Upregulation of <i>Lactobacillus spp</i> . in gut microbiota as a novel mechanism for environmental eustress-induced anti-pancreatic cancer effects

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with limited effective treatment options. Emerging evidence links enriched environment (EE)-induced eustress to PDAC inhibition. However, the underlying mechanisms remain unclear. In this study, we explored the role of gut microbiota in PDAC-suppressive effects of EE. We demonstrated that depletion of gut microbiota with antibiotics abolished EE-induced tumor suppression, while fecal microbiota transplantation (FMT) from EE mice significantly inhibited tumor growth in both subcutaneous and orthotopic PDAC models housed in standard environment. 16S rRNA sequencing revealed that EE enhanced gut microbiota diversity and selectively enriched probiotic <i>Lactobacillus</i>, particularly <i>L. reuteri</i>. Treatment with <i>L. reuteri</i> significantly suppressed PDAC tumor growth and increased natural killer (NK) cell infiltration into the tumor microenvironment. Depletion of NK cells alleviated the anti-tumor effects of <i>L. reuteri</i>, underscoring the essential role of NK cell-mediated immunity in anti-tumor response. Clinical analysis of PDAC patients showed that higher fecal <i>Lactobacillus</i> abundance correlated with improved progression-free and overall survival, further supporting the therapeutic potential of <i>L. reuteri</i> in PDAC. Overall, this study identifies gut microbiota as a systemic regulator of PDAC under psychological stress. Supplementation of psychobiotic <i>Lactobacillus</i> may offer a novel therapeutic strategy for PDAC.