Potential therapeutic effects of Lactobacillus on Pancreatic ductal adenocarcinoma through its metabolite Harmaline

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and lethal form of cancer. Recent research has uncovered the role of the gut microbiota in influencing PDAC progression and treatment outcomes. Dysbiosis of gut microbiota in PDAC patients has been shown to negatively impact disease progression and treatment efficacy, indicating the therapeutic potential targeting the gut microbe. As PDAC progresses, there is a significant decrease in the abundance of Lactobacillus. Utilizing a subcutaneous tumor model in mice with PDAC, we found that orally administering Lactobacillus inhibited tumor growth and induced apoptosis, accompanied by a beneficial shift in the gut microbial composition. We also observed that Lactobacillus metabolites significantly suppressed pancreatic cancer growth and induced apoptosis in both PDAC cell lines and PDAC organoids. RNA-seq analysis revealed the activation of apoptosis-related pathways in cancer cells treated with Lactobacillus metabolites. Untargeted metabolomics identified Harmaline, a metabolite of Lactobacillus, as a key inhibitor of cancer cell proliferation and inducer of apoptosis through the TNF-NFκB signaling pathway. Our findings demonstrate the potential of Lactobacillus as a novel therapeutic agent for PDAC by modulating the gut microbiota, inhibiting tumor growth, and inducing apoptosis. The therapeutic potential of Lactobacillus and its metabolite, Harmaline, is evident in PDAC treatment. Lactobacillus given through gavage can reduce PDAC growth in nude mice and promote apoptosis. Harmaline suppresses the growth and movement of PDAC cells via the TNF-NFκB signaling pathway.