The Impact of Bacterial Dysbiosis on the Development of Pancreatic Cancer and Its Treatment in Humans?

Pancreatic cancer (PC) is characterised by a high mortality rate and low survival rates. It is classified as the third most common cancer as a cause of cancer deaths, right after lung cancer and colon cancer. The estimated number of deaths in 2024 from pancreatic cancer in the United States for both sexes is 66.440 thousand, of which 51.750 thousand will be fatal cases, accounting for 77.89% of pancreatic cancer mortality (Siegel et al. 2023; Siegel et al. 2024). A study by Santucci et al. (2024) forecasts a continued decline in cancer mortality across the EU, with age-standardized rates expected to fall by 6.5% for men and 4.3% for women relative to 2018 levels. On the contrary, pancreatic cancer shows an unfavorable prediction in studies in the EU, and mortality from this cancer is increasing in both sexes. Mortality rates for both sexes (+1.6% in men and +4.0% in women) (Santucci et al. 2024).

Pancreatic cancer is non-specific and difficult to diagnose in its early stages. The anatomical location of the pancreas is an additional complication in the diagnosis of pancreatic cancer (Maitra et al. 2024). The cancer can develop in the exocrine cells of the pancreas, which are responsible for producing digestive juices, or in the endocrine cells of the pancreas, which produce hormones. However, pancreatic cancer starts to develop in the exocrine cells in approximately 95% of cases and belongs to the histological subtype of ductal adenocarcinoma, which is associated with a poor prognosis and a lack of effective therapies (Grant et al. 2016; PDQ Adult Treatment Editorial Board 2024). Pancreatic exocrine insufficiency, resulting from obstruction of the pancreatic duct, fibrosis, or tissue loss, contributes to malnutrition and weight loss in patients (Vujasinovic et al. 2017; de la Iglesia et al. 2020; Sabater et al. 2016).

The etiological factors of PC include non-modifiable germline genetic factors as well as modifiable factors such as smoking, obesity, and diabetes (Stanciu et al. 2022; Gentiluomo et al. 2022). Approximately 5-10% of pancreatic cancer patients have a familial background, while the genetic contribution in the remaining cases is unknown, suggesting a role for the environment in the etiology of the disease (Goggins et al. 2020). Molecularly, epigenetic alterations and somatic mutations, especially activating mutations in the KRAS gene, play a central role in the pathogenesis of PC. KRAS mutations, though rarely inherited, are commonly acquired and act as a critical driver of tumor initiation and progression (Baylin and Jones 2016; Chen et al. 2021; Alonso-Curbelo et al. 2021).

The study and development of epigenetic mechanisms of metastasis in pancreatic duodenal carcinoma has the potential to facilitate effective therapeutic intervention(Wang et al. 2021; Chen et al. 2021).

Recently, the role of the microbiome in the context of pancreatic cancer has also received much attention. A correlation has been observed between the commensal microbiome (classified as an environmental factor) and certain gastrointestinal cancers, including those affecting patients with pancreatic cancer. However, the available data remain inconclusive (Sexton et al., 2022). Further study of the epigenetic mechanisms underlying metastasis in pancreatic duodenal carcinoma could facilitate the development of effective therapeutic interventions. The natural ecosystem of microorganisms is also susceptible to various environmental factors, which may contribute to the disruption of the organism’s overall homeostasis. It has been shown that alterations of the microbiota in the pancreas-gut axis can cause chronic pancreatic inflammation, which is one of the risk factors for pancreatic cancer. It has been proven that fungal intestinal microbiota is also associated with carcinogenesis. Fungal dysbiosis with yeasts of the genus Malassezia has been implicated in the development of cancer at an early stage (Speth et al. 2022). The previous studies have shown the influence of fecal and oral microbiomes not only on pancreatic carcinogenesis but also on immune modulation in pancreatitis (Thomas and Jobin 2020). Microbiota can be a powerful source of biomarkers for identifying individuals with pancreatic ductal adenocarcinoma and their prognosis (Pourali et al. 2024).

This review specifically highlights research on the bacterial microbiome, which represents the most extensively studied microbial group in the context of pancreatic cancer. In this article, we present a general overview of what is known about the impact of the bacterial oral and gut microbiome on the incidence of pancreatic cancer and discuss the effectiveness of therapy by modulating the microbiome. A literature search was performed using databases such as PubMed and Google Scholar, with search terms including “Pancreatic Cancer,” “Resistance,” “Therapy” and “Microbiota”. The analysis included 89 articles, which were primarily based on meta-analyses, as well as prospective, retrospective, clinical, metagenomic, and expectorant studies. The study population comprised individuals diagnosed with pancreatic cancer or pancreatic ductal adenocarcinoma, as well as a control group of healthy individuals. We also included pancreatitis as one of the most important etiological factors of pancreatic cancer.

To date, 619 bacterial taxa representing 13 phyla have been identified in the human oral microbiome (Dewhirst et al. 2010). It is a highly diverse and dynamically changing group of microorganisms that varies even in terms of where the sample is taken from, for example oral mucous membrane, tooth pockets, teeth, and tongue. Examples include saliva, tongue plaque, and mouthwash (Nearing et al. 2020). Saliva contains a broad spectrum of bacterial species, and the sampling method is convenient and relatively cost-effective. Studies show that using diagnostic models to characterize the oral microbiota, microbial biomarkers can provide a diagnostic tool for pancreatic cancer. The studies with 16S rRNA sequencing revealed there are significant differences in quantitative and qualitative species composition between the microorganisms found in the saliva of healthy individuals and those with pancreatic cancer or a pre-cancerous condition (Fan et al. 2018; Wei et al. 2020). A malignant condition such as pancreatic ductal adenocarcinoma, is a consequence of chronic inflammation and is driven by ongoing inflammation associated with immunosuppressive CD4+ T lymphocytes. It can be concluded that chronic inflammation of the pancreas induces carcinogenesis (Guerra et al. 2007).

In the study presented by Chen et al. (2023), a group of patients with pancreatic cancer and chronic pancreatitis was compared to healthy controls. Fecal and saliva samples analyzed by the 16S rRNA sequencing method and real-time qPCR revealed that oral pathogenic genera significantly predominated in pancreatic cancer, especially Granulicatella, Peptostreptococcus, Alloprevotella, Veillonella, Bacteroidetes, Firmicutes, and Proteobacteria, accounting on average for more than 80% of all observed species. In patients with chronic pancreatitis, the average relative abundance of the two phyla of Firmicutes and Verrucomicrobia was significantly higher than that in healthy controls. A marked enrichment of pathogenic bacterial genera, including Granulicatella, Peptostreptococcus, Alloprevotella, Veillonella, Solobacterium, and Streptococcus, was detected in the oral microbiota of patients diagnosed with pancreatitis. These results were similar to those described by Farell et al. (2012). Other studies, using the same technology of sequencing, demonstrated that the relative abundance of Porphyromonas, Haemophilus, and Paraprevotella genera was significantly higher in the healthy tongue plaque microbiome, while in patients with chronic pancreatitis, Leptotrichia, Fusobacterium, Actinomyces, Rothia, Solobacterium, Oribacterium, Campylobacter, Atopobium, and Parvimonas families occurred significantly more often. The most notable differences between the microbiota of the tongue lining of patients with chronic pancreatitis and healthy controls were low levels of Haemophilus and Porphyromonas and high levels of Leptotrichia and Fusobacterium (Mitsuhashi et al. 2015; Lu et al. 2019).

Further extensive research included: 361 cases of pancreatic adenocarcinoma and 371 matched controls selected from two large prospective cohort studies: The American Cancer Society Cancer Prevention Study II (CPS-II) and the National Cancer Institute Prostate, Lung, Colorectal and Ovarian Cancer (PLCO) Screening Trial. The pre-diagnostic oral wash samples collected from participants were also analyzed by 16S rRNA gene sequencing. It showed that carrying Tannerella forsythia and Prevotella intermedia in the mouth, in contrast to Porphyromonas gingivalis, was not associated with pancreatic cancer risk. This association was evident for both those with low bacterial abundance (below the median relative abundance) and those with high bacterial abundance (above the median relative abundance) (Fan et al. 2018). Another large European prospective cohort study – The European Prospective Investigation into Cancer and Nutrition (EPIC) – analyzed 405 patients with pancreatic cancer compared to 416 controls. Using Luminex-based immunoassays, it was noted that individuals with high levels (>200 ng/ml) of antibodies to the periodontal pathogen Porphorymonas gingivalis had twice the risk of pancreatic cancer compared to those with lower levels of these antibodies (≤200 ng/ml). It was found that people with consistently high levels of antibodies to common oral bacteria had a 45% lower risk of pancreatic cancer compared to those with lower levels of antibodies. The antibody levels were measured in blood samples taken up to 10 years before the cancer was diagnosed, which is likely to minimize changes in the immune response after the development of pancreatic cancer (Michaud et al. 2013). The association between an elevated level of Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans and an increased risk of pancreatic cancer was also shown. A long-term study involving 59,000 African American women, with a follow-up period of 21 years, found that participants with poor dental health had a higher likelihood of developing pancreatic cancer. Periodontitis has been associated with at least a 50% increased risk of pancreatic cancer and can be considered a potential risk factor for this malignancy (Pietzner et al. 2021; Ungureanu et al. 2023). Kaci et al. (2014) also found that the most prominent feature of the oral microbiome for pancreatic ductal adenocarcinoma was a significant reduction in Streptococcus salivarius, a bacterium known for its anti-inflammatory properties. It has been demonstrated that metabolically active Streptococcus salivarius JIM8772 exerts significant anti-inflammatory effects in murine models of both moderate and severe colitis. Based on these findings, it can be hypothesized that high levels of Streptococcus salivarius colonization in the mouth and intestine may be associated with a reduced risk of pancreatic cancer, possibly due to its anti-inflammatory and immunomodulatory effects (Kaci et al. 2014). In another study, it was shown that Ganoderma atrum polysaccharide (PSG) and White Hyacinth Bean polysaccharide (WHBP) were used to investigate their effects on the microbiota of the oral cavity, gut, pancreas, and lungs in rats with type 2 diabetes. The results showed that oral microbiota was significantly similar to pancreatic microbiota, more than the gut microbiota. This suggests a potential role for saliva as an early biomarker of pancreatic changes. Treatment with PSG and WHBP not only improved pancreatic condition but also helped stabilize the oral microbiota, indicating a strong correlation between these two environments (Wu et al. 2022).

It is well known that the human gut microbiota plays an important role in the functioning of the body, both by influencing metabolism and regulating the immune system. Disturbances in the bacterial balance can have negative effects on various organs, including the pancreas (Adolph et al. 2019; Zhou et al. 2020). Altered gut microbiota is influenced by factors related to inflammatory, metabolic, and malignant diseases (Montenegro et al. 2022; Maev et al. 2023). A study involving 1.795 volunteers who provided stool samples found that changes in gut microbiota composition were primarily associated with pancreatic stromal cell function. Ductal cell function appeared to play a less significant role (Frost et al. 2019). To detect bacteria in human pancreatic ductal adenocarcinoma (PDAC) samples, Geller et al. (2017) used real-time quantitative polymerase chain reaction targeting the bacterial 16S rRNA gene and confirmed bacterial presence with non-PCR methods: ribosomal RNA fluorescence in situ hybridization (FISH) and immunohistochemistry using an anti-LPS antibody. Research has shown that the most frequently identified species in pancreatic ductal adenocarcinoma (approx. 52% of all reads) belong to the class Gammaproteobacteria, with the majority represented by the Enterobacteriaceae and Pseudomonadaceae families in the Proteobacteria cluster. Proteobacteria are abundant in the duodenum, into which the pancreatic duct opens. This suggests that retrograde migration of bacteria from the duodenum into the pancreas may be the source of bacteria associated with pancreatic ductal adenocarcinoma (Geller et al. 2017). In a study comparing the gut microbiota between pancreatic cancer patients and healthy controls, it was found that the composition of the gut microbiota was similar in both groups, among the bacterial phyla, Firmicutes and Bacteroidetes were dominant. However, it showed again that patients with pancreatic ductal adenocarcinoma had a significantly higher presence of Proteobacteria, Synergistetes, and Euryarchaeota phyla compared to the control group (Pushalkar et al. 2018).

The above study mentioned Chen et al. (2023) described an interesting study of the gut microbiome in a group of cancer patients compared to healthy participants. They found that Prevotella spp. was present at significantly higher levels in cancer patients. In the study, its percentage of the pancreatic microbiota was 17.64% (relative average) compared to the control group, in which Prevotella spp. accounted for only 6.4% of the tested microbiota (relative average). Andréasson et al. (2024) analyzed stool samples from rheumatoid arthritis (RA) patients (n=50) before and after treatment using a 16S rRNA-based GA-map Dysbiosis Test and qPCR for Prevotella copri, assessing microbiota changes in relation to disease activity (DAS28-CRP). They have shown that Prevotella copri was involved in the development of RA in mice through the Th17/IL-17 pathway. Similarly, isolated P. copri strains (n=13) from RA patients and healthy controls were whole-genome sequenced. To assess their arthritis-inducing potential, two mouse models were used: collagen-induced arthritis under specific-pathogen-free conditions and SKG mice monocolonized with P. copri. In vitro stimulation of bone marrow–derived dendritic cells (BMDCs) showed that P. copri induced stronger IL-17 and Th17-related cytokine responses (IL-6, IL-23), suggesting a higher pro-inflammatory potential (Nii et al. 2023). The same pathway can also accelerate the development of pancreatic precancerous conditions (PanIN), suggesting that Prevotella copri may play a role in promoting pancreatic cancer through Th17 activation.

Additionally, multicenter study revealed distinctive gut microbiota profiles for PDAC patients, including significant increases in Streptococcus spp. and Veillonella spp. and a reduction in Faecalibacterium prausnitzii. The study was based on shotgun metagenomic analysis of fecal and salivary samples collected from 47 treatment-naïve PDAC patients and 235 non-PDAC controls across Japan, Spain, and Germany (Nagata et al. 2022). Studies have also shown that a cancerous pancreas contains a significantly more diverse microbiome compared to a healthy pancreas. An increased number of specific types of bacteria have been observed in pancreatic ductal adenocarcinoma compared to their presence in the gut, and it has been shown that these bacteria can migrate through the pancreatic duct (Dickson 2018; Del Castillo et al. 2019). Studies investigating the presence of bacteria in pancreatic juice and bile from patients with pancreatic ductal adenocarcinoma, using PCR targeting the 16S rRNA gene, consistently identified Enterococcus spp. and Enterobacter spp. as predominant in bile samples, suggesting a potential route of pancreatic infection. This method was applied in two separate studies: one analyzing 36 samples (Maekawa et al. 2018) and another analyzing 101 samples (Stein-Thoeringer et al. 2025), both confirming the frequent presence of bacterial DNA. Additionally, pancreatic cancer patients showed significantly elevated serum antibody levels against Enterococcus faecalis envelope polysaccharide compared to healthy individuals.

Analysis of the gut microbial profile showed that 15 taxonomic groups were significantly enriched in pancreatic cancer patients, mainly including the genera Prevotella, Veillonella, Klebsiella, Selenomonas, Hallella, Enterobacter, and Cronobacter. On the contrary, 25 taxonomic groups, primarily Gemmiger, Bifidobacterium, Coprococcus, Clostridium cluster IV, Blautia, Flavonifractor, Anaerostipes, Butyricicoccus, and Dorea were significantly reduced in fecal samples from pancreatic cancer patients compared to healthy individuals. The results were obtained using linear discriminant analysis. These studies also highlight differences in microbial composition depending on the stage of pancreatic cancer. The genera Lactobacillus, Haemophilus, and Streptococcus were significantly more abundant in patients with stage II disease compared to those with stage I (Ren et al. 2017). Also, patients with a stomach infection due to pathophysiological colonization of Helicobacter pylori, may be at higher risk for increased pancreatic cancer (Maisonneuve and Lowenfels, 2015). Seropositivity of antibodies to H. pylori and its virulence protein for CagA-positive strains of H. pylori was determined using commercial IgG immunoassays. The results of these studies suggest that colonization by Cag A-negative strains of H. pylori may affect the risk of pancreatic cancer. It is associated with changes in stomach acidity, Cag A-negative strain, and hyperchlorhydria modulate pancreatic carcinogens and increase the morbidity of pancreatic cancer (Risch et al. 2014). Gastric acidity stimulates bicarbonate and fluid secretion from pancreatic ductal cells. This mechanism allows H. pylori to reside in the stomach and interfere with the function of the pancreatic ductal epithelium. Thus, it can be suggested that the differential modification of chronic gastric acidity by CagA-negative strains of H. pylori may affect the risk of pancreatic cancer. However, further studies analyzing this relationship are needed to draw firm conclusions (Risch 2012; Hirabayashi et al. 2019), because the seropositivity of H. pylori strains varies depending on the continent where the study was conducted, so the seropositivity test may show different results depending on the origin of the study group (Wang et al. 2014; Huang et al. 2017). There is a lot of evidence that H. pylori is significantly correlated with the occurrence of pancreatic cancer. Based on the results of a study of the Asian population, a correlation between H. pylori infection and the incidence of pancreatic cancer was proven (Hsu et al. 2014; Xu et al. 2022).

Literature data clearly indicate that differences in the composition of the gut microbiota may reflect or be associated with the presence of pancreatic cancer (Daley, 2022). This may become an important diagnostic marker. However, it should be remembered that patients with pancreatic cancer are often a heterogeneous group of patients with other comorbidities. Therefore, samples from cancer patients differ significantly in the microorganism’s composition. Nevertheless, higher proportions of bacterial genera belonging to the phyla Bacteroidetes and Firmicutes have been observed in pancreatic cancer patients compared to healthy individuals (Half et al. 2015). The pancreas, which secretes substances outside the intestine, plays an important role in shaping the composition and stability of microorganisms found in the intestines of healthy people who do not suffer from any pancreatic diseases. Pancreatic lipase, trypsin, and glycoprotein 2 play an important role in shaping the composition and stability of microorganisms found in the intestines of healthy individuals. These enzymes also protect the intestines by inducing bacterial lysis and acting as antimicrobial agents (Nishiyama et al. 2018; Edogawa et al. 2020; Shin and Seeley, 2019). Figure 1 shows the types of microorganisms whose decreased or elevated levels in the mouth and intestines can increase the incidence of pancreatic cancer (Fig. 1).

Figure 1.

Occurrence of taxonomic groups of bacteria in the oral and intestinal microbiome of patients with pancreatic cancer compared to the population of healthy people. Red fields in the pie chart - a decrease in the number of bacteria, blue fields in the pie chart - an increase in the number of bacteria. Original graphic.

Microbial dysbiosis as well as epithelial barrier dysfunction may affect tumor transformation through bacterial translocation (Plottel and Blaser, 2011). In most malignancies, the intestinal microbiome is in direct contact with or near the diseased organ. On the contrary, the anatomical location of the pancreas does not indicate that the gut microbiome can influence disease development (Meng et al. 2018). Changes in the microbiota may result from the movement of bacteria from the duodenal intestine to the pancreas through the opening of the pancreatic duct in the duodenal papilla, but this movement may not be a normal physiological process. However, studies suggest that there is a specific gut and pancreatic microbiome associated with pancreatic cancer that may accelerate the development of the disease by weakening the body’s immune response (Pushalkar et al. 2018). Performing bacterial ablation leads to immunogenic reprogramming of the PDAC tumor microenvironment. It decreased the number of bone marrow-derived suppressor cells, and increased the differentiation of M1 macrophages, promoted the differentiation of CD4 Th1 T cells, and the activation of CD8 T cells. In addition, bacterial ablation enhanced the efficacy of checkpoint-targeted immunotherapy by upregulating PD-1 expression. Mechanically, the PDAC microbiome generated a tolerogenic immune program through differential activation of selected Toll-like receptors in monocyte cells (Seifert et al. 2016; Pushalkar et al. 2018). A continuous decrease in the number of short-chain fatty acid-producing bacteria, such as Faecalibacterium prausnitzii, Eubacterium rectale, and Ruminococcus bicirculans, was observed in the intestines of patients with pancreatic adenocarcinoma. This decline partially coincided with the characteristic changes in the gut microbiome found in various diseases. Short-chain fatty acids regulate intestinal immune function through G-protein-coupled receptors on the cell surface. Their absence leads to inflammation, which may promote the development of PDAC (Parada Venegas et al. 2019; Ubachs et al. 2021). In turn, oral pathogens such as Porphyromonas gingivalis cause mutations in the pro-tumorigenic genes TP53 and KRAS by secreting peptidylarginine deaminase. On the other hand, Fusobacterium nucleatum promotes tumor formation and metastasis in several ways: it binds to host cells via FadA adhesion proteins, enabling their internalization and activation of NF-κB and IL-6 pathways, leading to pro-inflammatory cascades (Kostic et al. 2013; Gnanasekaran et al. 2020). Fecal microbiota transplantation is also beginning to play an increasingly important role. An experiment was performed in which fecal microbiota was transplanted from donors who were pancreatic cancer patients with either short- or long-term survival. As a result, scientists were able to influence tumor growth and immune infiltration of the tumor. This shows that the composition of the pancreatic microbiota of PDAC patients, communicating with the gut microbiota, influences the host immune response (Riquelme et al. 2019; Yang et al. 2022).

An increasing number of studies indicate that the intestinal microbiota may play a dual role in pancreatic cancer by contributing to its pathogenesis and modulating the efficacy and toxicity of anticancer therapies. These effects are mediated through alterations in drug pharmacokinetics, changes in the host metabolic milieu, and modulation of the tumor microenvironment composition. As a result, intestinal microbiota can affect the effectiveness of treatment, and its modulation can lead to different therapeutic effects. Microbes can be responsible for the resistance of cancer cells to various chemotherapeutic agents, for example, gemcitabine, 5-fluorouracil, or oxaliplatin. These drugs are used in pancreatic cancer treatment regimens, among others. While most of the studies on gut microbiota, and the efficacy of chemotherapy are based on colorectal cancers, it can be speculated that the same mechanisms occur in pancreatic cancer patients due to the use of a similar treatment regimen and the presence of similar microorganisms also in the pancreatic cancer microenvironment such as Fusobacterium nucleatum and bacteria belonging to Gammaproteobacteria class (Nejman et al. 2020; Sevcikova et al. 2022). The presence of these bacteria contributes to resistance to oxaliplatin and/or 5-fluorouracil therapies by activating autophagy in tumor cells (Yu et al. 2017) or increasing BIRC3 expression, which inhibits tumor cell apoptosis (Zhang et al. 2019).

Tests on human pancreatic ductal adenocarcinoma samples taken during surgery revealed the presence of an average of one bacterium per 146 human cells. These bacteria are part of the pancreatic tumor microenvironment. The most detected species belong to the class Gammaproteobacteria, mainly to the Enterobacteriaceae and Pseudomonadaceae families, which express CDDL. Gemcitabine is particularly important in the treatment of pancreatic cancer, and the presence of these bacteria may contribute to resistance to the drug (Geller et al. 2017). It can be eliminated after effective antibiotic therapy and contribute to clinical success (Ramanathan et al. 2016; Imai et al. 2019; Fulop et al. 2023). However, when the microenvironment of the pancreas is examined, fungi are found in addition to bacteria. Fungal ablation enhanced the effect of gemcitabine-based chemotherapy. It is also worth noting that fluconazole treatment had a protective effect. Moreover, consistent with the absence of increased fungal infiltration in pancreatitis, antifungal drugs did not alleviate mild pancreatitis. Thus, it can be concluded that fungal removal may have therapeutic effects only for pancreatic cancer patients (Aykut et al. 2019). There is a high degree of inter-individual variability, and an excess of different microbiota taxa and host-microbiota interactions are highly dynamic and complex. These include not only direct interactions between the microbiota and the tumor, but also indirect interactions through the immune system. All these mechanisms are not yet fully understood.

An increasingly successful therapeutic option is immune checkpoint therapy (O’Reilly et al. 2019). Drugs such as durvalumab and tremelimumab are the human monoclonal antibodies (mAbs) against programmed death 1 (anti-PD-L1) IgG class 1 and human anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) IgG class 2, respectively. In a study of PDAC patients, the two therapies were combined in the hope of an additive or synergistic effect of the drugs, but this did not have the desired effect. The use of anti-CTLA-4 blockade alone as part of the combination therapy shows a positive anti-tumor effect in patients participating in the clinical trial (Le et al. 2013). The modulation of the immune response by microbiota is significant and thus can have a huge impact on the efficacy of immunotherapy. The intestinal microbiome ablation performed showed protection against pre-invasive and invasive pancreatic ductal adenocarcinoma, while transfer of bacteria from pancreatic ductal adenocarcinoma hosts, but not from the control group, nullifies this anti-tumor protection. Bacterial ablation leads to immunogenic reprogramming of the PDAC tumor microenvironment, including reduction of bone marrow-derived suppressor cells and increased differentiation of M1 macrophages, which in turn promotes differentiation of CD4+ Th1 T cells and activation of CD8+ T cells. In addition, bacterial ablation enhances the efficacy of checkpoint-targeted immunotherapy by upregulating PD-1 expression (Pushalkar et al. 2018).

A complex from the NOD-like receptor family, the inflammasome containing pyrin domain 3 (NLRP3), is responsible for the initiation of innate inflammatory responses. During the study, NLRP3 levels were shown to be significantly increased in patients with pancreatic cancer in general, and it was demonstrated that selective ligation of NLRP3 could sustain this pro-tumorigenic pancreatic inflammation (Daley et al. 2017). Inhibition of dipeptidyl peptidase (DPP) may increase the efficacy of immunotherapy in pancreatic cancer. In mouse models, after oral administration and intraperitoneal injections of BXCL701, which is an oral small-molecule dipeptidyl peptidase inhibitor, increased NK and T cell immune infiltration and decreased tumor growth were observed. BXCL701 increases the movement of CXCR3+ NK and CD8+ T cells into tumors, which mediates tumor regression (Fitzgerald et al. 2021). Positively transforms the PDAC immune microenvironment, enhancing antitumor activity and improving the effectiveness of therapy. It should be noted here that the gut microbiota reduces the activity of tumor-infiltrating NK cells, which in effect promotes the development of pancreatic ductal adenocarcinoma. To improve patient survival, one possible solution may be to modulate microbiomes with antibiotic therapy, which may not be enough if patients have immune deficiencies. Reducing the number of NK cells with antibodies has been shown to lead to advanced cancers, even in the absence of microbiota (Shi et al. 2023; Yu et al. 2022).

With the development and plethora of immune therapies, the question arises as to how individual diversity, immunocompetence or lack thereof, and the individual microbiota of a pancreatic cancer patient affect the effectiveness of treatment.

The association between microbiome and pancreatic cancer is a rapidly evolving field that holds immense potential for early detection, risk assessment, and therapeutic intervention. It was proved that both the oral and gut microbiomes play significant roles in the pathogenesis of pancreatic cancer, with emerging evidence suggesting that microbial dysbiosis, imbalanced or altered microbial communities, may contribute to tumorigenesis through inflammatory pathways, immune modulation, and bacterial translocation to the pancreas. Specifically, bacteria like Porphyromonas gingivalis, Fusobacterium nucleatum, and Prevotella spp. have been implicated in promoting carcinogenesis via pro-inflammatory pathways, immune system manipulation, and direct interaction with cancerous cells.

Additionally, the composition of the microbiome in both the oral cavity and gut has been found to significantly differ in pancreatic cancer patients compared to healthy individuals. These differences in microbial composition could serve as diagnostic biomarkers or therapeutic targets in the future. More importantly, the role of microbiomes in modulating the efficacy of pancreatic cancer treatments, such as chemotherapy and immunotherapy, highlights the critical need for personalized therapeutic strategies that account for individual microbiome variations.

Furthermore, microbial interactions with the immune system, particularly through immune checkpoint inhibition and microbial ablation strategies, suggest that modulating the microbiome could enhance the effectiveness of current treatment options and offer a novel approach to improving patient outcomes. Although there is still much to learn about the complex associations between microbiota and pancreatic cancer, the growing body of research offers promising avenues for both early detection and innovative treatments that leverage microbiome modulation.

As we move forward, understanding the intricate role of the microbiome in pancreatic cancer will likely open doors to more effective, personalized therapies and could ultimately transform the way we approach both the diagnosis and treatment of this devastating disease. However, larger-scale studies and clinical trials are necessary to fully understand the underlying mechanisms and to validate microbiome-based diagnostic and therapeutic interventions.

Table 1. is a collection of studies analyzed in the article. It shows how the associations between the microbiome and the risk of pancreatic cancer were studied and what the conclusions of the studies were (Table 1).