World Journal of Gastroenterology

The gut microbiome plays an important role in the variation of pharmacologic response. This aspect is especially important in the era of precision medicine, where understanding how and to what extent the gut microbiome interacts with drugs and their actions will be key to individualizing therapy. The impact of the composition of the gut microbiome on the efficacy of newer cancer therapies such as immune checkpoint inhibitors and chimeric antigen receptor T-cell treatment has become an active area of research. Pancreatic adenocarcinoma (PAC) has a poor prognosis even in those with potentially resectable disease, and treatment options are very limited. Newer studies have concluded that there is a synergistic effect for immunotherapy in combination with cytotoxic drugs, in the treatment of PAC. A variety of commensal microbiota can affect the efficacy of conventional chemotherapy and immunotherapy by modulating the tumor microenvironment in the treatment of PAC. This review will provide newer insights on the impact that alterations made in the gut microbial system have in the development and treatment of PAC.

[1]  Biao Yang,et al.  T cells in pancreatic cancer stroma: Tryptophan metabolism plays an important role in immunoregulation , 2023, World journal of gastroenterology.

[2]  Qijiang Mao,et al.  Microbiota Regulates Pancreatic Cancer Carcinogenesis through Altered Immune Response , 2023, Microorganisms.

[3]  C. Figueiredo,et al.  Harnessing the Microbiome to Reduce Pancreatic Cancer Burden , 2023, Cancers.

[4]  D. Daley,et al.  The Gut Microbiome and Pancreatic Cancer Development and Treatment , 2023, Cancer journal.

[5]  Victor G. Puelles,et al.  Microbiota-derived 3-IAA influences chemotherapy efficacy in pancreatic cancer , 2023, Nature.

[6]  A. Gasbarrini,et al.  Pancreatic Cancer Resistance to Treatment: The Role of Microbiota , 2023, Biomedicines.

[7]  A. Cucchetti,et al.  Microbiota in the Natural History of Pancreatic Cancer: From Predisposition to Therapy , 2022, Cancers.

[8]  C. Dang,et al.  The microbiome-derived metabolite TMAO drives immune activation and boosts responses to immune checkpoint blockade in pancreatic cancer , 2022, Science Immunology.

[9]  Xiaopeng Chen,et al.  microRNA-497 prevents pancreatic cancer stem cell gemcitabine resistance, migration, and invasion by directly targeting nuclear factor kappa B 1 , 2022, Aging.

[10]  Xiaoxue Zhou,et al.  Microbiota in Tumors: From Understanding to Application , 2022, Advanced science.

[11]  M. Malafa,et al.  Pancreatic Ductal Carcinoma Risk Associated With Hereditary Cancer-Risk Genes , 2022, Journal of the National Cancer Institute.

[12]  S. Hecht,et al.  Metabolic Activation and DNA Interactions of Carcinogenic N-Nitrosamines to Which Humans Are Commonly Exposed , 2022, International journal of molecular sciences.

[13]  C. Guinane,et al.  The impact of the human microbiome in tumorigenesis, cancer progression, and biotherapeutic development , 2022, BMC microbiology.

[14]  E. Giovannetti,et al.  A Comprehensive Review of the Current and Future Role of the Microbiome in Pancreatic Ductal Adenocarcinoma , 2022, Cancers.

[15]  E. Stachowska,et al.  Pancreatic Cancer and Gut Microbiome-Related Aspects: A Comprehensive Review and Dietary Recommendations , 2021, Nutrients.

[16]  S. Gea-Sorlí,et al.  Inhibition of miR-222 by Oncolytic Adenovirus-Encoded miRNA Sponges Promotes Viral Oncolysis and Elicits Antitumor Effects in Pancreatic Cancer Models , 2021, Cancers.

[17]  B. Nelson,et al.  CEACAM7 Is an Effective Target for CAR T-cell Therapy of Pancreatic Ductal Adenocarcinoma , 2021, Clinical Cancer Research.

[18]  V. Pazienza,et al.  High Levels of Prebiotic Resistant Starch in Diet Modulate a Specific Pattern of miRNAs Expression Profile Associated to a Better Overall Survival in Pancreatic Cancer , 2020, Biomolecules.

[19]  W. Fisher,et al.  Microbiome changes associated with acute and chronic pancreatitis: A systematic review. , 2020, Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.].

[20]  Shruti S Sawant,et al.  Microbes as Medicines: Harnessing the Power of Bacteria in Advancing Cancer Treatment , 2020, International journal of molecular sciences.

[21]  G. Nussbaum,et al.  Intracellular Porphyromonas gingivalis Promotes the Tumorigenic Behavior of Pancreatic Carcinoma Cells , 2020, Cancers.

[22]  D. Metz,et al.  The association of Helicobacter pylori with pancreatic cancer , 2020, GastroHep.

[23]  Noam Shental,et al.  The human tumor microbiome is composed of tumor type–specific intracellular bacteria , 2020, Science.

[24]  F. He,et al.  [Effects of Akkermansia muciniphila on the Proliferation, Apoptosis and Insulin Secretion of Rat Islet Cell Tumor Cells]. , 2020, Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition.

[25]  C. Xiong,et al.  Mechanisms of Oral Bacterial Virulence Factors in Pancreatic Cancer , 2019, Front. Cell. Infect. Microbiol..

[26]  J. Shim,et al.  Microbial Metabolites Determine Host Health and the Status of Some Diseases , 2019, International journal of molecular sciences.

[27]  Z. Karányi,et al.  Lithocholic Acid, a Metabolite of the Microbiome, Increases Oxidative Stress in Breast Cancer , 2019, Cancers.

[28]  Christine B. Peterson,et al.  Tumor Microbiome Diversity and Composition Influence Pancreatic Cancer Outcomes , 2019, Cell.

[29]  Zhuling Yang,et al.  Expression of FXR and HRG and their clinicopathological significance in benign and malignant pancreatic lesions. , 2019, International journal of clinical and experimental pathology.

[30]  Xianjun Yu,et al.  The microbiota and microbiome in pancreatic cancer: more influential than expected , 2019, Molecular cancer.

[31]  M. Inoue,et al.  Helicobacter pylori infection, atrophic gastritis, and risk of pancreatic cancer: A population-based cohort study in a large Japanese population: the JPHC Study , 2019, Scientific Reports.

[32]  B. Helmink,et al.  The microbiome, cancer, and cancer therapy , 2019, Nature Medicine.

[33]  H. Eguchi,et al.  Possible involvement of Enterococcus infection in the pathogenesis of chronic pancreatitis and cancer. , 2018, Biochemical and biophysical research communications.

[34]  N. Merchant,et al.  Microbial Dysbiosis and polyamine metabolism as predictive markers for early detection of pancreatic cancer , 2018, bioRxiv.

[35]  J. Goedert,et al.  Lithocholic acid, a bacterial metabolite reduces breast cancer cell proliferation and aggressiveness. , 2018, Biochimica et biophysica acta. Bioenergetics.

[36]  Y. Yamaoka,et al.  Aggregatibacter actinomycetemcomitans infection causes DNA double‐strand breaks in host cells , 2018, Genes to cells : devoted to molecular & cellular mechanisms.

[37]  G. Jenkins,et al.  Comparison of the composition of bile acids in bile of patients with adenocarcinoma of the pancreas and benign disease , 2017, The Journal of Steroid Biochemistry and Molecular Biology.

[38]  Noam Shental,et al.  Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine , 2017, Science.

[39]  S. Amar,et al.  Periodontal disease, edentulism, and pancreatic cancer: a meta-analysis , 2017, Annals of oncology : official journal of the European Society for Medical Oncology.

[40]  R. Hayes,et al.  Human oral microbiome and prospective risk for pancreatic cancer: a population-based nested case-control study , 2016, Gut.

[41]  Qi Zhang,et al.  The hepatitis B virus X protein promotes pancreatic cancer through modulation of the PI3K/AKT signaling pathway. , 2016, Cancer letters.

[42]  A. Khorana,et al.  Metastatic Pancreatic Cancer: American Society of Clinical Oncology Clinical Practice Guideline. , 2016, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[43]  Hui-Yi Feng,et al.  Role of bile acids in carcinogenesis of pancreatic cancer: An old topic with new perspective , 2016, World journal of gastroenterology.

[44]  P. Hylemon,et al.  Consequences of bile salt biotransformations by intestinal bacteria , 2016, Gut microbes.

[45]  Dong Soo Lee,et al.  Helicobacter pylori in gastric carcinogenesis. , 2015, World journal of gastrointestinal oncology.

[46]  F. Ginhoux,et al.  Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota , 2015, Science.

[47]  G. Kouraklis,et al.  Pregnane X Receptor Expression in Human Pancreatic Adenocarcinoma: Associations With Clinicopathologic Parameters, Tumor Proliferative Capacity, Patients’ Survival, and Retinoid X Receptor Expression , 2015, Pancreas.

[48]  S. Jonjić,et al.  Binding of the Fap2 protein of Fusobacterium nucleatum to human inhibitory receptor TIGIT protects tumors from immune cell attack. , 2015, Immunity.

[49]  E. Kallay,et al.  The vitamin D system is deregulated in pancreatic diseases , 2014, The Journal of Steroid Biochemistry and Molecular Biology.

[50]  G. Mirey,et al.  The Cytolethal Distending Toxin Effects on Mammalian Cells: A DNA Damage Perspective , 2014, Cells.

[51]  Jacques Izard,et al.  Microbiota, Oral Microbiome, and Pancreatic Cancer , 2014, Cancer journal.

[52]  K. S. Prabhu,et al.  The microbiome and obesity-an established risk for certain types of cancer. , 2014, Cancer journal.

[53]  Xi Chen,et al.  Novel mechanistic insights into ectodomain shedding of EGFR Ligands Amphiregulin and TGF-α: impact on gastrointestinal cancers driven by secondary bile acids. , 2014, Cancer research.

[54]  A. Schieber,et al.  The Role of Intestinal Microbiota in Development of Irinotecan Toxicity and in Toxicity Reduction through Dietary Fibres in Rats , 2014, PloS one.

[55]  P. Gérard.  Metabolism of Cholesterol and Bile Acids by the Gut Microbiota , 2013, Pathogens.

[56]  F. Marincola,et al.  Commensal Bacteria Control Cancer Response to Therapy by Modulating the Tumor Microenvironment , 2013, Science.

[57]  M. R. Rubinstein,et al.  Fusobacterium nucleatum promotes colorectal carcinogenesis by modulating E-cadherin/β-catenin signaling via its FadA adhesin. , 2013, Cell host & microbe.

[58]  K. Brown,et al.  Current trends in preoperative biliary stenting in patients with pancreatic cancer. , 2013, Surgery.

[59]  A. Gurney,et al.  Canonical wnt signaling is required for pancreatic carcinogenesis. , 2013, Cancer research.

[60]  Qiang Feng,et al.  A metagenome-wide association study of gut microbiota in type 2 diabetes , 2012, Nature.

[61]  F. Clavel-Chapelon,et al.  Plasma antibodies to oral bacteria and risk of pancreatic cancer in a large European prospective cohort study , 2012, Gut.

[62]  D. Heron,et al.  Adjuvant Stereotactic Body Radiotherapy for Resected Pancreatic Adenocarcinoma with Close or Positive Margins , 2012, Journal of Gastrointestinal Cancer.

[63]  T. Mak,et al.  Natural killer cell activation enhances immune pathology and promotes chronic infection by limiting CD8+ T-cell immunity , 2011, Proceedings of the National Academy of Sciences.

[64]  A. Maitra,et al.  Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[65]  M. Shoham,et al.  Fusobacterium nucleatum adhesin FadA binds vascular endothelial cadherin and alters endothelial integrity , 2011, Molecular microbiology.

[66]  V. Lemmens,et al.  Improving outcome for patients with pancreatic cancer through centralization , 2011, The British journal of surgery.

[67]  P. Woster,et al.  Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis-induced colon tumorigenesis , 2011, Proceedings of the National Academy of Sciences.

[68]  Matthew R. Redinbo,et al.  Alleviating Cancer Drug Toxicity by Inhibiting a Bacterial Enzyme , 2010, Science.

[69]  Malte Buchholz,et al.  Stromal biology and therapy in pancreatic cancer , 2010, Gut.

[70]  F. C. Gibson,et al.  Review: Pathogen-induced inflammation at sites distant from oral infection: bacterial persistence and induction of cell-specific innate immune inflammatory pathways. , 2010, Molecular oral microbiology.

[71]  N. Neerchal,et al.  Image-Guided Stereotactic Radiosurgery for Locally Advanced Pancreatic Adenocarcinoma Results of First 85 Patients , 2010, Journal of Gastrointestinal Surgery.

[72]  Tibor Schuster,et al.  Preoperative/Neoadjuvant Therapy in Pancreatic Cancer: A Systematic Review and Meta-analysis of Response and Resection Percentages , 2010, PLoS medicine.

[73]  S. Sørensen,et al.  Gut Microbiota in Human Adults with Type 2 Diabetes Differs from Non-Diabetic Adults , 2010, PloS one.

[74]  D. Gouma,et al.  Preoperative biliary drainage for cancer of the head of the pancreas. , 2010, The New England journal of medicine.

[75]  E. Díaz-Rubio,et al.  Second-line therapy for advanced pancreatic cancer: a review of the literature and future directions. , 2009, Cancer treatment reviews.

[76]  R. Hruban,et al.  Assessment of “Gene–Environment” Interaction in Cases of Familial and Sporadic Pancreatic Cancer , 2009, Journal of Gastrointestinal Surgery.

[77]  Alison P. Klein,et al.  Exomic Sequencing Identifies PALB2 as a Pancreatic Cancer Susceptibility Gene , 2009, Science.

[78]  P. Allavena,et al.  Cancer-related inflammation , 2008, Nature.

[79]  Douglas B. Evans,et al.  Role of adjuvant chemoradiation therapy in adenocarcinomas of the ampulla of vater. , 2008, International journal of radiation oncology, biology, physics.

[80]  D. Ankerst,et al.  The Role of Adjuvant Chemotherapy for Patients with Resected Pancreatic Cancer: Systematic Review of Randomized Controlled Trials and Meta-Analysis , 2008, Oncology.

[81]  P. Murawa,et al.  Erlotinib Plus Gemcitabine Compared With Gemcitabine Alone in Patients With Advanced Pancreatic Cancer: A Phase III Trial of the National Cancer Institute of Canada Clinical Trials Group , 2023, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[82]  A. Yoon,et al.  Suicide cancer gene therapy using pore-forming toxin, streptolysin O , 2006, Molecular Cancer Therapeutics.

[83]  U. Stenram,et al.  Helicobacter species ribosomal DNA in the pancreas, stomach and duodenum of pancreatic cancer patients. , 2006, World journal of gastroenterology.

[84]  M. Kudo,et al.  Dynamic imaging of pancreatic diseases by contrast enhanced coded phase inversion harmonic ultrasonography , 2004, Gut.

[85]  H. Friess,et al.  Curative resection is the single most important factor determining outcome in patients with pancreatic adenocarcinoma , 2004, The British journal of surgery.

[86]  Alison P. Klein,et al.  Prospective Risk of Pancreatic Cancer in Familial Pancreatic Cancer Kindreds , 2004, Cancer Research.

[87]  R. Jeffrey,et al.  MDCT in Pancreatic adenocarcinoma: prediction of vascular invasion and resectability using a multiphasic technique with curved planar reformations. , 2004, AJR. American journal of roentgenology.

[88]  Agneta Richter-Dahlfors,et al.  Vesicle-Mediated Export and Assembly of Pore-Forming Oligomers of the Enterobacterial ClyA Cytotoxin , 2003, Cell.

[89]  A. Ziegler,et al.  BRCA2 germline mutations in familial pancreatic carcinoma. , 2003, Journal of the National Cancer Institute.

[90]  R. Jeffrey,et al.  Local staging of pancreatic carcinoma with multi-detector row CT: use of curved planar reformations initial experience. , 2002, Radiology.

[91]  W. Schima,et al.  Diagnosis and staging of pancreatic cancer: comparison of mangafodipir trisodium-enhanced MR imaging and contrast-enhanced helical hydro-CT. , 2002, AJR. American journal of roentgenology.

[92]  Hong-Jin Kim,et al.  Does neoadjuvant chemoradiation downstage locally advanced pancreatic cancer? , 2002, Journal of Gastrointestinal Surgery.

[93]  S. Rickes,et al.  Differentiation of Pancreatic Tumours by Conventional Ultrasound, Unenhanced and Echo-Enhanced Power Doppler Sonography , 2002, Scandinavian journal of gastroenterology.

[94]  T. Ichikawa,et al.  Duct-penetrating sign at MRCP: usefulness for differentiating inflammatory pancreatic mass from pancreatic carcinomas. , 2001, Radiology.

[95]  M. Blaser,et al.  Helicobacter pylori Seropositivity as a Risk Factor for Pancreatic Cancer , 2001 .

[96]  D. Kerr,et al.  European Study Group for Pancreatic Cancer‐1 interim results: a European randomized study to assess the roles of adjuvant chemotherapy and chemoradiation in resectable pancreatic cancer , 2001 .

[97]  J. Laméris,et al.  MRI with mangafodipir trisodium in the detection and staging of pancreatic cancer , 2000, Journal of magnetic resonance imaging : JMRI.

[98]  J. Rastad,et al.  Abdominal US for diagnosis of pancreatic tumor: prospective cohort analysis. , 1999, Radiology.

[99]  Jeffrey E. Lee,et al.  Rapid-fractionation preoperative chemoradiation, pancreaticoduodenectomy, and intraoperative radiation therapy for resectable pancreatic adenocarcinoma. , 1998, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[100]  J Coste,et al.  Pancreatic tumors: comparison of dual-phase helical CT and endoscopic sonography. , 1998, AJR. American journal of roentgenology.

[101]  D. V. Von Hoff,et al.  Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. , 1997, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[102]  B. Marincek,et al.  Pancreatic tumors: evaluation with endoscopic US, CT, and MR imaging. , 1994, Radiology.

[103]  S. Goodman,et al.  K-ras oncogene activation in adenocarcinoma of the human pancreas. A study of 82 carcinomas using a combination of mutant-enriched polymerase chain reaction analysis and allele-specific oligonucleotide hybridization. , 1993, The American journal of pathology.

[104]  E. Deitch,et al.  Absence of intestinal bile promotes bacterial translocation. , 1992, The American surgeon.

[105]  V. Dest,et al.  When the diagnosis is pancreatic cancer. , 1991, RN.

[106]  S. Ellenberg,et al.  Pancreatic cancer. Adjuvant combined radiation and chemotherapy following curative resection. , 1985, Archives of surgery.

[107]  S. Hirano,et al.  [Transformation of bile acids by Bacteroides fragilis strains isolated from the human intestine (author's transl)]. , 1979, Nihon saikingaku zasshi. Japanese journal of bacteriology.

[108]  H. Kocher,et al.  Pancreatic Cancer , 2019, Methods in Molecular Biology.

[109]  Hodgkin Lymphoma.  NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines , 2014 .

[110]  E. Diamandis,et al.  Pancreatic cancer. , 2013, Clinical chemistry.

[111]  Yuchen Jiao,et al.  ATM mutations in patients with hereditary pancreatic cancer. , 2012, Cancer discovery.

[112]  S. Onda,et al.  [Pancreatic carcinoma]. , 2012, Nihon rinsho. Japanese journal of clinical medicine.

[113]  C. Catalano,et al.  Pancreatic carcinoma: the role of high-resolution multislice spiral CT in the diagnosis and assessment of resectability , 2002, European Radiology.

[114]  C. Compton,et al.  AJCC Cancer Staging Manual , 2002, Springer New York.

[115]  D. Roe,et al.  Quantitative relationship between oral nitrate-reducing activity and the endogenous formation of N-nitrosoamino acids in humans. , 1991, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[116]  I. M. Neiman,et al.  [Inflammation and cancer]. , 1974, Patologicheskaia fiziologiia i eksperimental'naia terapiia.