Elephant-derived Bacillus licheniformis modulates immune cells shedding light on cancer resistance

Introduction Colorectal cancer (CRC) is currently a leading cause of cancer-related morbidity and mortality globally, underscoring the need for innovative therapeutic strategies. Probiotic treatment is increasingly appreciated as an innovative method for ameliorating inflammation and modulating the tumor microenvironment, especially in gastrointestinal diseases. Many bacterial species isolated from human and animal sources are proven effective in potential disease treatments. Elephants, renowned for their exceptional resistance to cancer, have traditionally been linked to their TP53 gene multiplicity. However, the potential contribution of their evolutionarily-refined gut microbiota to their remarkable cancer resistance remained largely unexplored. Methods Here, we investigated this underexplored avenue by analyzing the elephant gut microbiome and isolating a probiotic bacterium. We utilized whole genome sequencing (WGS) to assess its genomic profile. The in vivo efficacy was evaluated in mouse models of gut inflammation and colorectal tumors. Underlying mechanisms were investigated using transcriptomic analysis, flow cytometry, and integrative metabolomics. Finally, in vitro experimental validations were conducted on mouse and human CRC cell lines using the bacterial culture supernatant. Results We found that elephants possess a highly specialized gut microbiome finely tuned to metabolize complex polysaccharides. WGS of the isolated Bacillus licheniformis revealed its metabolic and functioning roles and confirmed the absence of virulence factors. We demonstrated that this elephant-derived strain effectively alleviated gut inflammation and suppressed the progression of colorectal tumors in mouse models. Transcriptomic analysis and flow cytometry revealed that B. licheniformis remodeled the immune microenvironment, specifically activating tumor-infiltrating T cell response and cell cytotoxicity. Integrative metabolomics identified several key metabolites as potential soluble mediators correlated with tumor regression. Furthermore, the supernatant of B. licheniformis culture significantly enhanced cytotoxicity and upregulated p53 expression in CRC cell lines in vitro . Discussion Collectively, these findings unveil previously unrecognized therapeutic potentials inherent in elephant-derived probiotics, suggesting a mechanism of functional immune regulation for CRC prevention.