Mendelian analysis reveals novel pancreatic cancer-associated gut bacteria with tumor-suppressive effects.

PURPOSE: The gut microbiota has been implicated in the development and progression of pancreatic cancer (PC), yet few specific bacterial species have been reported to exert functional effect on PC. This study aimed to identify novel PC-associated gut bacterial species with tumor-regulatory effects and explore the potential molecular mediators of their effect.

METHODS

A bidirectional two-sample mendelian randomization (MR) analysis was performed using summary statistics from the MiBioGen consortium (n = 18,340) for gut microbiota and from the GWAS Catalog (587 PC cases, 455,761 controls) to assess their causal relationship. A two-step MR analysis incorporating blood metabolite data (n = 8,299 from the GWAS Catalog) was conducted to investigate potential mediation via circulating metabolites. Functional validation of identified bacterial taxa was carried out in murine models of PC via oral gavage of representative species.

RESULTS

Six bacterial taxa, including four genera, demonstrated reliable evidence of causal associations with PC. Eggerthella and Parasutterella were identified as protective for PC, whereas Sutterella and Coprococcus1 were associated with increased PC risk. Additionally, 26 blood metabolites showed causal associations with PC. After evaluating the causal relationships between PC-associated gut microbiota and blood metabolites, we found that the Eggerthella genus and Sutterella genus exert causal effect on PC by reducing the circulating levels of deoxycarnitine and hypotaurine, respectively. In two distinct orthotopic PC models, oral administration of Eggerthella lenta (E. lenta, the type species of the Eggerthella genus) or Parasutterella excrementihominis (P. excrementihominis, the type species of the Parasutterella genus) consistently exerted significant tumor-suppressive effects on the growth of pancreatic tumors. Moreover, E. lenta administration enhanced the infiltration of CD8⁺ T cells and NKT cells within orthotopic pancreatic tumors, suggesting a potential role of E. lenta in reshaping the tumor immune microenvironment to favor antitumor immunity.

CONCLUSIONS

This study identifies E. lenta and P. excrementihominis as novel PC-associated gut bacterial species with tumor-suppressive effects, offering potential candidates for probiotic-based interventions in PC. CLINICAL TRIAL NUMBER: Not applicable.