BACKGROUND: The gut microbiota, composed by several species of microorganisms, works to preserve the liver-gut homeostasis and plays an important role during digestion and absorption of nutrients, and in the immune response of the host. In this review, we analyzed the influence of microbiota in patients with cholangiocarcinoma (CCA) who were candidates for elective surgery. METHODS: A literature review was conducted to identify papers that provided empiric evidence to support that the altered microbiota composition (dysbiosis) is related also to CCA development. RESULTS: Bacteria such as Helicobacter pylori, Helicobacter hepaticus, and Opisthorchis viverrini increase the risk of CCA. The most abundant genera were Enterococcus, Streptococcus, Bacteroides, Klebsiella, and Pyramidobacter in CCA's biliary microbiota. Additionally, levels of Bacteroides, Geobacillus, Meiothermus, and Anoxybacillus genera were significantly higher. An enrichment of Bifidobacteriaceae, Enterobacteriaceae, and Enterococcaceae families has also been observed in CCA tumor tissue. Microbiota is related to postoperative outcomes in abdominal surgery. The combination of caloric restriction diets in liver cancer or CCA increases the effect of the chemotherapy treatment. CONCLUSION: The correct use of nutrition for microbiota modulation according to each patient's needs could be a therapeutic tool in combination with elective surgery and chemotherapy to diminish side effects and improve prognosis. Further investigations are needed to fully understand the mechanisms by which they are related.

Department of General Visceral and Transplantation Surgery Clinic and University Hospital Virgen de La Arrixaca IMIB ARRIXACA 30120 Murcia Spain

Department of Hepatology Virgen de La Arrixaca University Hospital Murcia Spain

Department of Surgery and Transplantation Swiss Hepato Pancreato Biliary Center University Hospital Zurich Zurich Switzerland

Department of Translational Stem Cell Biology Research Institute of the Medical University of Varna Varna Bulgaria

Digestive and Endocrine Surgery and Transplantation of Abdominal Organs Research Group Biomedical Research Institute of Murcia Murcia Spain

Division of Digestive and General Surgery Niigata University Graduate School of Medical and Dental Sciences Niigata Japan

International Clinical Research Center St Anne's University Hospital Brno Czech Republic

Obesity and Metabolism Laboratory Biomedical Research Institute of Murcia Murcia Spain

Zobrazit více v PubMed

Banales JM, Marin JJG, Lamarca A, Rodrigues PM, Khan SA, Roberts LR, Cardinale V et al (2020) Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol 17:557–588 PubMed PMC

Wu HJ, Chu PY (2019) Role of cancer stem cells in cholangiocarcinoma and therapeutic implications. Int J Mol Sci 20:4154

Asadi H, Hollingsworth R, Pennycooke K, Thanaratnam P, Given M, Keeling A, Lee M (2016) A review of percutaneous transhepatic biliary drainage at a tertiary referral centre. Clin Radiol 71:1312 e1317-1312 e1311

DeOliveira ML, Cunningham SC, Cameron JL, Kamangar F, Winter JM, Lillemoe KD, Choti MA et al (2007) Cholangiocarcinoma: thirty-one-year experience with 564 patients at a single institution. Ann Surg 245:755–762 PubMed PMC

Thursby E, Juge N (2017) Introduction to the human gut microbiota. Biochem J 474:1823–1836 PubMed

Underhill DM, Iliev ID (2014) The mycobiota: interactions between commensal fungi and the host immune system. Nat Rev Immunol 14:405–416 PubMed PMC

Tripathi A, Debelius J, Brenner DA, Karin M, Loomba R, Schnabl B, Knight R (2018) The gut-liver axis and the intersection with the microbiome. Nat Rev Gastroenterol Hepatol 15:397–411 PubMed PMC

Arab JP, Martin-Mateos RM, Shah VH (2018) Gut-liver axis, cirrhosis and portal hypertension: the chicken and the egg. Hepatol Int 12:24–33 PubMed

Sun J, Zhang J, Wang X, Ji F, Ronco C, Tian J, Yin Y (2020) Gut-liver crosstalk in sepsis-induced liver injury. Crit Care 24:614 PubMed PMC

Carding S, Verbeke K, Vipond DT, Corfe BM, Owen LJ (2015) Dysbiosis of the gut microbiota in disease. Microb Ecol Health Dis 26:26191 PubMed

Segura-López FK, Güitrón-Cantú A, Torres J (2015) Association between Helicobacter spp. infections and hepatobiliary malignancies: a review. World J Gastroenterol 21:1414–1423 PubMed PMC

Zhou D, Wang JD, Weng MZ, Zhang Y, Wang XF, Gong W, Quan ZW (2013) Infections of Helicobacter spp. in the biliary system are associated with biliary tract cancer: a meta-analysis. Eur J Gastroenterol Hepatol 25:447–454 PubMed

Jala I, Almanfaluthi ML, Laha T, Kanthawong S, Tangkawattana S, Saichua P, Suttiprapa S et al (2021) Helicobacter pylori GroEL seropositivity is associated with an increased risk of Opisthorchis viverrini-associated hepatobiliary abnormalities and cholangiocarcinoma. Korean J Parasitol 59:363–368 PubMed PMC

Shimoyama T, Takahashi R, Abe D, Mizuki I, Endo T, Fukuda S (2010) Serological analysis of Helicobacter hepaticus infection in patients with biliary and pancreatic diseases. J Gastroenterol Hepatol 25(Suppl 1):S86-89 PubMed

Thinkhamrop K, Khuntikeo N, Laohasiriwong W, Chupanit P, Kelly M, Suwannatrai AT (2021) Association of comorbidity between Opisthorchis viverrini infection and diabetes mellitus in the development of cholangiocarcinoma among a high-risk population, northeastern Thailand. PLoS Negl Trop Dis 15:e0009741 PubMed PMC

Avilés-Jiménez F, Guitron A, Segura-López F, Méndez-Tenorio A, Iwai S, Hernández-Guerrero A, Torres J (2016) Microbiota studies in the bile duct strongly suggest a role for Helicobacter pylori in extrahepatic cholangiocarcinoma. Clin Microbiol Infect 22:178.e111-178.e122

Rao B, Ren T, Wang X, Wang H, Zou Y, Sun Y, Liu S et al (2021) Dysbiosis in the human microbiome of Cholangiocarcinoma. Front Physiol 12:715536 PubMed PMC

Saab M, Mestivier D, Sohrabi M, Rodriguez C, Khonsari MR, Faraji A, Sobhani I (2021) Characterization of biliary microbiota dysbiosis in extrahepatic cholangiocarcinoma. PLoS One 16:e0247798 PubMed PMC

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

Chen B, Fu SW, Lu L, Zhao H (2019) A Preliminary study of biliary microbiota in patients with bile duct stones or distal cholangiocarcinoma. Biomed Res Int 2019:1092563 PubMed PMC

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

Lee H, Lee HK, Min SK, Lee WH (2020) 16S rDNA microbiome composition pattern analysis as a diagnostic biomarker for biliary tract cancer. World J Surg Oncol 18(1):19 PubMed PMC

Banales JM, Cardinale V, Carpino G, Marzioni M, Andersen JB, Invernizzi P, Lind GE et al (2016) 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 13:261–280 PubMed

Kirstein MM, Vogel A (2016) Epidemiology and risk factors of cholangiocarcinoma. Visc Med 32:395–400 PubMed PMC

Kim TS, Pak JH, Kim JB, Bahk YY (2016) Clonorchis sinensis, an oriental liver fluke, as a human biological agent of cholangiocarcinoma: a brief review. BMB Rep 49:590–597 PubMed PMC

Zheng S, Zhu Y, Zhao Z, Wu Z, Okanurak K, Lv Z (2017) Liver fluke infection and cholangiocarcinoma: a review. Parasitol Res 116:11–19 PubMed

Ketpueak T, Thiennimitr P, Apaijai N, Chattipakorn SC, Chattipakorn N (2020) Association of chronic opisthorchis infestation and microbiota alteration on tumorigenesis in cholangiocarcinoma. Clin Transl Gastroenterol 12:e00292 PubMed PMC

Thinkhamrop K, Khuntikeo N, Phonjitt P, Chamadol N, Thinkhamrop B, Moore MA, Promthet S (2015) Association between diabetes mellitus and fatty liver based on ultrasonography screening in the world’s highest cholangiocarcinoma incidence region, Northeast Thailand. Asian Pac J Cancer Prev 16:3931–3936 PubMed

Park JH, Hong JY, Kwon M, Lee J, Han K, Han IW, Kang W et al (2021) Association between non-alcoholic fatty liver disease and the risk of biliary tract cancers: a South Korean nationwide cohort study. Eur J Cancer 150:73–82 PubMed

Zhang Q, Ma C, Duan Y, Heinrich B, Rosato U, Diggs LP, Ma L et al (2021) Gut microbiome directs hepatocytes to recruit MDS’s and promote cholangiocarcinoma. Cancer Discov 11:1248–1267 PubMed

Labib PL, Goodchild G, Pereira SP (2019) Molecular pathogenesis of cholangiocarcinoma. BMC Cancer 19:185 PubMed PMC

Lin J, Shi J, Guo H, Yang X, Jiang Y, Long J, Bai Y et al (2019) Alterations in DNA damage repair genes in primary liver cancer. Clin Cancer Res 25:4701–4711 PubMed

Mar WA, Shon AM, Lu Y, Yu JH, Berggruen SM, Guzman G, Ray CE Jr et al (2016) Imaging spectrum of cholangiocarcinoma: role in diagnosis, staging, and posttreatment evaluation. Abdom Radiol (NY) 41:553–567 PubMed

Ruys AT, Busch OR, Rauws EA, Gouma DJ, van Gulik TM (2013) Prognostic impact of preoperative imaging parameters on resectability of hilar cholangiocarcinoma. HPB Surg 2013:657309 PubMed PMC

Choi YH, Lee JM, Lee JY, Han CJ, Choi JY, Han JK, Choi BI (2008) Biliary malignancy: value of arterial, pancreatic, and hepatic phase imaging with multidetector-row computed tomography. J Comput Assist Tomogr 32:362–368 PubMed

Yeh BM, Liu PS, Soto JA, Corvera CA, Hussain HK (2009) MR imaging and CT of the biliary tract. Radiographics 29:1669–1688 PubMed

Park HS, Lee JM, Choi JY, Lee MW, Kim HJ, Han JK, Choi BI (2008) Preoperative evaluation of bile duct cancer: MRI combined with MR cholangiopancreatography versus MDCT with direct cholangiography. AJR Am J Roentgenol 190:396–405 PubMed

Yin L, Zhao S, Zhu H, Ji G, Zhang X (2021) Primary tumor resection improves survival in patients with multifocal intrahepatic cholangiocarcinoma based on a population study. Sci Rep 11:12166 PubMed PMC

Groot Koerkamp B, Wiggers JK, Gonen M, Doussot A, Allen PJ, Besselink MGH, Blumgart LH et al (2015) Survival after resection of perihilar cholangiocarcinoma-development and external validation of a prognostic nomogram. Ann Oncol 26:1930–1935 PubMed PMC

Strijker M, Belkouz A, van der Geest LG, van Gulik TM, van Hooft JE, de Meijer VE, Haj Mohammad N et al (2019) Treatment and survival of resected and unresected distal cholangiocarcinoma: a nationwide study. Acta Oncol 58:1048–1055 PubMed

Lee SG, Song GW, Hwang S, Ha TY, Moon DB, Jung DH, Kim KH et al (2010) Surgical treatment of hilar cholangiocarcinoma in the new era: the Asan experience. J Hepatobiliary Pancreat Sci 17:476–489 PubMed

Mavros MN, Economopoulos KP, Alexiou VG, Pawlik TM (2014) Treatment and prognosis for patients with intrahepatic cholangiocarcinoma: systematic review and meta-analysis. JAMA Surg 149:565–574 PubMed

Robles R, Figueras J, Turrión VS, Margarit C, Moya A, Varo E, Calleja J et al (2004) Spanish experience in liver transplantation for hilar and peripheral cholangiocarcinoma. Ann Surg 239:265–271 PubMed PMC

Panayotova GG, Paterno F, Guarrera JV, Lunsford KE (2020) Liver transplantation for cholangiocarcinoma: insights into the prognosis and the evolving indications. Curr Oncol Rep 22:49 PubMed

Sapisochin G, Facciuto M, Rubbia-Brandt L, Marti J, Mehta N, Yao FY, Vibert E et al (2016) Liver transplantation for “very early” intrahepatic cholangiocarcinoma: international retrospective study supporting a prospective assessment. Hepatology 64:1178–1188 PubMed

De Martin E, Rayar M, Golse N, Dupeux M, Gelli M, Gnemmi V, Allard MA et al (2020) Analysis of liver resection versus liver transplantation on outcome of small intrahepatic cholangiocarcinoma and combined hepatocellular-cholangiocarcinoma in the setting of cirrhosis. Liver Transpl 26:785–798 PubMed

Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, Madhusudan S et al (2010) Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 362:1273–1281 PubMed

Agnes A, Puccioni C, D’Ugo D, Gasbarrini A, Biondi A, Persiani R (2021) The gut microbiota and colorectal surgery outcomes: facts or hype? A narrative review. BMC Surg 21:83 PubMed PMC

Romero R, Hassan SS, Gajer P, Tarca AL, Fadrosh DW, Bieda J, Chaemsaithong P et al (2014) The vaginal microbiota of pregnant women who subsequently have spontaneous preterm labor and delivery and those with a normal delivery at term. Microbiome 2:18 PubMed PMC

Shogan BD, Belogortseva N, Luong PM, Zaborin A, Lax S, Bethel C, Ward M et al (2015) Collagen degradation and MMP9 activation by Enterococcus faecalis contribute to intestinal anastomotic leak. Sci Transl Med 7:286ra268

Paun BC, Cassie S, MacLean AR, Dixon E, Buie WD (2010) Postoperative complications following surgery for rectal cancer. Ann Surg 251:807–818 PubMed

Schardey HM, Joosten U, Finke U, Staubach KH, Schauer R, Heiss A, Kooistra A et al (1997) The prevention of anastomotic leakage after total gastrectomy with local decontamination. A prospective, randomized, double-blind, placebo-controlled multicenter trial. Ann Surg 225:172–180 PubMed PMC

Shogan BD, Chen J, Duchalais E, Collins D, Chang M, Krull K, Krezalek MA et al (2020) Alterations of the rectal microbiome are associated with the development of postoperative ileus in patients undergoing colorectal surgery. J Gastrointest Surg 24:1663–1672 PubMed

Carpelan-Holmstrom M, Koskenvuo L, Haapamaki C, Renkonen-Sinisalo L, Lepisto A (2020) Clinical management of 52 consecutive retro-rectal tumours treated at a tertiary referral centre. Colorectal Dis 22:1279–1285 PubMed

Shin SY, Hussain Z, Lee YJ, Park H (2021) An altered composition of fecal microbiota, organic acids, and the effect of probiotics in the guinea pig model of postoperative ileus. Neurogastroenterol Motil 33:e13966 PubMed

Lederer AK, Chikhladze S, Kohnert E, Huber R, Müller A (2021) Current insights: the impact of gut microbiota on postoperative complications in visceral surgery-a barrative review. Diagnostics (Basel) 11:2099

Alverdy JC, Hyoju SK, Weigerinck M, Gilbert JA (2017) The gut microbiome and the mechanism of surgical infection. Br J Surg 104:e14–e23 PubMed

Rodriguez-Palacios A, Harding A, Menghini P, Himmelman C, Retuerto M, Nickerson KP, Lam M et al (2018) The artificial sweetener splenda promotes gut proteobacteria, dysbiosis, and myeloperoxidase reactivity in Crohn’s disease-like ileitis. Inflamm Bowel Dis 24:1005–1020 PubMed PMC

Vernocchi P, Del Chierico F, Putignani L (2020) Gut microbiota metabolism and interaction with food components. Int J Mol Sci 21:3688

de Roos B, Brennan L (2017) Personalised interventions-a precision approach for the next generation of dietary intervention studies. Nutrients 9:847