Pancreatic cancer (PC) is among the most aggressive malignant neoplasms, characterized by an insidious onset and poor prognosis (Siegel et al., 2018). Approximately 10% of patients diagnosed with PC have a familial predisposition (Klein, 2012; Klein et al., 2004). The high mortality rate associated with PC is primarily attributed to delayed diagnosis and limited therapeutic options (Kamisawa et al., 2016). The disease often presents with nonspecific symptoms that become apparent only at advanced stages, frequently rendering the tumor unresectable or indicative of metastatic progression, thereby limiting therapeutic efficacy. Epidemiological data indicate an estimated annual incidence of approximately 216,000 new cases worldwide. The 1-year survival rate is approximately 23%, while the 5-year survival rate remains as low as 5% (McGuire, 2016). Currently, the primary strategies for PC prevention and early detection rely on advanced pancreatic imaging to identify precancerous lesions (Siegel et al., 2022; Catalano et al., 2003; Ichikawa et al., 2001). However, due to the impracticality of large-scale population screening with this approach, there is a critical need to develop novel diagnostic techniques to improve early detection, prognostication, and overall survival outcomes.

Recent studies have proposed a potential association between the intestinal microbiota and various gastrointestinal malignancies, including PC (Zitvogel et al., 2018; Gopalakrishnan et al., 2018; Sepich-Poore et al., 2021). A study by Chen et al. (2023) reported substantial changes in microbial community composition in patients with PC compared to control groups. An increased abundance of oral pathogenic bacteria (Granulicatella, Peptostreptococcus, Alloprevotella, Veillonella, Solobacterium, Streptococcus, etc.) was observed in patients with PC. Within the intestinal microbiota, beneficial bacteria such as Bifidobacterium and Butyricococcus, including probiotics, demonstrated a significant reduction, whereas opportunistic bacteria (Prevotella, Escherichia Shigella, Peptostreptococcus, Actinomyces, etc.) were significantly increased. Further studies by Tan et al. (2022) identified a relationship between Porphyromonas gingivalis, a pathogen implicated in chronic periodontitis, and the development of pancreatic ductal adenocarcinoma (PDAC) (Wei et al., 2019). Mechanistically, intratumoral P. gingivalis promotes PC progression by increasing the secretion of neutrophilic chemokines and neutrophil elastase (NE). The potential role of Helicobacter pylori in PDAC development is under investigation (Kumar et al., 2020; Hirabayashi et al., 2019; Nilsson et al., 2006). However, its classification as a definitive risk factor for PC remains controversial.

The introduction of 16S rRNA sequencing technology and fluorescence in situ hybridization (FISH) has facilitated the identification of significant changes in the abundance and composition of intestinal microbiota in patients with PC compared to healthy controls. A study by Kartal et al. (2022) identified distinct associations between various microbial groups present in intestinal and pancreatic tissues. The enrichment of specific bacterial taxa in tumor tissue compared to adjacent healthy tissue indicates a potential link between PC and intestinal microbiota. Similarly, findings by Geller et al. (2017) demonstrated an increased presence of bacterial DNA in PC tissue compared to normal pancreatic tissue. Additionally, Aykut et al. (2019) utilized FISH technology to detect bacterial ribosomal DNA in 76% of patients with PC, whereas bacterial ribosomal DNA was observed in only 15% of patients with normal pancreatic tissue.

Although previous studies have reported alterations in the gut microbiota composition of patients with PC, a comprehensive systematic evaluation of the relationship between gut microbiota and PC is still lacking. This study, through a meta-analysis, reveals an association between PC and changes in gut microbiota composition. It aims to provide a comprehensive clinical reference to improve the diagnosis and treatment of PC.

This study constitutes the first meta-analysis on intestinal microbiota in patients with PC, based on the current knowledge levels. A comprehensive review of 2,237 articles was conducted, leading to the rigorous selection of 10 case-control studies, encompassing 324 patients with PC and 413 age-matched healthy controls.

Notable differences were identified at both the species and genus taxonomic levels upon detailed evaluation. At the phylum level, an increased abundance of Bacteroides, Fusobacterium, and Actinobacteria was observed in patients with PC compared to the healthy control group, along with a reduction in Firmicutes and Proteobacteria.

Further analysis at the genus level revealed distinct variations in microbial composition within fecal samples from patients with PC compared to healthy controls. A decreased presence of Bacteroides, Neisseria, Porphyromonas, Prevotella, and Actinomyces was noted, while an increased abundance of Fusobacterium, Rothia, Streptococcus, Veillonella, and Escherichia-Shigella was observed.

These findings highlight the potential of microbial markers as non-invasive tools for PC diagnosis, early detection, and therapeutic strategies. The identification of such microbiota-associated signatures contributes to the efforts aimed at reducing PC-related mortality. The clinical significance of this study lies in its contribution to advancing knowledge in the field and informing future research on microbiota-based approaches in PC management.

The assessment of alpha diversity is widely used in scientific research (Lozupone and Knight, 2008). It is generally hypothesized that greater microbial diversity is beneficial to the host, and consequently, a reduction in alpha diversity is expected in patients with PC. This assumption is supported by a study conducted by Sidiropoulos et al. (2024), which analyzed the fecal microbiomes of patients with PC. They found that the Chao1 and Shannon indices of PC patients were significantly decreased.

However, the meta-analysis did not identify statistically significant differences in diversity indices between the two survivor groups, providing a nuanced perspective on the proposed reduction in alpha diversity among patients with PC.

An increased abundance of Bacteroides and Fusobacterium was observed in patients with PC compared to healthy controls. This finding is consistent with an investigation by Kohi et al. (2022) which reported an enrichment of Fusobacterium in the duodenal fluid microbiota of patients with PDAC, particularly those with shorter survival durations compared to the healthy control group. Fusobacterium has been identified as an independent adverse prognostic biomarker for PC (Dapito et al., 2012).

Further exploration into the carcinogenic role of Fusobacterium was conducted by Klein (2012) who delineated its interaction with E-cadherin in epithelial cells. This interaction promotes phosphorylation and internalization of extracellular vesicles on the membrane, leading to the activation of the Wnt pathway. As a result, reduced phosphorylation of catenin occurs, facilitating β-catenin accumulation in the cytoplasm and its subsequent translocation to the nucleus (Bangolo et al., 2023). The enhancement of Wnt signaling and activation of the Wnt/β-catenin pathway have been identified as key mechanisms in the initiation of PC. Recent studies have shown that certain species of Fusobacterium, such as Fusobacterium nucleatum, can stimulate the production of specific cytokines like GM-CSF and CXCL1 (Tabrizi et al., 2024). GM-CSF promotes the proliferation, growth, and spread of pancreatic cancer cells in the body. CXCL1, a chemokine closely related to inflammation and immune responses, plays a key role in promoting pancreatic cancer cell metastasis and conferring chemoresistance (Udayasuryan et al., 2022).

At the genus level, Prevotella was identified as the predominant genus within the intestinal microbiota. Recent studies have convincingly demonstrated that Prevotella is involved in the development of PC, although the precise mechanisms remain unclear (Chen et al., 2023; Eid et al., 2024). Evidence suggests that Prevotella participates in the pathogenesis of rheumatoid arthritis in murine models via activation of the Th17/IL-17 pathway. Additionally, Prevotella accelerates the progression of pancreatic intraepithelial neoplasia (Maeda et al., 2016; Bernard, 2014; Alpizar-Rodriguez et al., 2019; McAllister et al., 2014). These findings indicate the possibility that Prevotella contributes to PC development through activation of the Th17/IL-17 pathway.

Furthermore, the meta-analysis revealed an increased abundance of Streptococcus and Veillonella in individuals with PC, which is consistent with findings from two independent group studies conducted in China and Israel. These studies reported a similar enrichment of Streptococcus and Veillonella within the intestinal microbiota of patients with PC, indicating potential microbial commonalities associated with PC across different ethnic groups (Ren et al., 2017).

The meta analysis of this study systematically revealed gut microbiota characteristics of PC patients, finding that changes in Fusobacterium and Streptococcus might link to PC progression. Although clinical information gaps (e.g., staging, treatment status) in the original data restricted the analysis, the results still offer key clues for developing non-invasive microbiota-based diagnostic tools and targeted interventions.

Future research should focus on the following directions: First, prospective cohort or multicenter studies are needed to clarify the dynamic changes in the gut microbiota across different tumor stages (such as early vs. late stages), treatment statuses (pre-/post-surgery, chemotherapy/radiotherapy), and comorbidities (diabetes, obesity, etc.), in order to identify biomarkers with clinical translation value. Second, the integration of metagenomic and metabolomic approaches can help elucidate the molecular mechanisms of specific strains’ functional genes and their metabolic products (such as short-chain fatty acids, bile acid derivatives) in PC development, offering a theoretical basis for targeted interventions. Finally, it is recommended to establish unified clinical data reporting standards (such as the STROBE guidelines) to ensure the standardized recording of variables like tumor stage, treatment details, and comorbidities. This will enhance the comparability and integrability of data across studies. These explorations will help bridge the gap from “correlation” to “causality” and ultimately enable precision diagnosis and treatment strategies based on microbiome regulation.

This study adhered strictly to predefined inclusion and exclusion criteria, incorporating a comprehensive search, screening, and systematic evaluation in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Page et al., 2021a,b). A total of 10 studies involving 324 patients with PC were included in the analysis, with results derived through an objective analytical approach.

Despite these methodological rigors, several limitations inherent to this meta-analysis should be acknowledged: (1) The body of available literature and research suitable for inclusion remained limited. (2) Substantial variability in sample sizes across included studies may disproportionately amplify effects from underpowered trials. (3) Some indicators, such as alpha diversity, show a high degree of heterogeneity. (4) Geographical differences: Although efforts were made to minimize heterogeneity by controlling for variables such as gender, race, diet, sample size, and geographic distribution, there were unavoidable discrepancies which persisted across studies. (5) Methodological differences: In analyses utilizing 16S rRNA sequencing technology, potential sources of variability—including differences in researchers, sequencing timelines, sequencing platforms, and experimental methodologies—may have contributed to inconsistencies in findings. (6) The pathophysiological progression of PC itself may influence changes in the intestinal microbiota, further complicating interpretations of microbiota changes. (7) This study identifies an association between intestinal microbiota composition and PC but does not establish a causal relationship.

The findings of this meta-analysis indicate no statistically significant differences in the alpha diversity index between patients with PC and healthy controls. However, an association was observed between the increased abundance of specific bacteria—Fusobacterium, Veillonella, and Streptococcus—and PC. It is important to emphasize that this meta-analysis establishes only a correlation between intestinal microbiota composition and the pathogenesis of PC, with conclusions constrained by the limited body of available research. Therefore, further primary and clinical studies are necessary to elucidate the complex interplay between intestinal microbiota dysbiosis and the pathogenesis and progression of PC.