Abstract
Background:
Chronic stress and gut dysbiosis are established risk factors for colorectal adenocarcinoma, yet their synergistic effects on the development of intestinal precancerous lesions remain poorly understood.
Methods:
This study investigates the molecular mechanisms through which chronic stress interacts with opportunistic pathogen Listeria monocytogenes to drive intestinal tumorigenesis in Apc Min/+ mice, with particular focus on the involvement of tumor immune microenvironment remodeling.
Results:
The combination of L. monocytogenes infection and chronic stress, rather than bacterial infection alone, significantly increased colonic adenoma burden and epithelial dysplasia, suggesting that chronic stress establishes a permissive microenvironment for opportunistic pathogens to exert pro-tumorigenic effects. Mechanistically, chronic stress downregulated intestinal epithelial Muc-2 expression and reduced microbial diversity, thereby compromising mucus/microbial barrier integrity and enhancing L. monocytogenes colonization. Under dual stress-pathogen exposure, we observed the expansion of myeloid-derived suppressor cells (MDSCs) in spleen and the upregulation of IL-6 in colonic mucosa, which facilitated MDSCs recruitment to tumor sites. Infiltrating MDSCs driven CD8+ T cell depletion through cAMP/PKA/CREB signaling, leading to the establishment of immunosuppressive microenvironment.
Conclusion:
Our results propose that chronic stress-induced gut barrier disruption may serve as a prerequisite for opportunistic pathogens to accelerate the development of precancerous lesions. Their synergistic effects reshape systemic/local immune responses, creating a microenvironment conducive to malignant transformation and tumor cell survival. These preliminary findings highlight potential clinical applications of psychological interventions and immune modulation strategies in preventing intestinal carcinogenesis.
Keywords:
Listeria monocytogenes; MDSCs; adenoma; chronic stress; intestinal barrier.