Tryptophan-Containing Antimicrobial Peptides Attenuate Colorectal Cancer Progression by Inhibiting the Growth of Fusobacterium nucleatum

Colorectal cancer, which originates in the epithelial cells of the colon or rectum, is closely associated with dysbiosis of the gut microbiota. Increasing evidence has shown that Fusobacterium nucleatum plays a significant role in colorectal cancer progression by activating inflammatory responses, modulating the tumor microenvironment, and promoting tumor cell proliferation. Antimicrobial peptides targeting Fusobacterium nucleatum have the potential to serve as more effective and less toxic therapeutic agents compared to chemotherapy drugs. In this study, we systematically evaluated the antibacterial activity of Trp-containing peptides, including natural peptides isolated from the skin secretions of the Chinese brown frog (Rana chensinensis) and their derivatives, which exhibit potent antibacterial activity against Fusobacterium nucleatum with minimal cytotoxicity. Mechanistic investigations using membrane permeability assays and membrane potential-sensitive dyes indicated that Trp-containing peptides exert their antimicrobial effects by disrupting the bacterial membrane structure, increasing membrane permeability, and interfering with membrane potential. In a colorectal cancer mouse model infected with Fusobacterium nucleatum, treatment with Trp-containing peptides significantly alleviated tumor-related symptoms, reduced colonic inflammatory cytokine levels, and alleviated colonic tissue damage, as confirmed by histopathological analysis. Importantly, no apparent toxicity or adverse effects were observed during the treatment. These findings indicate that Trp-containing peptides, as lead compounds, not only exhibit potent antibacterial activity but also attenuate Fusobacterium nucleatum associated colorectal cancer progression, providing critical evidence to support the development of innovative therapeutic strategies with combined antimicrobial and antitumor properties.