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  • Review Article
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Multifaceted effects of the microbiome in pancreatic cancer: from association to modulation

Nature Reviews Gastroenterology & Hepatology volume 22, pages 829–845 (2025)Cite this article

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Abstract

Investigations into the microbiome in human diseases have exponentially increased over the past several decades, and the microbiome has been associated with nearly every malignancy, with research moving beyond associative studies to investigations into the microbiome as a causative factor in carcinogenesis. Pancreatic ductal adenocarcinoma (PDAC), the most common malignancy of the pancreas, is a major cause of worldwide cancer mortality owing to the lack of screening methods, late stage at diagnosis and poor response to currently available treatments. Microbiome–pancreatic cancer research has advanced, with research demonstrating that elements of the gut microbiome can modulate antitumour immune function, and microbial-derived products have been shown to influence response to chemotherapy. Additionally, microbiome-based ‘signatures’ have been identified that can act as biomarkers to predict PDAC and improve on currently available serum tumour markers. In this Review, how the microbiome mechanistically influences pancreatic tumours, with a focus on PDAC, and its clinical implications is described using ground-breaking historical and contemporary studies as a framework. The direction for future studies is also discussed.

Key points

  • Bacterial, viral and fungal microbiomes have been associated with pancreatic ductal adenocarcinoma.

  • Intrapancreatic as well as the gut microbiome both have a critical role in immunomodulation within the tumour microenvironment of pancreatic cancer.

  • The microbiome can influence the immunosuppressive tumour microenvironment of pancreatic cancer and facilitate activation of antitumour immune cells.

  • Microbial-derived metabolites and by-products have been shown to influence pancreatic carcinogenesis and treatment response.

  • Evidence exists that sequencing the bacterial microbiome from faeces, when combined with the clinically used serum marker CA19-9, can provide diagnostic accuracy for pancreatic cancer superior to CA19-9 alone.

  • Elements of the microbiome have been shown to influence the response of pancreatic ductal adenocarcinoma to systemic chemotherapy and immunotherapy either directly or indirectly.

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Fig. 1: Role of microbiome modulation of immune function in PDAC.
Fig. 2: The influence of the gut microbiome on treatment efficacy.

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References

  1. Russell, W. An address on a characteristic organism of cancer. Br. Med. J. 2, 1356–1360 (1890).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Whipps, J. M., Lewis, K. & Cooke, R. C. in Fungi in Biological Control Systems (ed. Burge, M. N.) 161–187 (Manchester Univ. Press, 1988).

  3. Huang, D. W., Sherman, B. T. & Lempicki, R. A. Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res. 37, 1–13 (2009).

    Article  PubMed  Google Scholar 

  4. Di Bella, J. M., Bao, Y., Gloor, G. B., Burton, J. P. & Reid, G. High throughput sequencing methods and analysis for microbiome research. J. Microbiol. Methods 95, 401–414 (2013).

    Article  PubMed  Google Scholar 

  5. Staley, C. & Sadowsky, M. J. Practical considerations for sampling and data analysis in contemporary metagenomics-based environmental studies. J. Microbiol. Methods 154, 14–18 (2018).

    Article  PubMed  Google Scholar 

  6. Thomas, R. M. & Jobin, C. The microbiome and cancer: is the “oncobiome” mirage real? Trends Cancer 1, 24–35 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Rose, C., Parker, A., Jefferson, B. & Cartmell, E. The characterization of feces and urine: a review of the literature to inform advanced treatment technology. Crit. Rev. Environ. Sci. Technol. 45, 1827–1879 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Borges-Canha, M. et al. Role of colonic microbiota in colorectal carcinogenesis: a systematic review. Rev. Esp. Enferm. Dig. 107, 659–671 (2015).

    Article  PubMed  Google Scholar 

  9. Sobhani, I. et al. Microbial dysbiosis in colorectal cancer (CRC) patients. PLoS ONE 6, e16393 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Schwabe, R. F. & Jobin, C. The microbiome and cancer. Nat. Rev. Cancer 13, 800–812 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Rahib, L. et al. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 74, 2913–2921 (2014).

    Article  PubMed  Google Scholar 

  12. Siegel, R. L., Giaquinto, A. N. & Jemal, A. Cancer statistics, 2024. CA Cancer J. Clin. 74, 12–49 (2024).

    PubMed  Google Scholar 

  13. Cruz, M. S., Tintelnot, J. & Gagliani, N. Roles of microbiota in pancreatic cancer development and treatment. Gut Microbes 16, 2320280 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Da Silver Xavier, G. The cells of the islets of langerhans. J. Clin. Med. 7, 54 (2018).

    Article  Google Scholar 

  15. Sedlack, A. J. H. et al. Update in the management of gastroenteropancreatic neuroendocrine tumors. Cancer 130, 3090–3105 (2024).

    Article  PubMed  Google Scholar 

  16. Zhang, C.-Y. et al. Investigating the causal relationship between gut microbiota and gastroenteropancreatic neuroendocrine neoplasms: a bidirectional Mendelian randomization study. Front. Microbiol. 15, 1420167 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Kurki, M. I. et al. FinnGen provides genetic insights from a well-phenotyped isolated population. Nature 613, 508–518 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Kurilshikov, A. et al. Large-scale association analyses identify host factors influencing human gut microbiome composition. Nat. Genet. 53, 156–165 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Chen, Z., Wang, Z., Bao, H. & Ma, S. Gut microbiota and pancreatic cancer risk, and the mediating role of immune cells and inflammatory cytokines: a Mendelian randomization study. Front. Immunol. 15, 1408770 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Dorrestein, P. C., Mazmanian, S. K. & Knight, R. Finding the missing links among metabolites, microbes, and the host. Immunity 40, 824–832 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Nejman, D. et al. The human tumor microbiome is composed of tumor type-specific intracellular bacteria. Science 368, 973–980 (2020). A comprehensive profiling of the intratumoural microbiome of seven different tumour types, including PDAC, demonstrates the compositional differences between tumour microbiomes and that most bacteria are present intracellularly, specifically within tumour and immune cells.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Massironi, S. et al. Intratumor microbiome in neuroendocrine neoplasms: a new partner of tumor microenvironment? A pilot study. Cells 11, 692 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Underhill, D. M. & Iliev, I. D. The mycobiota: interactions between commensal fungi and the host immune system. Nat. Rev. Immunol. 14, 405–416 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Honkanen, J. et al. Fungal dysbiosis and intestinal inflammation in children with beta-cell autoimmunity. Front. Immunol. 11, 468 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Salamon, D. et al. Analysis of the gut mycobiome in adult patients with type 1 and type 2 diabetes using next-generation sequencing (NGS) with increased sensitivity-pilot study. Nutrients 13, 1066 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Steenblock, C. et al. Viral infiltration of pancreatic islets in patients with COVID-19. Nat. Commun. 12, 3534 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Dotta, F. et al. Coxsackie B4 virus infection of β cells and natural killer cell insulitis in recent-onset type 1 diabetic patients. Proc. Natl Acad. Sci. USA 104, 5115–5120 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Müller, J. A. et al. SARS-CoV-2 infects and replicates in cells of the human endocrine and exocrine pancreas. Nat. Metab. 3, 149–165 (2021).

    Article  PubMed  Google Scholar 

  29. Isaacs, S. R. et al. Enteroviruses and risk of islet autoimmunity or type 1 diabetes: systematic review and meta-analysis of controlled observational studies detecting viral nucleic acids and proteins. Lancet Diabetes Endocrinol. 11, 578–592 (2023).

    Article  PubMed  Google Scholar 

  30. Hruban, R. H., Goggins, M., Parsons, J. & Kern, S. E. Progression model for pancreatic cancer. Clin. Cancer Res. 6, 2969–2972 (2000). Comprehensive review illustrating the model of progression of pancreatic cancer that is necessary for a general understanding of this disease.

    PubMed  Google Scholar 

  31. Iacobuzio-Donahue, C. A., Velculescu, V. E., Wolfgang, C. L. & Hruban, R. H. Genetic basis of pancreas cancer development and progression: insights from whole-exome and whole-genome sequencing. Clin. Cancer Res. 18, 4257–4265 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Rawla, P., Sunkara, T. & Gaduputi, V. Epidemiology of pancreatic cancer: global trends, etiology and risk factors. World J. Oncol. 10, 10–27 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Jandhyala, S. M. et al. Altered intestinal microbiota in patients with chronic pancreatitis: implications in diabetes and metabolic abnormalities. Sci. Rep. 7, 43640 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Isaiah, A., Parambeth, J. C., Steiner, J. M., Lidbury, J. A. & Suchodolski, J. S. The fecal microbiome of dogs with exocrine pancreatic insufficiency. Anaerobe 45, 50–58 (2017).

    Article  PubMed  Google Scholar 

  35. Zhang, X. M. et al. Intestinal microbial community differs between acute pancreatitis patients and healthy volunteers. Biomed. Environ. Sci. 31, 81–86 (2018).

    PubMed  Google Scholar 

  36. Hong, J. et al. Gut microbiome changes associated with chronic pancreatitis and pancreatic cancer: a systematic review and meta-analysis. Int. J. Surg. 110, 5781–5794 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Sonika, U. et al. Mechanism of increased intestinal permeability in acute pancreatitis: alteration in tight junction proteins. J. Clin. Gastroenterol. 51, 461–466 (2017).

    Article  PubMed  Google Scholar 

  38. Ammori, B. J. et al. Early increase in intestinal permeability in patients with severe acute pancreatitis: correlation with endotoxemia, organ failure, and mortality. J. Gastrointest. Surg. 3, 252–262 (1999).

    Article  PubMed  Google Scholar 

  39. Dougherty, M. W. & Jobin, C. Intestinal bacteria and colorectal cancer: etiology and treatment. Gut Microbes 15, 2185028 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Thomas, R. M. Microbial molecules, metabolites, and malignancy. Neoplasia 60, 101128 (2025).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Matthaei, H., Schulick, R. D., Hruban, R. H. & Maitra, A. Cystic precursors to invasive pancreatic cancer. Nat. Rev. Gastroenterol. Hepatol. 8, 141–150 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Basturk, O. et al. A revised classification system and recommendations from the Baltimore consensus meeting for neoplastic precursor lesions in the pancreas. Am. J. Surg. Pathol. 39, 1730–1741 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  43. Maker, A. V. et al. Cyst fluid biosignature to predict intraductal papillary mucinous neoplasms of the pancreas with high malignant potential. J. Am. Coll. Surg. 228, 721–729 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Matthaei, H. et al. miRNA biomarkers in cyst fluid augment the diagnosis and management of pancreatic cysts. Clin. Cancer Res. 18, 4713–4724 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Pust, M.-M. et al. Absence of a pancreatic microbiome in intraductal papillary mucinous neoplasm. Gut 73, 1131–1141 (2024).

    Article  PubMed  Google Scholar 

  46. Caporaso, J. G. et al. Global patterns of 16S rRNA diversity at a depth of millions of sequences per sample. Proc. Natl Acad. Sci. USA 108, 4516–4522 (2011).

    Article  PubMed  Google Scholar 

  47. Goodrich, J. K. et al. Conducting a microbiome study. Cell 158, 250–262 (2014). A critical manuscript outlining the necessary steps to design, carry out and analyse a microbiome study, regardless of hypothesis or disease type.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Li, S. et al. Pancreatic cyst fluid harbors a unique microbiome. Microbiome 5, 147 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Gaiser, R. A. et al. Enrichment of oral microbiota in early cystic precursors to invasive pancreatic cancer. Gut 68, 2186–2194 (2019).

    Article  PubMed  Google Scholar 

  50. Wang, B. et al. The roles and interactions of Porphyromonas gingivalis and fusobacterium nucleatum in oral and gastrointestinal carcinogenesis: a narrative review. Pathogens 13, 93 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Pushalkar, S. et al. The pancreatic cancer microbiome promotes oncogenesis by induction of innate and adaptive immune suppression. Cancer Discov. 8, 403–416 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Thomas, R. M. et al. Intestinal microbiota enhances pancreatic carcinogenesis in preclinical models. Carcinogenesis 39, 1068–1078 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Halimi, A. et al. Isolation of pancreatic microbiota from cystic precursors of pancreatic cancer with intracellular growth and DNA damaging properties. Gut Microbes 13, 1983101 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Hingorani, S. R. et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 4, 437–450 (2003).

    Article  PubMed  Google Scholar 

  55. Hingorani, S. R. et al. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 7, 469–483 (2005).

    Article  PubMed  Google Scholar 

  56. Hill, R. et al. PTEN loss accelerates KrasG12D-induced pancreatic cancer development. Cancer Res. 70, 7114–7124 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Saba, E. et al. Oral bacteria accelerate pancreatic cancer development in mice. Gut 73, 770–786 (2024).

    Article  PubMed  Google Scholar 

  58. Ma, H., Luo, W. & Gu, Y. Does oral microbiota have a close relationship with pancreatic cancer? a systematic review and meta-analysis. Ann. Surg. Oncol. 30, 8635–8641 (2023).

    Article  PubMed  Google Scholar 

  59. Storz, P. Acinar cell plasticity and development of pancreatic ductal adenocarcinoma. Nat. Rev. Gastroenterol. Hepatol. 14, 296–304 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Kleeff, J. et al. Pancreatic cancer. Nat. Rev. Dis. Primers 2, 16022 (2016).

    Article  PubMed  Google Scholar 

  61. McGuigan, A. et al. Pancreatic cancer: a review of clinical diagnosis, epidemiology, treatment and outcomes. World J. Gastroenterol. 24, 4846–4861 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Raderer, M. et al. Association between Helicobacter pylori infection and pancreatic cancer. Oncology 55, 16–19 (1998).

    Article  PubMed  Google Scholar 

  63. Stolzenberg-Solomon, R. Z. et al. Helicobacter pylori seropositivity as a risk factor for pancreatic cancer. J. Natl Cancer Inst. 93, 937–941 (2001).

    Article  PubMed  Google Scholar 

  64. Yu, G. et al. Seropositivity to Helicobacter pylori and risk of pancreatic cancer. Cancer Epidemiol. Biomark. Prev. 22, 2416–2419 (2013).

    Article  Google Scholar 

  65. Maisonneuve, P., Amar, S. & Lowenfels, A. B. Periodontal disease, edentulism, and pancreatic cancer: a meta-analysis. Ann. Oncol. 28, 985–995 (2017).

    Article  PubMed  Google Scholar 

  66. Cutler, C. W., Kalmar, J. R. & Genco, C. A. Pathogenic strategies of the oral anaerobe, Porphyromonas gingivalis. Trends Microbiol. 3, 45–51 (1995).

    Article  PubMed  Google Scholar 

  67. Ahn, J., Segers, S. & Hayes, R. B. Periodontal disease, Porphyromonas gingivalis serum antibody levels and orodigestive cancer mortality. Carcinogenesis 33, 1055–1058 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  68. Michaud, D. S. et al. Plasma antibodies to oral bacteria and risk of pancreatic cancer in a large European prospective cohort study. Gut 62, 1764–1770 (2013).

    Article  PubMed  Google Scholar 

  69. Duan, D. et al. Advances in multi-omics integrated analysis methods based on the gut microbiome and their applications. Front. Microbiol. 15, 1509117 (2024).

    Article  PubMed  Google Scholar 

  70. Farrell, J. J. et al. Variations of oral microbiota are associated with pancreatic diseases including pancreatic cancer. Gut 61, 582–588 (2012). One of the earliest investigations demonstrating an association of a microbiota, in this case the salivary microbiota, with pancreatic cancer.

    Article  PubMed  Google Scholar 

  71. Ren, Z. et al. Gut microbial profile analysis by MiSeq sequencing of pancreatic carcinoma patients in China. Oncotarget 8, 95176–95191 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Chen, J., Zhao, K.-N. & Vitetta, L. Effects of intestinal microbial-elaborated butyrate on oncogenic signaling pathways. Nutrients 11, 1026 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Encarnação, J. C. et al. Butyrate, a dietary fiber derivative that improves irinotecan effect in colon cancer cells. J. Nutr. Biochem. 56, 183–192 (2018).

    Article  PubMed  Google Scholar 

  74. Zhu, X. et al. Microbial metabolite butyrate promotes anti-PD-1 antitumor efficacy by modulating T cell receptor signaling of cytotoxic CD8 T cell. Gut Microbes 15, 2249143 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Turner, B. G. et al. Diagnosis of pancreatic neoplasia with EUS and FNA: a report of accuracy. Gastrointest. Endosc. 71, 91–98 (2010).

    Article  PubMed  Google Scholar 

  76. Chen, G., Liu, S., Zhao, Y., Dai, M. & Zhang, T. Diagnostic accuracy of endoscopic ultrasound-guided fine-needle aspiration for pancreatic cancer: a meta-analysis. Pancreatology 13, 298–304 (2013).

    Article  PubMed  Google Scholar 

  77. Yao, D.-W., Qin, M.-Z., Jiang, H.-X. & Qin, S.-Y. Comparison of EUS−FNA and EUS−FNB for diagnosis of solid pancreatic mass lesions: a meta-analysis of prospective studies. Scand. J. Gastroenterol. 59, 972–979 (2024).

    Article  PubMed  Google Scholar 

  78. Geller, L. T. et al. Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine. Science 357, 1156–1160 (2017). This investigation demonstrates that resistance to the common pancreatic cancer chemotherapy gemcitabine might be secondary to the presence of intratumoural Gammaproteobacteria that possesses the more active form (‘long form’) of the bacterial enzyme cytidine deaminase.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Thomas, R. M. & Jobin, C. Microbiota in pancreatic health and disease: the next frontier in microbiome research. Nat. Rev. Gastroenterol. Hepatol. 17, 53–64 (2020).

    Article  PubMed  Google Scholar 

  80. Kohi, S. et al. Alterations in the duodenal fluid microbiome of patients with pancreatic cancer. Clin. Gastroenterol. Hepatol. 20, e196–e227 (2022).

    Article  PubMed  Google Scholar 

  81. Jackson, M. A. et al. Proton pump inhibitors alter the composition of the gut microbiota. Gut 65, 749–756 (2016).

    Article  PubMed  Google Scholar 

  82. Aykut, B. et al. The fungal mycobiome promotes pancreatic oncogenesis via activation of MBL. Nature 574, 264–267 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  83. Narunsky-Haziza, L. et al. Pan-cancer analyses reveal cancer-type-specific fungal ecologies and bacteriome interactions. Cell 185, 3789–3806.e17 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Alam, A. et al. Fungal mycobiome drives IL-33 secretion and type 2 immunity in pancreatic cancer. Cancer Cell 40, 153–167.e11 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  85. Fletcher, A. A., Kelly, M. S., Eckhoff, A. M. & Allen, P. J. Revisiting the intrinsic mycobiome in pancreatic cancer. Nature 620, E1–E6 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  86. Xu, F., Saxena, D., Pushalkar, S. & Miller, G. Reply to: revisiting the intrinsic mycobiome in pancreatic cancer. Nature 620, E7–E9 (2023).

    Article  PubMed  Google Scholar 

  87. Kartal, E. et al. A faecal microbiota signature with high specificity for pancreatic cancer. Gut 71, 1359–1372 (2022). This study demonstrates the feasibility of faecal microbiota testing to detect pancreatic cancer and, when the microbiome signature was combined with the currently available pancreatic cancer tumour marker CA19-9, an even higher diagnostic accuracy was reported.

    Article  PubMed  Google Scholar 

  88. Zhang, P. et al. Metagenomic analysis reveals altered gut virome and diagnostic potential in pancreatic cancer. J. Med. Virol. 96, e29809 (2024).

    Article  PubMed  Google Scholar 

  89. Atarashi, K. et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331, 337–341 (2011).

    Article  PubMed  Google Scholar 

  90. Nutsch, K. M. & Hsieh, C.-S. T cell tolerance and immunity to commensal bacteria. Curr. Opin. Immunol. 24, 385–391 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  91. Zhu, Y.-H. et al. Immunosuppression, immune escape, and immunotherapy in pancreatic cancer: focused on the tumor microenvironment. Cell Oncol. 46, 17–48 (2023).

    Article  Google Scholar 

  92. Ho, W. J., Jaffee, E. M. & Zheng, L. The tumour microenvironment in pancreatic cancer — clinical challenges and opportunities. Nat. Rev. Clin. Oncol. 17, 527–540 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  93. Sethi, V. et al. Gut microbiota promotes tumor growth in mice by modulating immune response. Gastroenterology 155, 33–37.e6 (2018).

    Article  PubMed  Google Scholar 

  94. Yu, Q. et al. Intestinal microbiota modulates pancreatic carcinogenesis through intratumoral natural killer cells. Gut Microbes 14, 2112881 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Riquelme, E. et al. Tumor microbiome diversity and composition influence pancreatic cancer outcomes. Cell 178, 795–806.e12 (2019). Although pancreatic cancer survival is traditionally low, there are patients who are long-term survivors. This study reports that the tumour microbiome composition of short-term survivors is statistically different than long-term survivors through decreased α-diversity. This difference influences the host immune response and probably survival.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Turner, M. W. The role of mannose-binding lectin in health and disease. Mol. Immunol. 40, 423–429 (2003).

    Article  PubMed  Google Scholar 

  97. Garred, P., Larsen, F., Seyfarth, J., Fujita, R. & Madsen, H. O. Mannose-binding lectin and its genetic variants. Genes Immun. 7, 85–94 (2006).

    Article  PubMed  Google Scholar 

  98. Afshar-Kharghan, V. The role of the complement system in cancer. J. Clin. Invest. 127, 780–789 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  99. Ikebe, M. et al. Lipopolysaccharide (LPS) increases the invasive ability of pancreatic cancer cells through the TLR4/MyD88 signaling pathway. J. Surg. Oncol. 100, 725–731 (2009).

    Article  PubMed  Google Scholar 

  100. Dai, Z.-L., Wu, G. & Zhu, W.-Y. Amino acid metabolism in intestinal bacteria: links between gut ecology and host health. Front. Biosci. 16, 1768–1786 (2011).

    Article  Google Scholar 

  101. Lin, R., Liu, W., Piao, M. & Zhu, H. A review of the relationship between the gut microbiota and amino acid metabolism. Amino Acids 49, 2083–2090 (2017).

    Article  PubMed  Google Scholar 

  102. al-Waiz, M., Mikov, M., Mitchell, S. C. & Smith, R. L. The exogenous origin of trimethylamine in the mouse. Metab. Clin. Exp. 41, 135–136 (1992).

    Article  PubMed  Google Scholar 

  103. Mirji, G. et al. The microbiome-derived metabolite TMAO drives immune activation and boosts responses to immune checkpoint blockade in pancreatic cancer. Sci. Immunol. 7, eabn0704 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Heath-Pagliuso, S. et al. Activation of the Ah receptor by tryptophan and tryptophan metabolites. Biochemistry 37, 11508–11515 (1998).

    Article  PubMed  Google Scholar 

  105. Shinde, R. & McGaha, T. L. The aryl hydrocarbon receptor: connecting immunity to the microenvironment. Trends Immunol. 39, 1005–1020 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Xue, P., Fu, J. & Zhou, Y. The aryl hydrocarbon receptor and tumor immunity. Front. Immunol. 9, 286 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Hezaveh, K. et al. Tryptophan-derived microbial metabolites activate the aryl hydrocarbon receptor in tumor-associated macrophages to suppress anti-tumor immunity. Immunity 55, 324–340.e8 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  108. Roager, H. M. & Licht, T. R. Microbial tryptophan catabolites in health and disease. Nat. Commun. 9, 3294 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  109. Agrawal, R. & Natarajan, K. N. Oncogenic signaling pathways in pancreatic ductal adenocarcinoma. Adv. Cancer Res. 159, 251–283 (2023).

    Article  PubMed  Google Scholar 

  110. Yang, Q. et al. A review of gut microbiota-derived metabolites in tumor progression and cancer therapy. Adv. Sci. 10, e2207366 (2023).

    Article  Google Scholar 

  111. D’Amico, D. et al. Impact of the natural compound urolithin A on health, disease, and aging. Trends Mol. Med. 27, 687–699 (2021).

    Article  PubMed  Google Scholar 

  112. Totiger, T. M. et al. Urolithin A, a novel natural compound to target PI3K/AKT/mTOR pathway in pancreatic cancer. Mol. Cancer Ther. 18, 301–311 (2019).

    Article  PubMed  Google Scholar 

  113. Morrison, D. J. & Preston, T. Formation of short chain fatty acids by the gut microbiota and their impact on human metabolism. Gut Microbes 7, 189–200 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  114. Corrêa-Oliveira, R., Fachi, J. L., Vieira, A., Sato, F. T. & Vinolo, M. A. R. Regulation of immune cell function by short-chain fatty acids. Clin. Transl. Immunol. 5, e73 (2016).

    Article  Google Scholar 

  115. Bachem, A. et al. Microbiota-derived short-chain fatty acids promote the memory potential of antigen-activated CD8+ T cells. Immunity 51, 285–297.e5 (2019).

    Article  PubMed  Google Scholar 

  116. Coutza, C. et al. Systemic short chain fatty acids limit antitumor effect of CTLA-4 blockade in hosts with cancer. Nat. Commun. 11, 2165 (2020).

    Google Scholar 

  117. Nomura, M. et al. Association of short-chain fatty acids in the gut microbiome with clinical response to treatment with nivolumab or pembrolizumab in patients with solid cancer tumors. JAMA Netw. Open 3, e202895 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Ziemons, J. et al. Fecal levels of SCFA and BCFA during capecitabine in patients with metastatic or unresectable colorectal cancer. Clin. Exp. Med. 23, 3919–3933 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  119. Sono, M. et al. Reduction of butyrate-producing bacteria in the gut microbiome of Japanese patients with pancreatic cancer. Pancreatology 24, 1031–1039 (2024).

    Article  PubMed  Google Scholar 

  120. Zhou, W. et al. The fecal microbiota of patients with pancreatic ductal adenocarcinoma and autoimmune pancreatitis characterized by metagenomic sequencing. J. Transl. Med. 19, 215 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  121. Weir, T. L. et al. Stool microbiome and metabolome differences between colorectal cancer patients and healthy adults. PLoS ONE 8, e70803 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  122. Wu, N. et al. Dysbiosis signature of fecal microbiota in colorectal cancer patients. Microb. Ecol. 66, 462–470 (2013).

    Article  PubMed  Google Scholar 

  123. Mirzaei, R. et al. Role of microbiota-derived short-chain fatty acids in cancer development and prevention. Biomed. Pharmacother. 139, 111619 (2021).

    Article  PubMed  Google Scholar 

  124. Markowiak-Kopeć, P. & Śliżewska, K. The effect of probiotics on the production of short-chain fatty acids by human intestinal microbiome. Nutrients 12, 1107 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  125. Yang, X. et al. Clostridium butyricum and its metabolite butyrate promote ferroptosis susceptibility in pancreatic ductal adenocarcinoma. Cell Oncol. 46, 1645–1658 (2023).

    Article  Google Scholar 

  126. Irajizad, E. et al. A blood-based metabolomic signature predictive of risk for pancreatic cancer. Cell Rep. Med. 4, 101194 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  127. Nagata, N. et al. Metagenomic identification of microbial signatures predicting pancreatic cancer from a multinational study. Gastroenterology 163, 222–238 (2022).

    Article  PubMed  Google Scholar 

  128. Wallace, B. D. et al. Alleviating cancer drug toxicity by inhibiting a bacterial enzyme. Science 330, 831–835 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  129. de Castilhos, J. et al. Microbiome and pancreatic cancer: time to think about chemotherapy. Gut Microbes 16, 2374596 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  130. Yang, W. et al. Intestinal microbiota-derived short-chain fatty acids regulation of immune cell IL-22 production and gut immunity. Nat. Commun. 11, 4457 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  131. Ratajczak, W. et al. Immunomodulatory potential of gut microbiome-derived short-chain fatty acids (SCFAs). Acta Biochim. Pol. 66, 1–12 (2019).

    PubMed  Google Scholar 

  132. Tintelnot, J. et al. Microbiota-derived 3-IAA influences chemotherapy efficacy in pancreatic cancer. Nature 615, 168–174 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  133. Fu, S.-F. et al. Indole-3-acetic acid: a widespread physiological code in interactions of fungi with other organisms. Plant Signal. Behav. 10, e1048052 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  134. Von Hoff, D. D. et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N. Engl. J. Med. 369, 1691–1703 (2013).

    Article  Google Scholar 

  135. Conroy, T. et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N. Engl. J. Med. 364, 1817–1825 (2011).

    Article  PubMed  Google Scholar 

  136. Shiravand, Y. et al. Immune checkpoint inhibitors in cancer therapy. Curr. Oncol. 29, 3044–3060 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  137. Vitiello, G. A., Cohen, D. J. & Miller, G. Harnessing the microbiome for pancreatic cancer immunotherapy. Trends Cancer 5, 670–676 (2019).

    Article  PubMed  Google Scholar 

  138. Sethi, V., Vitiello, G. A., Saxena, D., Miller, G. & Dudeja, V. The role of the microbiome in immunologic development and its implication for pancreatic cancer immunotherapy. Gastroenterology 156, 2097–2115.e2 (2019).

    Article  PubMed  Google Scholar 

  139. Rogers, S., Charles, A. & Thomas, R. M. The prospect of harnessing the microbiome to improve immunotherapeutic response in pancreatic cancer. Cancers 15, 5708 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  140. Han, Z.-Y. et al. Probiotics functionalized with a gallium-polyphenol network modulate the intratumor microbiota and promote anti-tumor immune responses in pancreatic cancer. Nat. Commun. 15, 7096 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  141. Ni, Y. et al. Distinct composition and metabolic functions of human gut microbiota are associated with cachexia in lung cancer patients. ISME J. 15, 3207–3220 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  142. Yang-Jensen, S. K. et al. Intestinal host-microbe interactions fuel pulmonary inflammation in cigarette smoke exposed mice. Gut Microbes 17, 2519699 (2025).

    Article  PubMed  PubMed Central  Google Scholar 

  143. Dilmore, A. H. et al. Medication use is associated with distinct microbial features in anxiety and depression. Mol. Pyschiatry 30, 2545–2557 (2025).

    Article  Google Scholar 

  144. Szajewska, H. et al. Antibiotic-perturbed microbiota and the role of probiotics. Nat. Rev. Gastroenterol. Hepatol. 22, 155–172 (2025).

    Article  PubMed  Google Scholar 

  145. Mirzayi, C. et al. Reporting guidelines for human microbiome research: the STORMS checklist. Nat. Med. 27, 1885–1892 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  146. Knight, R. et al. Best practices for analysing microbiomes. Nat. Rev. Microbiol. 16, 410–422 (2018).

    Article  PubMed  Google Scholar 

  147. Fierer, N. et al. Guidelines for preventing and reporting contamination in low-biomass microbiome studies. Nat. Microbiol. 10, 1570–1580 (2025).

    Article  PubMed  Google Scholar 

  148. Salter, S. J. et al. Reagent and laboratory contamination can critically impact sequence-based microbiome analyses. BMC Biol. 12, 87 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  149. Caruso, V., Song, X., Asquith, M. & Karstens, L. Performance of microbiome sequence inference methods in environments with varying biomass. mSystems 4, e00163-18 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  150. Eisenhofer, R. et al. Contamination in low microbial biomass microbiome studies: issues and recommendations. Trends Microbiol. 27, 105–117 (2019).

    Article  PubMed  Google Scholar 

  151. He, Y. et al. Regional variation limits applications of healthy gut microbiome reference ranges and disease models. Nat. Med. 24, 1532–1535 (2018).

    Article  PubMed  Google Scholar 

  152. Olsson, L. M. et al. Dynamics of the normal gut microbiota: a longitudinal one-year population study in Sweden. Cell Host Microbe 30, 726–739.e3 (2022).

    Article  PubMed  Google Scholar 

  153. Xu, Z., Malmer, D., Langille, M. G. I., Way, S. F. & Knight, R. Which is more important for classifying microbial communities: who’s there or what they can do? ISME J. 8, 2357–2359 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  154. Abbas, S. et al. Bacteriophage therapy: a possible alternative therapy against antibiotic-resistant strains of Klebsiella pneumoniae. Front. Microbiol. 16, 1443430 (2025).

    Article  PubMed  PubMed Central  Google Scholar 

  155. Yarahmadi, A. et al. Beyond antibiotics: exploring multifaceted approaches to combat bacterial resistance in the modern era: a comprehensive review. Front. Cell. Infect. Microbiol. 15, 1493915 (2025).

    Article  PubMed  PubMed Central  Google Scholar 

  156. Li, Y., Li, X.-M., Duan, H.-Y., Yang, K. & Ye, J.-F. Advances and optimization strategies in bacteriophage therapy for treating inflammatory bowel disease. Front. Immunol. 15, 1398652 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  157. Xiao, Y. et al. The role of bacteriophage in inflammatory bowel disease and its therapeutic potential. Crit. Rev. Microbiol. https://doi.org/10.1080/1040841X.2025.2492154 (2025).

  158. Gilbert, J. A. et al. Clinical translation of microbiome research. Nat. Med. 31, 1099–1113 (2025).

    Article  PubMed  Google Scholar 

  159. Porcari, S. et al. International consensus statement on microbiome testing in clinical practice. Lancet Gastroenterol. Hepatol. 10, 154–167 (2025).

    Article  PubMed  Google Scholar 

  160. Tran, K. A. et al. Deep learning in cancer diagnosis, prognosis and treatment selection. Genome Med. 13, 152 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  161. McCulloch, J. A. et al. Intestinal microbiota signatures of clinical response and immune-related adverse events in melanoma patients treated with anti-PD-1. Nat. Med. 28, 545–556 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  162. Wu, G. et al. A core microbiome signature as an indicator of health. Cell 187, 6550–6565.e11 (2024).

    Article  PubMed  Google Scholar 

  163. Derosa, L. et al. Custom scoring based on ecological topology of gut microbiota associated with cancer immunotherapy outcome. Cell 187, 3373–3389.e16 (2024).

    Article  PubMed  Google Scholar 

  164. Lazaros, K. et al. Non-invasive biomarkers in the era of big data and machine learning. Sensors 25, 1396 (2025).

    Article  PubMed  PubMed Central  Google Scholar 

  165. Arulvasan, W. et al. Optimized breath analysis: customized analytical methods and enhanced workflow for broader detection of VOCs. Metabolomics 21, 17 (2025).

    Article  PubMed  PubMed Central  Google Scholar 

  166. Hutkins, R. et al. Classifying compounds as prebiotics — scientific perspectives and recommendations. Nat. Rev. Gastroenterol. Hepatol. 22, 54–70 (2025).

    Article  PubMed  Google Scholar 

  167. Armengaud, J. The dawn of the revolution that will allow us to precisely describe how microbiomes function. J. Proteom. 316, 105430 (2025).

    Article  Google Scholar 

  168. Zaramela, L. S. et al. The sum is greater than the parts: exploiting microbial communities to achieve complex functions. Curr. Opin. Biotechnol. 67, 149–157 (2021).

    Article  PubMed  Google Scholar 

  169. Sharma, K. R., Colvis, C. M., Rodgers, G. P. & Sheeley, D. M. Illuminating the druggable genome: pathways to progress. Drug Discov. Today 29, 103805 (2024).

    Article  PubMed  Google Scholar 

  170. Villani, A. et al. A powerful machine learning approach to identify interactions of differentially abundant gut microbial subsets in patients with metastatic and non-metastatic pancreatic cancer. Gut Microbes 16, 2375483 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  171. Bolyen, E. et al. Reproducible, interactive, scalable and extensible microbiome data science using QIIME 2. Nat. Biotechnol. 37, 852–857 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  172. Shalon, D. et al. Profiling the human intestinal environment under physiological conditions. Nature 617, 581–591 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  173. Schmidt, F. et al. Noninvasive assessment of gut function using transcriptional recording sentinel cells. Science 376, eabm6038 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Surgery, University of Florida College of Medicine, Gainesville, FL, USA

    Ryan M. Thomas

  2. Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, FL, USA

    Ryan M. Thomas

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Glossary

Abundance

Refers to the total amount of microorganisms in a particular sample. Also referred to as the microbial load, the abundance can be represented either as the absolute amount or as the relative abundance, which is the proportion of a particular organism or taxa to the total amount of investigated microorganisms.

Bioinformatic pipelines

A series of data manipulations and workflow analysis to convert raw sequencing or other large biological data sets into an interpretable form such as tables or graphics.

Commensal

In terms of microbiome research, commensal refers to organisms that live on and within the human body that benefit from the human host but provide no benefit or harm.

Diversity

Refers to the number of different taxa within a specimen and can be reported as α-diversity, which refers to the number of different taxa within a particular specimen, or β-diversity, which refers to the similarity or dissimilarity between two different cohorts.

Metabolomic

The study or analysis of small molecules or other metabolic processes derived from cellular physiology.

Microbiome

A group of common microorganisms (bacteria, fungus, viruses or archaea) living in a particular environment and creating a unique community structure. Unique names have been given to microbiomes comprising specific microorganisms such as the mycobiome (fungi) or virome (viruses).

Neoplasms

Any abnormal growth of cells that either do not possess the ability to spread elsewhere in the body (benign neoplasm) or do have such an ability (malignant neoplasm).

Oncobiome

The field of research that is focused on the interplay between the human microbiome and cancer development.

Pathobiont

In terms of microbiome research, pathobiont refers to microorganisms that live on and within the human body that can cause disease or harm to the host depending on genetic or environmental changes.

Symbiotic

In terms of microbiome research, symbiotic refers to microorganisms that live on and within the human body in which both host and organisms benefit from the interaction.

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Thomas, R.M. Multifaceted effects of the microbiome in pancreatic cancer: from association to modulation. Nat Rev Gastroenterol Hepatol 22, 829–845 (2025). https://doi.org/10.1038/s41575-025-01119-y

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