Discovery and characterization of antitumor gut microbiota from amphibians and reptiles: Ewingella americana as a novel therapeutic agent with dual cytotoxic and immunomodulatory properties

ABSTRACT

The utilization of gut microbiota in cancer therapy has attracted considerable attention as an emerging therapeutic frontier. In this study, we systematically evaluated the antitumor effects of nine bacterial strains isolated from the intestines of amphibians (Dryophytes japonicus and Cynops pyrrhogaster) and a reptile (Takydromus tachydromoides). Among the isolates, Ewingella americana exhibited remarkably potent cytotoxic activity with selective tumor-targeting ability characteristic of facultative anaerobic bacteria. Mechanistic investigations revealed that E. americana functions through a dual-action mechanism: direct tumor cell killing and robust activation of host immunity, leading to enhanced T cell, neutrophil, and B cell-mediated tumor attack. Treatment with E. americana significantly outperformed standard therapies, including anti-PD-L1 antibody and doxorubicin, in tumor regression studies. Importantly, comprehensive safety evaluations in murine models demonstrated that the gut-derived E. americana strain exhibits minimal pathogenicity and exerts no significant adverse effects at therapeutically effective doses, contrasting favorably with genetically modified bacterial therapeutics. Comparative analysis revealed superior therapeutic efficacy of E. americana over conventional treatments while maintaining an excellent safety profile. These findings suggest that gut microbiomes of lower vertebrates harbor numerous uncharacterized bacterial species with exceptional therapeutic potential. Our study establishes a foundation for developing naturally occurring, non-pathogenic bacterial therapeutics and underscores the critical importance of microbial biodiversity in advancing cancer treatment strategies.