Pancreatic cancer is a highly lethal malignancy, with a poor prognosis that reflects late-stage diagnosis and the limited effectiveness of available treatments. Tobacco use, obesity, and a family history of pancreatic cancer are well-established risk factors, along with genetic mutations such as breast cancer gene 1 and 2 (BRCA1/2) and Kirsten rat sarcoma viral oncogene homolog (KRAS). Chronic inflammation, especially in conditions like pancreatitis, has also been implicated in increasing the risk of pancreatic cancer. However, despite these known risk factors, early detection remains elusive, and most patients are diagnosed at advanced stages when curative treatment is no longer an option.

Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, is resistant to chemotherapy and radiation, contributing to its high mortality rate. In the quest for novel treatment strategies and biomarkers for early detection, research into the role of the microbiome in cancer development has emerged as a promising field of investigation. The human microbiome, particularly the gut microbiome, consists of a complex community of bacteria, archaea, fungi, and viruses that co-evolve with the host.

The gut microbioma plays a crucial role in liver and pancreas health, influencing diseases such as non-alcoholic fatty liver disease (NAFLD), liver cirrhosis, porto-sinusoidal vascular disease (PSVD), pancreatitis, and pancreatic cancer (1, 2).

The microbial community has been implicated in various cancers, including colorectal, gastric, and hepatic cancers. Emerging evidence suggests that dysbiosis - an imbalance in microbial composition - may also contribute to pancreatic cancer. Microbial signatures in both gut and pancreas itself have been found to differ between healthy individuals and pancreatic cancer patients. Furthermore, the microbiome is thought to influence pancreatic cancer through various mechanisms, including immune modulation, chronic inflammation, and the production of microbial metabolites that impact tumor growth.

This review aims to provide a comprehensive overview of the current understanding of the microbiome’s involvement in pancreatic cancer development and progression. We will explore the links between specific microbial taxa and pancreatic cancer, outline potential mechanisms of action, and discuss how microbiome-based therapies could offer new avenues for treatment and early detection.

The literature search for this narrative review was conducted using the PubMed and Scopus databases. The search included articles published from January 2018 to January 2025 and was performed using combinations of the following keywords: “pancreatic cancer”, “biliary stent”, “dysbiosis”, “gut microbiota”, and “chemotherapy resistance”.

Articles were initially screened based on their relevance to the relationship between biliary drainage procedures, microbiota alterations, and pancreatic cancer development, progression, or treatment response. Both preclinical and clinical studies were considered, including observational studies, experimental studies, and relevant review articles.

Inclusion criteria were: (i) studies investigating the microbiome of the gut, bile, or pancreatic tissue in patients with pancreatic cancer; (ii) studies evaluating the impact of biliary stent placement or biliary drainage procedures on microbial composition; and (iii) studies addressing the role of microbiota in pancreatic cancer progression, immune modulation, inflammation, or chemotherapy resistance. Exclusion criteria included: (i) articles not written in English; (ii) studies unrelated to pancreatic cancer or biliary interventions; (iii) case reports with insufficient microbiological or mechanistic data; and (iv) abstracts without full-text availability.

After title and abstract screening, full texts of potentially eligible articles were assessed, and 66 studies published within the predefined time frame were selected for detailed analysis. Titles and abstracts were screened independently by the authors, and discrepancies were resolved through discussion.

In addition, seminal studies, landmark papers, published outside the selected time period were included to provide historical background and to support the biological and conceptual framework of the review. These additional references were not part of the structured selection process but were cited to ensure a comprehensive and contextual discussion of the topic.

Given the narrative nature of this review, no formal quality assessment or scoring system was applied. The literature search and article selection process is summarized in Figure 1. The flow diagram is intended to provide a descriptive overview of the study selection process and does not follow PRISMA guidelines, which are specific to systematic reviews.

Historically, the pancreas was considered a sterile organ due to its position in the retroperitoneum and the production of digestive enzymes capable of destroying bacteria, whose presence was regarded as a sign of infection or disease. This belief began to change with advancements in DNA sequencing and microbial detection techniques (such as 16S rRNA sequencing), which have allowed researchers to identify microbial communities in areas previously thought to be sterile, such as the pancreas. Within the pancreas, there exists a small but distinct microbiome, primarily composed of bacteria commonly found in other parts of the gastrointestinal tract. These bacteria, although present in lower numbers compared to the gut, appear to play a role in maintaining the health and normal function of the organ. Certain bacterial phyla, particularly Proteobacteria, Firmicutes, and Bacteroidetes, have been consistently identified in healthy pancreatic tissue. The phylum Proteobacteria includes a variety of Gram-negative bacteria, some of which are known for their role in inflammation and metabolic processes. Firmicutes, on the other hand, include beneficial gut bacteria such as Lactobacillus and Clostridium, which may help balance immune responses within the pancreas. Bacteroidetes are abundant Gram-negative bacteria in the gut and may influence the local immune environment of the pancreas. In addition to bacteria, some evidence suggests the presence of fungal and viral components within the pancreatic microbiome, although these microorganisms have been less extensively studied (3).

The origin of the pancreatic microbiome is still the subject of ongoing research. One hypothesis is that bacteria reach the pancreas from the intestine, traveling through the biliary and pancreatic ducts, while many others believe it is possible through systemic circulation or as a result of endoscopic procedures involving stent placement. The presence of bacteria in the pancreas associated with the intestine supports the concept of microbial translocation. This theory aligns with the gut-pancreas axis, a concept suggesting a bidirectional relationship between the microbiomes of the gut and the pancreas (4).

In recent years, research has shown that the microbiome is not only involved in maintaining homeostasis but under conditions of dysbiosis it can also contribute to the development of diseases, such as pancreatitis, diabetes and cancer (5).

Microbiome dysbiosis has been implicated in carcinogenesis through several mechanisms, such as inflammation, genotoxicity, and modulation of the immune system.

Emerging evidence suggests that the normal microbiome can play a protective role in the pancreas, potentially influencing the development of pancreatic cancer. The human microbiome, particularly the gut microbiome, interacts with the immune system and modulates inflammation, which is critical in preventing or promoting cancer development (6).

In the following paragraphs the interplay between the commensal microbiota and the immune system function in homeostasis and pancreatic cancer will be discussed.

The role of the microbiome in cancer has been well-established in gastrointestinal cancers, particularly colorectal cancer. Bacteria such as Fusobacterium nucleatum and Helicobacter pylori have been directly linked to tumorigenesis through mechanisms involving chronic inflammation, immune evasion, and the production of carcinogenic metabolites (28, 29).

Given the close anatomical and functional relationship between the pancreas and the gut, it is plausible that the microbiome could also influence the development of pancreatic cancer.

The normal microbiome varies between individuals and body sites, influenced by local conditions, host genetics, diet, antibiotic consumption, and lifestyle. In healthy conditions, commensal microorganisms interact symbiotically with the host. Dysbiosis, a disruption of this existing balance, can contribute to the pathogenesis of many diseases, including cancer (30). Nejman et al. demonstrated that each tumor type has a distinct microbial composition (31). Geller et al. compared pancreatic tumor tissues and normal pancreatic tissues, identifying bacterial DNA in 76% of tumors and in 15% of normal tissues (32). They identified Gammaproteobacteria as the most common taxa, including members of the Enterobacteriaceae and Pseudomonadaceae families, with Pseudomonas, Citrobacter, Klebsiella, Streptococcus, and Acinetobacter as the genera with the highest relative abundances. These findings are consistent with those reported by Nejman et al., demonstrating that over 60% of pancreatic tumors were positive for bacterial DNA. Consequently, it was also observed that bacterial DNA profiles were similar between the pancreas and duodenum of the same subjects, further supporting the migration of bacteria from the gut to the pancreas (33). These results suggest bacterial reflux from the duodenum to the pancreas through the major/minor papilla and the pancreatic duct, as Proteobacteria dominate the normal duodenal microbiome (31, 32). Nejman and colleagues also demonstrated that microbial populations present in tumor tissues of various cancer types are similar to those in adjacent normal tissues (31), leading to the hypothesis that the tumor microbiome evolves from microbes existing in normal tissues.

Pushalkar et al. demonstrated that the gut microbiome in patients with PDAC showed reduced bacterial diversity and an overrepresentation of certain bacterial genera, such as Proteobacteria and Firmicutes (34). The study also highlighted that these microbial changes led to alterations in the immune microenvironment, including the suppression of anti-tumor immune responses. For instance, Fusobacterium nucleatum, implicated in colorectal cancer, has also been found in pancreatic tumors. Furthermore, the presence of certain bacteria in pancreatic tissue has been correlated with patient prognosis and a reduced response to immunotherapy. A study by Riquelme et al. found that the dysbiosis within pancreatic tumors was associated with worse survival outcomes, and tumor cells harboring specific bacterial taxa were less responsive to immune checkpoint inhibitors, suggesting that the microbiome can influence the effectiveness of cancer treatments (35).

Finally, bile contamination, mainly related to biliary stenting and endoscopic procedures, was significantly found in patients affected by PDAC. The more represented species in bile samples (collected during endoscopic procedures or surgery) were Escherichia coli and different species of Pseudomonas, Enterobacter, and Enterococcus (36–39).

Furthermore, the presence of these microorganisms can interfere with normal cellular functions through the production of microbial metabolites and toxins. Bacterial metabolites like LPS can activate TLRs on pancreatic cells, leading to downstream signaling that promotes oncogenic pathways. Similarly, fungal components such as β-glucans, which are polysaccharides found in the cell walls of fungi, can activate the complement pathways. This activation promotes enhanced inflammatory responses, which, in turn, may create a microenvironment favorable to tumor progression (40).

Biliary stents, commonly used to manage obstructive jaundice caused by biliary strictures or tumors, represent another critical factor in the pancreatic ecosystem.

Physiologically, bile flows from the common bile duct (CBD) into the duodenum in only one direction. This process is controlled by the sphincter of Oddi, which prevents duodenal contents from refluxing into the biliary tree. When a biliary stent is placed endoscopically through the papilla of Vater, it bypasses the sphincter of Oddi. This eliminates its barrier function and creates a continuous connection between the duodenum and the biliary system. Loss of the sphincter’s ability to function properly disrupts the normal pressure gradient that pushes bile into the system. Under these circumstances, temporary increases in pressure in the duodenum can exceed the pressure in the bile ducts, causing duodenal fluid to reflux into the CBD. The stent also facilitates reflux by acting as a low-resistance channel and providing a surface that aids reverse transport.

While stents are effective at alleviating symptoms of bile duct obstruction, they also create a path for bacteria to migrate from the duodenum into the biliary system and, potentially, the pancreas and canthus altering the microbial environment. Bacteria can adhere to the stent surface, forming biofilms that are difficult to eradicate, even with antibiotic treatment. Stent-related infections often result from biofilm-forming bacteria like Escherichia coli, Klebsiella pneumoniae, and Enterococcus faecalis (Figure 2 and Table 1). These bacteria may also enter the pancreatic ductal system, exacerbating pancreatitis or contributing to secondary infections.

In patients with pancreatic cancer, biliary stents can further complicate the microbiome landscape. Given the immunosuppressive nature of pancreatic tumors, the altered microbial environment resulting from stent placement may contribute to tumor progression by promoting chronic inflammation or producing microbial metabolites that support cancer cell survival.

Blanco-Míguez et al. analyzed the microbial species present on biliary stents from 56 patients collected either during endoscopic procedures or during pancreaticoduodenectomy surgeries (41). Microbial DNA was extracted from cultivated biofilms. Indeed, in more than 80% of the samples, only three species were detected: Streptococcus anginosus, Escherichia coli, and Enterococcus faecalis. They then sought to investigate the potential bodily site of origin of the bacteria colonizing the stents. Escherichia coli, Klebsiella pneumoniae, and various lactic acid bacteria, were commonly the dominant species on the stents. In the evaluation of bile samples as a potential site of origin, only the first two bacteria were found with similar prevalence (42, 43). Instead, almost half of the prevalent species in the stents are common members of the human oral microbiome and, when present in the intestine, are predominantly associated with various diseases such as colorectal cancer, inflammatory bowel disease, atherosclerotic cardiovascular disease, and cirrhosis. No difference was detected in the type of stent, whether metallic or plastic.

Stents can also frequently become obstructed, preventing the flow of bile into the intestine, further altering the bacterial population. Cacaci et al., analyzed bile and the corresponding stent samples to determine the microbial population primarily involved in the stent occlusion process (44). The most common aerobic bacteria isolated from bile and stent samples were Gram-positive Enterococcus species, particularly Enterococcus faecalis and Enterococcus faecium, and Gram-negative bacteria Escherichia coli and Klebsiella pneumoniae (45, 46). Among yeasts, Candida albicans was found to be the predominant species (45, 46). The anaerobic bacteria identified varied among different studies. A study by Leung et al., reported the early attachment of Clostridium perfringens, Clostridium bifermentas, and Bacteroides fragilis to stents as a critical step toward the stent occlusion process (47). Another study reported the presence of Bacteroides spp, Prevotella spp., and Veillonella spp. as predominant anaerobic species (46), while another research identified Fusobacterium spp. and Veillonella spp. as the most observed anaerobic species (41).

Moreover, the role of pancreatic microbiota in tumor progression is evident even in cystic precursors of pancreatic cancer, such as intraductal papillary mucinous neoplasms (IPMNs). Halimi et al., cultured bacteria from these cystic lesions, identifying species such as Klebsiella pneumoniae, Enterococcus faecalis, and Granulicatella adiacens, which can survive inside pancreatic cells and cause DNA damage, suggesting a role in tumor progression (48).

Chemotherapy drugs can alter the gut microbiota composition, reducing beneficial bacteria like Lactobacillus and Bifidobacterium and increasing harmful bacteria such as Escherichia coli and Staphylococcus. This shift in microbiota composition is associated with an activated inflammatory pathway and impaired barrier function, making the host more vulnerable to pathogens (76). Chemotherapy can alter the gut and biliary microbiome, reducing microbial diversity and promoting the growth of resistant strains. This dysbiosis not only leads to increased susceptibility to infections but also has been shown to contribute to chemotherapy resistance (61).

Dysbiosis can affect the absorption and metabolism of chemotherapeutic agents, potentially leading to decreased efficacy and increased resistance (77). For instance, it was noted that the gut microbiota might contribute to resistance against chemotherapeutic drugs like gemcitabine by modulating the immune environment.

Interestingly, Klebsiella pneumoniae has been found to interfere with the efficacy of gemcitabine by expressing enzymes such as cytidine deaminase, which inactivates the drug (Figure 2C), highlighting the critical role of microbiota in influencing treatment outcomes (61, 78). Reducing such bacterial populations can enhance survival and response to treatment, indicating that dysbiosis can contribute to chemotherapy resistance (74). Furthermore, bacteria such as Gammaproteobacteria, which can metabolize chemotherapeutic agents like Gemcitabine, may contribute to chemoresistance, thus complicating treatment outcomes (Figure 2) (71, 72). Additionally, the authors investigate the interplay between chemotherapy and fungal dysbiosis, revealing that antifungal treatment can enhance the efficacy of gemcitabine chemotherapy (71, 72). Candida albicans infection might lead to dysbiosis, affecting the gut microbiota and potentially diminishing the efficacy of chemotherapy (75).

Dysbiosis can lead to an increase in Tregs and MDSCs, both of which suppress the immune system’s ability to attack tumor cells. This immune modulation can create a protective niche for cancer cells, enabling them to survive and proliferate despite chemotherapy (71).

Biliary stent placement is correlated with increased relative abundances of Enterobacteriaceae, a family of bacteria that has been implicated in conferring resistance to chemotherapy agents like gemcitabine, suggesting that biliary stents can alter the microbial environment in a way that may support tumor progression and impact the effectiveness of chemotherapy (40). The prolonged use of stents and exposure to antibiotics for managing stent-related infections can also select for resistant microbial populations, contributing to a cycle of dysbiosis and therapeutic resistance (71). The resistant bacterial strains identified (e.g., resistant to ampicillin-sulbactam, piperacillin-tazobactam, ciprofloxacin, and imipenem) due to preoperative biliary drainage (PBD) suggest that patients undergoing chemotherapy might experience reduced efficacy and increased resistance to these treatments due to the pre-existing resistant bacterial environment (79). Indeed, in patients undergoing chemotherapy, there is an increased risk of biliary sepsis, and the microbial organisms isolated from these stents showed high resistance rates to certain antibiotics, indicating that dysbiosis can contribute to chemotherapy resistance​​ (80).

Patients with pancreatic head cancer often suffer from obstructive jaundice, necessitating preoperative biliary stenting, especially in the context of neoadjuvant therapy.

The type of stent used for PBD also influences postoperative outcomes. Self-expandable metal stents have been shown to offer better patency and lower infection rates compared to plastic stents. A randomized trial by Soderlund et al. confirmed these findings, reporting a median better patency for metal stents (105). In contrast, plastic stents were associated with an increased incidence of cholangitis and greater bacterial resistance due to more frequent antibiotic use (106).

In an evidence based-review Dorcaratto et al., compared two methods of PBD in jaundiced patients undergoing pancreaticoduodenectomy (PD): PTBD and endoscopic biliary drainage (EBD). The analysis evaluates which method is superior in reducing complications, such as infection or liver function issues, before surgery (107). The review consolidates data from several studies to assess the safety, efficacy, and outcomes of each method in patients preparing for PD, with particular focus on the risks of cholangitis, stent dysfunction, and overall mortality rates. The review concludes that PTBD may offer certain advantages over EBD in the management of jaundiced patients awaiting PD. Specifically, PTBD is associated with a lower incidence of cholangitis and stent dysfunction, although the overall mortality rates between the two methods were similar. Moreover, in terms of bacterial load, the median was significantly higher in patients who underwent endoscopic biliary drainage, with a significantly higher Proteobacteria load. In addition, patients with biliary drainage showed a higher specific diversity.

PTBD is often associated with a reduced bacterial load due to continuous external drainage, potentially lessening microbiome alterations compared to stents. However, PTBD has its own risks, including catheter-related infections and higher rates of bile leakage, which might also modulate microbial dynamics (108, 109).

Recent studies have shown that the gut microbiota can influence tumor growth remotely. In heterotopic mouse xenograft models, Thomas et al., successfully halted PDAC growth through the administration of broad-spectrum antibiotics (110). This bacterial depletion led to increased expression of tumor suppressor genes such as death-associated protein kinase 2, Krüppel-like factor 9, and Lumican. In contrast, mice with an intact microbiota exhibited upregulation of pro-tumorigenic genes like tenascin C, chemokine ligand 10, and plexin-A4 (110). The immune status of TME in PDAC differed significantly depending on the presence or absence of the gut microbiota. In mice lacking an adaptive immune system (NOD-SCID), an increased number of CD45⁺ innate immune cells infiltrated PDAC tumors when treated with antibiotics. In contrast, untreated mice had fewer CD45⁺ cells, leading to larger tumor size. Moreover, microbial ablation has been shown to significantly slow the progression from pancreatic intraepithelial neoplasia (PanIN) to PDAC in vivo. These findings suggest that the intrapancreatic microbiota suppresses immune surveillance and innate immune responses, thus promoting tumor growth (110).

Additionally, in a human study, the depletion of Klebsiella pneumoniae, which is associated with gemcitabine resistance, improved patient survival. Bacterial ablation also enhanced the efficacy of checkpoint inhibitors by upregulating programmed PD-1 expression in PDAC mouse models. Interestingly, in renal and non-small cell lung carcinoma bacterial ablation reduced the effectiveness of checkpoint blockade therapy (111), likely due to the broad-spectrum nature of the antibiotics, which may eliminate both pro- and anti-tumorigenic bacterial species (33). This contradiction underscores the importance of selectively targeting harmful bacteria while preserving beneficial species. A more targeted bacterial ablation, combined with systemic therapies, could improve outcomes, especially given that human PDAC tissue predominantly harbors Gram-negative bacteria (34, 61).

Overall, the findings from these studies emphasize the importance of considering microbiota composition in the treatment and management of PDAC, particularly in patients with biliary stents. This disruption in microbiota composition is associated with activated inflammatory pathways and impaired barrier function, making the host more vulnerable to pathogens. Dysbiosis induced by biliary stenting and chemotherapy not only promotes tumor progression through chronic inflammation and immune modulation but also contributes to chemoresistance, complicating treatment efforts. As highlighted in the review, it would be better to avoid the use of biliary drainage in patients with jaundice due to pancreatic cancer, but clinical practice often differs from theory, so in these cases it is better to prefer transcutaneous biliary drainage rather than endoscopic drainage, used in combination with probiotics.

Probiotics and prebiotics represent promising adjunctive strategies in PC, capable of modulating dysbiosis, enhancing therapeutic response, and reducing treatment-related side effects. These findings support the integration of microbiome-based approaches into future personalized therapies.

Future therapeutic strategies should incorporate approaches to modulate the microbiota, potentially improving treatment efficacy and patient outcomes in PDAC.