2025 Volume 7 Issue 1 Pages 37-45
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive cancers with limited treatment options and a poor prognosis. Recent studies have emphasized the pivotal influence of the microbiome, particularly intratumoral and gut microbial systems, in driving PDAC progression and shaping therapeutic responses. Emerging strategies for microbiome modulation, such as fecal microbiota transplantation (FMT), have demonstrated the potential in preclinical models to enhance immune responses and inhibit tumor growth. However, significant challenges including donor variability, microbiome engraftment, and suboptimal delivery methods have hindered the transition of these strategies to clinical settings. Addressing these limitations by optimizing microbiota-based therapies is essential for harnessing their full potential as adjunct treatments for PDAC. This review delves into the intricate relationship between microbiota and PDAC, evaluates the therapeutic efficacy and limitations of FMT, and outlines future research trajectories to advance this emerging field.
The microbiome plays a critical role in shaping the prognosis and treatment efficacy of PDAC. Innovative strategies such as FMT hold considerable promise as adjunct treatments; however, their clinical application is hindered by substantial challenges, including donor selection, microbiome engraftment, and delivery methods. Future studies should focus on addressing these limitations to unlock the potential of microbiome-based therapies for PDAC.
Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related mortality worldwide with a dismal 5-year relative survival rate of approximately 13%, underscoring its exceptionally poor prognosis compared with other malignancies [1]. Standard treatment modalities for PDAC primarily include surgical resection and systemic chemotherapy with commonly employed regimens, such as gemcitabine combined with nab-paclitaxel or the multidrug FOLFIRINOX regimen, which integrates oxaliplatin, irinotecan, fluorouracil, and leucovorin [2, 3]. However, these treatments provide modest survival benefits, primarily because of their significant toxicity and marginal therapeutic efficacy. This underscores the urgent need for advancements in early detection techniques and development of more effective therapeutic strategies [4]. The etiology of PDAC is multifactorial, with several well-established risk factors contributing to its development. These include lifestyle factors such as alcohol consumption and smoking, family predispositions, genetic conditions such as hereditary pancreatitis, and metabolic disorders such as diabetes mellitus and obesity [5].
In recent years, beyond the established risk factors, microbial ecosystems–encompassing the gut microbiome and the intratumoral microbiome–have emerged as critical contributors to the development and progression of PDAC [6,7,8]. Moreover, microbiome-derived metabolites strongly influence the efficacy of chemotherapy in PDAC [9]. A growing body of evidence indicates the pivotal role of the microbiome in shaping PDAC pathology, including its influence on patient treatment responses.
Recent scientific advancements have highlighted various microbiome modulation strategies including fecal microbiota transplantation (FMT) and probiotic therapy as promising cancer treatment approaches [10]. In particular, FMT has demonstrated the ability to enhance immunotherapy efficacy in patients with melanoma, with significant progress made in uncovering the underlying mechanisms [11,12,13,14,15,16,17]. However, these approaches exhibit therapeutic benefits only in a subset of patients, with diverse patient-specific factors contributing to variable outcomes. Furthermore, clinical implementation is constrained by challenges, including donor selection complexities and limited availability [18].
In this review, we focus on PDAC, a malignancy requiring novel therapeutic strategies. We examined the bacterial species implicated in PDAC pathogenesis, followed by an in-depth exploration of the potential of FMT as a novel therapeutic modality, addressing its efficacy, associated challenges, and key considerations for its clinical application.
Nearly two decades have passed since Ley et al. first reported a close association between the microbiome of the host intestinal tract and phenotypic traits, particularly obesity [19, 20]. With the advent of next-generation sequencing technologies, these groundbreaking studies catalyzed extensive investigations into the role of the microbiome in human health by numerous groups, including our own [21,22,23,24,25]. Today, it is widely recognized that microbial communities and their metabolites, which reside not only in the gut but also on the skin and within the oral cavity, are integral for maintaining host immune homeostasis and metabolic functionality [26, 27].
In recent years, the interplay between the microbiome and cancer has garnered significant attention given the global health burden of malignancies. Emerging evidence suggests that specific microbial species are key contributors to cancer development, progression, and therapeutic outcomes [28]. For instance, Helicobacter pylori has been linked to gastric cancer, gastric lymphoma, and esophageal adenocarcinoma [29, 30], whereas Fusobacterium nucleatum has been associated with colorectal cancer [31]. These microbes influence tumorigenesis through mechanisms such as chronic inflammation, immune evasion, and direct interactions with tumor cells [28, 29]. Furthermore, the microbiome can affect patient response to cancer treatments, including chemotherapy and immunotherapy, by modulating drug metabolism and shaping immune regulation [32, 33].
To date, several bacterial species associated with PDAC have been identified. A previous study demonstrated that the diversity and composition of the tumor microbiome significantly influence patient outcomes in PDAC (Fig. 1) [6]. Notably, patients with higher intratumoral microbial diversity exhibit improved overall survival (OS). Specific bacterial genera such as Bacillus clausii, Pseudoxanthomonas, Saccharopolyspora, and Streptomyces, have been identified in long-term survivors (LTS), suggesting their beneficial role in generating a favorable tumor microenvironment. These bacteria are believed to enhance antitumor immune responses by promoting the activation and infiltration of CD[ T cells, thereby inhibiting tumor progression. Conversely, reduced tumor microbiome diversity has been associated with poorer outcomes, potentially due to diminished immune activity.
Microbiome alterations in patients with pancreatic ductal adenocarcinoma (PDAC). Recent studies have highlighted significant microbiome differences in patients with PDAC. Short-term survivors (STS) of PDAC exhibit lower intratumoral microbiome diversity compared to long-term survivors (LTS), accompanied by shifts in the relative abundance of specific bacterial taxa. Additionally, multiple studies have revealed a distinct gut microbiome in patients with PDAC, characterized by reduced microbiome diversity and altered composition, which are implicated in PDAC prognosis and pathogenesis.
Similarly, another study reported a positive correlation between the presence of Sphingomonas, Enterococcus, and Megasphaera within tumors and improved OS in Chinese patients with PDAC (Fig. 1) [34]. These bacterial species may enhance antitumor immune responses by modulating the tumor microenvironment to promote immune activation. Consistent with the observations of Riquelme et al. [6], this study also revealed higher intratumoral microbial diversity in long-term survivors than in short-term survivors (STS) at the same disease stage. In contrast, the presence of Aggregatibacter and Neisseria was negatively associated with improved OS, highlighting the complex relationship between the microbial composition and disease outcomes. In another study involving tissue samples from 283 patients with PDAC, the detection rate of the genus Fusobacterium in pancreatic tumors was relatively low (8.8%). However, patients with Fusobacterium-positive tumors exhibit significantly higher cancer-specific mortality rates than those without [35]. Based on these findings, we propose that Fusobacterium may serve as a potential biomarker for predicting PDAC patient prognosis.
Conversely, the normal pancreas harbors distinct microbiomes. A previous study identified diverse bacterial DNA within the pancreatic tissue of both PDAC and non-cancer patients, including bacterial taxa typically associated with the oral cavity [36]. Additionally, the bacterial DNA profiles detected in the duodenum and pancreas were unique to each individual, suggesting that bacteria from the digestive tract can access the pancreas via the duodenum. Supporting this, mouse experiments have demonstrated that orally introduced bacteria and fungi could migrate to the pancreas through the duodenum within a few hours [37], providing insights into the origins of the pancreatic microbiome, including its tumor-specific microbial communities [38].
Interestingly, although the digestive tract microbiome can invade the pancreas, it appears to be selectively engrafted within tumors rather than within normal pancreatic tissues [6]. These findings highlight the potential of the intratumoral microbiome as a biomarker for predicting the prognosis of patients with PDAC and their response to therapeutic interventions, despite the considerable variability in results due to the heterogeneity of patient backgrounds.
In addition to the intratumoral microbiome, comprehensive analyses have explored the relationships between the gut and oral microbiomes and PDAC. A multinational metagenomic study identified distinct microbial signatures in gut and oral microbiomes associated with PDAC (Fig. 1) [39]. Notably, enrichment of Streptococcus and Veillonella species, along with depletion of Faecalibacterium prausnitzii, were consistently observed as common gut microbial signatures in patients with PDAC across the Japanese, Spanish, and German cohorts. These consistent microbial patterns across diverse populations underscore the potential role of the microbiome in PDAC pathogenesis.
Another study that analyzed the fecal microbiota of patients with PDAC identified 14 bacterial features that distinguished them from healthy controls (HC). These included the enrichment of Akkermansia, Bacteroidales, and Veillonellaceae, along with the depletion of Clostridiales, Faecalibacterium, and Ruminococcaceae (Fig. 1) [40]. Additionally, reduced gut microbiome diversity has been observed in patients with PDAC compared with HC [41]. Notably, patients with PDAC exhibit an increase in pathogenic and lipopolysaccharide-producing bacteria, accompanied by a decrease in probiotic and butyrate-producing bacteria, highlighting alterations in microbial composition that may influence disease progression and host metabolism.
Previous studies have established that the pancreatic microbiome can be invaded by oral and upper gastrointestinal bacteria from the duodenum into the pancreas. More recently, it was demonstrated that bacteria from the small and large intestines can reach the pancreas through the portal vein or lymphatic vessels via mesenteric lymph nodes [38]. Furthermore, when the intestinal mucosal barrier is compromised by factors such as intestinal inflammation or dysbiosis, intestinal bacteria may translocate to distant tissues and organs, including the pancreas, via the bloodstream or lymphatic system. This translocation process may exacerbate the development of acute pancreatitis and systemic inflammation [42].
These findings challenge the traditional view that microbiomes of the small and large intestines are isolated from the pancreas. Instead, they highlight the dynamic interactions between these microbial communities and the pancreas, influencing tumor development, disease pathogenesis, and responsiveness to therapeutic interventions.
The oral environment also plays a significant role in shaping pancreatic and intestinal microbiomes. It is well established that oral diseases, including periodontal diseases, have profound effects on systemic health. For instance, Porphyromonas gingivalis, a bacterium associated with periodontitis, has been identified as a risk factor not only for periodontal disease, but also for various systemic conditions, such as aspiration pneumonia [43], diabetes mellitus [44], Alzheimer’s disease [45], arteriosclerosis [46], and low birth weight [47].
A groundbreaking study using data from prospective cohorts investigated the relationship between oral microbiome and PDAC. Based on their oral rinse samples, the results revealed that individuals with P. gingivalis and Aggregatibacter actinomycetemcomitans, another bacterium linked to periodontal disease, had a significantly higher risk of developing PDAC than those without these bacteria [48]. Conversely, the presence of Fusobacteria and Leptotrichia in the oral cavity was associated with a reduced risk of PDAC development [49]. Furthermore, patients with PDAC exhibited higher levels of bacterial families, such as Enterobacteriaceae, Lachnospiraceae G7, Bacteroidaceae, and Staphylococcaceae, whereas Haemophilus was less abundant compared to HC [50]. Another study found that Neisseria elongata and Streptococcus mitis were reduced in patients with PDAC compared to HC, suggesting their potential as biomarkers for PDAC [51].
The oral microbiome is highly dynamic and susceptible to external influences, making it prone to fluctuations. Although the generalizability of these findings is limited by factors, such as variability in patient backgrounds and differences in sample collection methods across studies, they provide valuable insights into the impact of oral bacteria on the development and progression of PDAC.
As demonstrated in this chapter, the microbiome plays a crucial role in PDAC pathogenesis, with compelling evidence highlighting the contributions of intratumoral, gut, and oral microbial communities to disease progression, prognosis, and therapeutic responses. These findings emphasize the potential of microbial signatures as biomarkers and therapeutic targets, offering promising avenues for future research and innovation in PDAC management.
To date, an early Phase 1 clinical trial for FMT in patients with PDAC is ongoing, led by the M. D. Anderson Cancer Center, and registered on ClinicalTrials.gov (NCT04975217). This trial, which was initiated in 2021, recruited patients aged 18 years and older. In this trial, patients received FMT via colonoscopy, followed by weekly oral FMT capsules for four weeks, unless disease progression or unacceptable toxicity occurred. Subsequently, the patient underwent tumor resection in combination with standard treatment.
Previous preclinical studies explored the use of FMT in PDAC models. A study demonstrated that while the gut microbiome does not colonize the normal pancreas, it has the ability to colonize pancreatic tumors [6]. Using germ-free mice, the authors transplanted fecal suspensions from patients with advanced PDAC and found that nearly 5% of the tumor microbiome in FMT-treated mice was derived from a human donor, compared to no detectable bacteria in mice that did not receive FMT. Additionally, approximately 40% of the bacteria in the feces of FMT-treated mice originated from human donors, illustrating that FMT can affect both intestinal and tumor microbiomes.
To further investigate the impact of FMT on PDAC growth, fecal samples were collected from three donor groups: STS and LTS with no evidence of disease (LTS-NED), who had undergone tumor resection over five years prior, and HC [6]. Fecal suspensions from these groups were administered to recipient mice that subsequently underwent orthotopic implantation of syngeneic cancer cell lines derived from genetically engineered Pdx1-Cre; LSL-KrasG12D/+; LSL-Trp53R172H/+ (KPC) mice. Tumor volumes were measured 35 days after transplantation. This study revealed that mice receiving FMT from LTS-NED donors exhibited a significant reduction in tumor growth compared to those receiving fecal suspensions from STS or HC donors. Importantly, the antitumor effects of the LTS-NED-derived FMT were mediated by CD8+ T cells. These findings suggest that the transplanted microbiota can colonize both the intestinal tract and pancreatic tumors, potentially influencing disease progression and prognosis in PDAC through immune system modulation.
In a 2021 pilot study, fecal suspensions from five patients with PDAC and five age- and sex-matched HC were transplanted into germ-free mice, and the microbiome of each human donor was administered to two mice, resulting in a total of 20 mice [52]. Both patients with PDAC and the mice transplanted with their microbiomes exhibited similar microbial profiles, characterized by increased levels of Clostridium bolteae, Clostridium_g24_unclassified, C. scindens, and Phascolarctobacterium faecium and decreased levels of Alistipes obesi, Lachnospiraceae PAC000196_s, and Coriobacteriaceae_unclassified. These microbial alterations were associated with a significant reduction in visceral fat mass in PDAC recipients compared to controls. However, no significant differences in subcutaneous adipose tissue, brown adipose tissue, or skeletal muscle mass were observed between the two groups. Contrary to their expectations, there were no significant differences in inflammatory cytokine levels, immune cell populations, or other metabolic parameters between the groups. These findings indicate that while FMT from patients with PDAC induces specific changes in gut microbiota composition and fat distribution in germ-free mice, it does not necessarily result in systemic inflammatory or immune alterations, suggesting a localized or microbiota-specific effect rather than a global metabolic or immune response.
Challenges and future directionsDonor selection is one of the two primary challenges associated with FMT (Fig. 2). Currently, feces from HC are the standard source for transplantation (ClinicalTrials.gov ID: NCT04975217, NCT03772899, NCT04105270, NCT06218602, NCT06026371, NCT04130763, NCT04163289, and NCT04056026; jRCT ID: jRCTs031240170) [16, 53, 54]. However, defining what qualifies as a “healthy individual” remains debatable, and the donor’s microbiome may not guarantee a favorable response to subsequent treatments in recipients. In addition, the risks of rejection and low engraftment rates pose significant obstacles.
Overview of fecal microbiota transplantation (FMT) for patients with PDAC. FMT for PDAC involves two critical components: selecting an appropriate donor and determining the delivery method. Donor options include healthy individuals, autologous transplantation using the patient’s own microbiota collected before disease onset, or microbiota from patients who responded well to specific treatments, such as immunotherapy. The method of microbiome delivery is equally important. While capsules are the most widely used due to their minimally invasive nature, upper endoscopic delivery is potentially more effective for targeting the pancreas via the duodenum. Colonoscopic transplantation remains an option but is less targeted for PDAC. Following FMT, integrating standard therapies such as surgery, chemotherapy, or immunotherapy is crucial, with treatment strategies tailored to the patient’s clinical course for optimal outcomes.
Autologous transplantation, in which a patient’s feces are stored prior to disease onset for later use, represents an alternative (NCT04577729). This method minimizes the risk of rejection compared to allogeneic transplantation. However, as with feces from HC donors, the unpredictability of patients’ responses to standard treatments remains a critical concern. Another emerging strategy involves transplanting the microbiome from patients who previously had the disease and responded well to treatment (NCT03353402, NCT03341143, NCT04577729, NCT05251389, NCT04521075, NCT04951583) [12, 13, 55]. As an adjuvant therapy for immunotherapy in melanoma, this approach has gained traction because of its promising efficacy and the growing body of supportive evidence.
The second challenge lies in determining the most effective method for microbiome delivery. Historically, the most common methods included enema (NCT04988841), colonoscopy (NCT04056026 and NCT04264975), and endoscopy (NCT04116775). Recently, oral administration via capsules has emerged as a mainstream approach, offering minimally invasive site-specific microbiome delivery. This method is widely used in clinical trials [56]. Moreover, combining multiple delivery methods, such as colonoscopy or endoscopy, has been reported to enhance microbiome engraftment rates [57]. In the context of PDAC, evidence suggests that the modification of the gut microbiome can alter the composition of the tumor microbiome. Consequently, microbiome modulation through FMT is poised to become an important treatment strategy for PDAC management. Although further research is needed to identify the most effective delivery method for FMT in PDAC treatment, current evidence suggests that a combination of multiple delivery methods has the greatest potential for success.
Further investigation is required to elucidate the role of FMT in PDAC treatment, particularly when used as an adjuvant to standard therapies (Fig. 2). Similar to its application in melanoma, its primary objective is to enhance the efficacy of conventional treatments. However, the effect of pre-FMT antibiotic treatment or FMT on the subsequent development of PDAC and patient treatment responses remains poorly understood. Antibiotics have been suggested to positively influence PDAC outcomes. A recent retrospective study found no significant differences in the OS or progression-free survival (PFS) between patients with resectable PDAC who received antibiotics and those who did not. In contrast, among patients with metastatic PDAC, antibiotic use was associated with a statistically significant improvement in both OS and PFS [58]. Similarly, a retrospective cohort study analyzing 3,850 patients with PDAC receiving gemcitabine (3,150 cases) or fluorouracil (700 cases) as first-line treatment revealed that 56.6% (2,178 cases) of the patients received antibiotics. Notably, in patients treated with gemcitabine, concurrent antibiotic use significantly improved OS. Another single-center retrospective study also reported that antibiotic administration was associated with enhanced efficacy of gemcitabine plus nab-paclitaxel (GnP), particularly with PFS as an indicator [59]. These findings suggest that antibiotics may not adversely affect PDAC progression and may positively influence outcomes, especially in conjunction with chemotherapy.
Although significant hurdles remain before FMT can be routinely employed as an adjuvant therapy for PDAC, its use in clinical practice for other conditions is rapidly expanding. For instance, Ferring Pharmaceuticals recently developed REBYOTA®, a first-in-class microbiota-based live biotherapeutic approved by the U.S. Food and Drug Administration (FDA) for preventing recurrent Clostridioides difficile infection (CDI) following its antibiotic treatment. In addition, the microbiome-gut-brain axis has emerged as a critical area of research in psychiatry, with an active exploration of FMT [60] as well as probiotic therapy [23, 61] for mental health disorders. This shift is driven in part by the high medication burden in these patients, as psychotropic drug use is associated with an increased risk of lifestyle-related diseases [62,63,64]. Consequently, the appeal for microbiome-based treatments, which have fewer side effects, is growing. The rapid expansion of microbiome-based therapeutic applications in various diseases underscores their potential for transformation. If these challenges can be addressed, FMT as an adjuvant therapy for PDAC could become a viable and effective treatment option in the near future.
Microbiome modification strategies such as FMT hold significant promise for augmenting standard therapies for PDAC. However, the successful clinical implementation of FMT requires overcoming key challenges, including optimizing donor selection, enhancing microbiome engraftment, and refining delivery methods. Addressing these obstacles will pave the way for advancing microbiome-based approaches, offering a transformative opportunity to improve treatment outcomes in patients with PDAC.
Masahiro Sonoshita is a shareholder of FlyWorks, K.K. and FlyWorks America, Inc.
We thank the members of The Sonoshita Laboratory for their constructive feedback and unwavering support.
