cancer or cholelithiasis. Asian Pacific. J Cancer Prev. 2018;19:961–7.

    CAS  Google Scholar 

  49. Poudel SK, Padmanabhan R, Chahal P, Sanaka M, Stevens T, Guinta K, et al. Microbiome signature of bile from pancreatic and biliary tract cancer patients: A pilot study. J Clin Oncol. 2019;37:e15744–e15744.

    Article  Google Scholar 

  50. Jia X, Lu S, Zeng Z, Liu Q, Dong Z, Chen Y, et al. Characterization of gut microbiota, bile acid metabolism, and cytokines in intrahepatic cholangiocarcinoma. Hepatology. 2020;71:893–906.

    CAS  PubMed  Article  Google Scholar 

  51. Chng KR, Chan SH, Ng AHQ, Li C, Jusakul A, Bertrand D, et al. Tissue microbiome profiling identifies an enrichment of specific enteric bacteria in opisthorchis viverrini associated cholangiocarcinoma. EBioMedicine. 2016;8:195–202.

    PubMed  PubMed Central  Article  Google Scholar 

  52. Chen B, Fu SW, Lu L, Zhao H. A preliminary study of biliary microbiota in patients with bile duct stones or distal cholangiocarcinoma. Biomed Res Int. 2019;1092563.

  53. Dangtakot R, Intuyod K, Ahooja A, Wongwiwatchai J, Hanpanich P, Lulitanond A, et al. Profiling of bile microbiome identifies district microbial population between choledocholithiasis and cholangiocarcinoma patients. Asian Pac J Cancer Prev. 2021;22:233–40.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. Zhang L, Wu YN, Chen T, Ren CH, Li X, Liu GX. Relationship between intestinal microbial dysbiosis and primary liver cancer. Hepatobiliary Pancreat Dis Int. 2019;18:149–57.

    PubMed  Article  Google Scholar 

  55. Lenz P, Steidl L, Cordes F, Kahl BC, Karch H, Dobrindt U, et al. Sa1328 analysis of the human biliary microbiome and its alterations in biliary tract diseases. Gastroenterology. 2015;148:S–293.

    Google Scholar 

  56. Katsuyuki M, Chandrasekhara V, Wongjarupong N, Chen J, Johnson S, Chia N, et al.The Role of the Biliary and Gut Microbiome in the Progression of Cholangiocarcinoma and Primary Sclerosing Cholangitis. Am J Gastroenterol. 2019;114:S25–6.

    Article  Google Scholar 

  57. Lee H, Lee HK, Min SK, Lee WH. 16S rDNA microbiome composition pattern analysis as a diagnostic biomarker for biliary tract cancer. World J Surg Oncol. 2020;18:19.

    PubMed  PubMed Central  Article  Google Scholar 

  58. Song X, Wang X, Hu Y, Li H, Ren T, Li Y, et al. A metagenomic study of biliary microbiome change along the cholecystitis‐carcinoma sequence. Clin Transl Med. 2020;10:e97.

    PubMed  PubMed Central  Google Scholar 

  59. Voigt AY, Costea PI, Kultima JR, Li SS, Zeller G, Sunagawa S, et al. Temporal and technical variability of human gut metagenomes. Genome Biol. 2015;16:73.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  60. Galloway-Peña JR, Smith DP, Sahasrabhojane P, Wadsworth WD, Fellman BM, Ajami NJ, et al. Characterization of oral and gut microbiome temporal variability in hospitalized cancer patients. Genome Med. 2017;9:21.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  61. He Y, Wu W, Zheng HM, Li P, McDonald D, Sheng HF, et al. Regional variation limits applications of healthy gut microbiome reference ranges and disease models. Nat Med. 2018;24:1532–5.

    CAS  PubMed  Article  Google Scholar 

  62. Flores GE, Caporaso JG, Henley JB, Rideout JR, Domogala D, Chase J, et al. Temporal variability is a personalized feature of the human microbiome. Genome Biol. 2014;15:531–531.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  63. Langheinrich M, Wirtz S, Kneis B, Gittler MM, Tyc O, Schierwagen R, et al. Microbiome Patterns in Matched Bile, Duodenal, Pancreatic Tumor Tissue, Drainage, and Stool Samples: Association with Preoperative Stenting and Postoperative Pancreatic Fistula Development. J Clin Med. 2020;9:2785.

    CAS  PubMed Central  Article  Google Scholar 

  64. Wang Z, Zolnik CP, Qiu Y, Usyk M, Wang T, Strickler HD, et al. Comparison of fecal collection methods for microbiome and metabolomics studies. Front Cell Infect Microbiol. 2018;8:301.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  65. Song SJ, Amir A, Metcalf JL, Amato KR, Xu ZZ, Humphrey G, et al. Preservation methods differ in fecal microbiome stability, affecting suitability for field studies. mSystems. 2016;1:21–37.

    Article  Google Scholar 

  66. Wu WK, Chen CC, Panyod S, Chen RA, Wu MS, Sheen LY, et al. Optimization of fecal sample processing for microbiome study—the journey from bathroom to bench. J Formos Med Assoc. 2019;118:545–55.

    PubMed  Article  Google Scholar 

  67. Gupta S, Mortensen MS, Schjørring S, Trivedi U, Vestergaard G, Stokholm J, et al. Amplicon sequencing provides more accurate microbiome information in healthy children compared to culturing. Commun Biol. 2019;2:1–7.

    CAS  Article  Google Scholar 

  68. Woo PCY, Lau SKP, Teng JLL, Tse H, Yuen KY. Then and now: Use of 16S rDNA gene sequencing for bacterial identification and discovery of novel bacteria in clinical microbiology laboratories. Clin Microbiol Infect. 2008;14:908–34.

    CAS  PubMed  Article  Google Scholar 

  69. Claassen S, du Toit E, Kaba M, Moodley C, Zar HJ, Nicol MP. A comparison of the efficiency of five different commercial DNA extraction kits for extraction of DNA from faecal samples. J Microbiol Methods. 2013;94:103–10.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. Pollock J, Glendinning L, Wisedchanwet T, Watson M. The madness of microbiome: attempting to find consensus “best practice” for 16S microbiome studies. Appl Environ Microbiol. 2018;84:e02627–17.

    PubMed  PubMed Central  Article  Google Scholar 

  71. Guo F, Zhang T. Biases during DNA extraction of activated sludge samples revealed by high throughput sequencing. Appl Microbiol Biotechnol. 2013;97:4607–16.

    CAS  PubMed  Article  Google Scholar 

  72. Yang B, Wang Y, Qian PY. Sensitivity and correlation of hypervariable regions in 16S rRNA genes in phylogenetic analysis. BMC Bioinforma. 2016;17:135.

    Article  CAS  Google Scholar 

  73. Tremblay J, Singh K, Fern A, Kirton ES, He S, Woyke T, et al. Primer and platform effects on 16S rRNA tag sequencing. Front Microbiol. 2015;6:771.

    PubMed  PubMed Central  Google Scholar 

  74. Bergsten E, Mestivier D, Sobhani I. The limits and avoidance of biases in metagenomic analyses of human fecal microbiota. Microorganisms. 2020;8:1954.

    CAS  PubMed Central  Article  Google Scholar 

  75. Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillère R, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 2018;359:91–7.

    CAS  PubMed  Article  Google Scholar 

  76. Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science. 2018;359:97–103.

    CAS  PubMed  Article  Google Scholar 

  77. Matson V, Fessler J, Bao R, Chongsuwat T, Zha Y, Alegre M-L, et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science. 2018;359:104–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. Riquelme E, Zhang Y, Zhang L, Montiel M, Zoltan M, Dong W, et al. Tumor microbiome diversity and composition influence pancreatic cancer outcomes. Cell. 2019;178:795–806.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  79. Geller LT, Barzily-Rokni M, Danino T, Jonas OH, Shental N, Nejman D, et al. Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine. Science. 2017;357:1156–60.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  80. McCoy AN, Araújo-Pérez F, Azcárate-Peril A, Yeh JJ, Sandler RS, Keku TO. Fusobacterium is associated with colorectal adenomas. PLoS ONE. 2013;8:e53653.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. Li YY, Ge QX, Cao J, Zhou YJ, Du YL, Shen B, et al. Association of Fusobacterium nucleatum infection with colorectal cancer in Chinese patients. World J Gastroenterol. 2016;22:3227–33.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. Ito M, Kanno S, Nosho K, Sukawa Y, Mitsuhashi K, Kurihara H, et al. Association of Fusobacterium nucleatum with clinical and molecular features in colorectal serrated pathway. Int J Cancer. 2015;137:1258–68.

    CAS  PubMed  Article  Google Scholar 

  83. Bullman S, Pedamallu CS, Sicinska E, Clancy TE, Zhang X, Cai D, et al. Analysis of Fusobacterium persistence and antibiotic response in colorectal cancer. Science. 2017;358:1443–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  84. Pereira P, Aho V, Arola J, Boyd S, Jokelainen K, Paulin L, et al. Bile microbiota in primary sclerosing cholangitis: Impact on disease progression and development of biliary dysplasia. PLoS ONE. 2017;12:e0182924.

  85. Lurienne L, Cervesi J, Duhalde L, de Gunzburg J, Andremont A, Zalcman G, et al. NSCLC immunotherapy efficacy and antibiotic use: a systematic review and meta-analysis. J Thorac Oncol. 2020;15:1147–59.

    CAS  PubMed  Article  Google Scholar 

  86. Wilson BE, Routy B, Nagrial A, Chin VT. The effect of antibiotics on clinical outcomes in immune-checkpoint blockade: a systematic review and meta-analysis of observational studies. Cancer Immunol Immunother. 2020;69:343–54.

    PubMed  Article  Google Scholar 

  87. Petrelli F, Iaculli A, Signorelli D, Ghidini A, Dottorini L, Perego G, et al. Survival of patients treated with antibiotics and immunotherapy for cancer: a systematic review and meta-analysis. J Clin Med. 2020;9:1458.

    CAS  PubMed Central  Article  Google Scholar 

  88. Baruch EN, Youngster I, Ben-Betzalel G, Ortenberg R, Lahat A, Katz L, et al. Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients. Science. 2021;371:602–9.

    CAS  PubMed  Article  Google Scholar 

  89. Gagnaire A, Nadel B, Raoult D, Neefjes J, Gorvel JP. Collateral damage: Insights into bacterial mechanisms that predispose host cells to cancer. Nat Rev Microbiol. 2017;15:1–20.

    Article  CAS  Google Scholar 

  90. Brennan CA, Garrett WS. Fusobacterium nucleatum—symbiont, opportunist and oncobacterium. Nat Rev Microbiol. 2019;17:156–66.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  91. Zhao H, Chu M, Huang Z, Yang X, Ran S, Hu B, et al. Variations in oral microbiota associated with oral cancer. Sci Rep. 2017;7:11773.

  92. Harrandah AM, Chukkapalli SS, Bhattacharyya I, Progulske-Fox A, Chan EKL. Fusobacteria modulate oral carcinogenesis and promote cancer progression. J Oral Microbiol. 2021;13:1849493.

    Article  CAS  Google Scholar 

  93. Yamamura K, Baba Y, Nakagawa S, Mima K, Miyake K, Nakamura K, et al. Human microbiome Fusobacterium nucleatum in esophageal cancer tissue is associated with prognosis. Clin Cancer Res. 2016;22:5574–81.

    CAS  PubMed  Article  Google Scholar 

  94. Liu Y, Baba Y, Ishimoto T, Tsutsuki H, Zhang T, Nomoto D, et al. Fusobacterium nucleatum confers chemoresistance by modulating autophagy in oesophageal squamous cell carcinoma. Br J Cancer. 2021;124:963–74.

    CAS  PubMed  Article  Google Scholar 

  95. Audirac-Chalifour A, Torres-Poveda K, Bahena-Román M, Téllez-Sosa J, Martínez-Barnetche J, Cortina-Ceballos B, et al. Cervical microbiome and cytokine profile at various stages of cervical cancer: a pilot study. PLoS ONE. 2016;11:e0153274.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  96. Hsieh YY, Tung SY, Pan HY, Yen CW, Xu HW, Lin YJ, et al. Increased Abundance of Clostridium and Fusobacterium in gastric microbiota of patients with gastric cancer in Taiwan. Sci Rep. 2018;8:158.

  97. Boehm ET, Thon C, Kupcinskas J, Steponaitiene R, Skieceviciene J, Canbay A, et al. Fusobacterium nucleatum is associated with worse prognosis in Lauren’s diffuse type gastric cancer patients. Sci Rep. 2020;10:16240.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  98. Yurdakul D, Yazgan-Karataş A, Şahin F. Enterobacter strains might promote colon cancer. Curr Microbiol. 2015;71:403–11.

    CAS  PubMed  Article  Google Scholar 

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Acknowledgements

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Funding

Dr. Roseanna C Wheatley is studying for an MD, funded by the Timpson Fellowship. The salary of Dr. Angela Lamarca is in part funded by The Christie Charity and the European Union’s Horizon 2020 Research and Innovation Programme [grant number 825510, ESCALON].

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RW drafted and revised the paper. EK reviewed and approved the final version of the paper. TJ performed the literature search and reviewed and approved the final version of the paper. AL reviewed and approved the final version of the paper. RAH reviewed and approved the final version of the paper. JWV reviewed and approved the final version of the paper. MMN concept initialisation and review and approval of draft and final version of the paper.

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Correspondence to Mairéad G. McNamara.

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Competing interests

RCW: no competing interests to declare. EK: no competing interests to declare. TJ: no competing interests to declare. AL: received travel and educational support from Ipsen, Pfizer, Bayer, AAA, SirtEx, Novartis, Mylan and Delcath; speaker honoraria from Merck, Pfizer, Ipsen, Incyte and AAA; advisory honoraria from EISAI, Nutricia Ipsen, QED and Roche; she is a member of the Knowledge Network and NETConnect Initiatives funded by Ipsen; all outside scope of this work. RAH has served on the advisory board for Roche, BMS, Eisai, Celgene, Beigene, Ipsen and BTG. He has received speaker fees from Eisai, Ipsen, Mylan and PrimeOncology, and has received travel and educational support from Bayer, BMS and Roche; all outside of the scope of this work. JWV received honoraria from Agios, AstraZeneca, Baxter, Genoscience Pharma, Hutchison Medipharma, Imaging Equipment Ltd (AAA), Incyte, Ipsen, Mundipharma EDO, Mylan, QED, Servier, Sirtex and Zymeworks; and grants, honoraria and non-financial support from NuCana, all outside of the scope of this work. MMN received research grant support from Servier, Ipsen and NuCana. She has received travel and accommodation support from Bayer and Ipsen and speaker honoraria from Pfizer, Ipsen, NuCana and Mylan. She has served on advisory boards for Celgene, Ipsen, Sirtex, Baxalta and Incyte; all outside of the scope of this work.

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Wheatley, R.C., Kilgour, E., Jacobs, T. et al. Potential influence of the microbiome environment in patients with biliary tract cancer and implications for therapy. Br J Cancer 126, 693–705 (2022). https://doi.org/10.1038/s41416-021-01583-8

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