The Crosstalk Between Exercise, the Gut Microbiome, and Cancer: Mechanistic Insights and Therapeutic Perspectives

Abstract

The bidirectional interaction between exercise, the gut microbiome, and cancer has become a key biological connection linking metabolism, immunity, and tumor biology. Growing evidence shows that physical activity not only lowers cancer risk but also affects treatment response, partly through microbiome-related mechanisms. This review combines experimental and clinical studies from 2010 to 2025 to explain how different types and intensities of exercise influence gut microbial composition, microbial metabolites, immune regulation, and cancer pathways. Regular moderate exercise consistently improves gut microbial diversity, boosts beneficial bacteria, and raises short-chain fatty acid (SCFA) production, which reduces systemic inflammation, strengthens intestinal barriers, and enhances immune monitoring. Conversely, gut dysbiosis promotes cancer development through chronic inflammation, genotoxic metabolite production, weakened mucosal defenses, and changes in tumor microenvironment signaling. New evidence suggests that exercise impacts bile acid metabolism, hydrogen sulfide levels, and reactive oxygen and nitrogen species, forming key links between muscle activity, gut immunity, and tumor control. Notably, while moderate and sustained physical activity provides protective effects via the microbiome, excessive or long-term high-intensity exercise might temporarily disrupt gut barrier function and increase inflammation. Although clinical applications are still limited, current research indicates that combining structured exercise programs with microbiome-targeted strategies could be a promising approach for cancer prevention and treatment, especially in colorectal cancer. Collectively, this review provides a mechanistic framework for understanding exercise–microbiome–cancer crosstalk and highlights future directions toward personalized, microbiome-informed exercise prescriptions to improve metabolic health, immune competence, and cancer outcomes.