Cannabidiol Is Associated with Improved Survival in Pancreatic Cancer and Modulation of Bile Acids and Gut Microbiota

Pancreatic ductal adenocarcinoma (PDAC) is among the most aggressive malignancies, with dismal survival rates. Cannabinoids have shown anticancer properties in various cancers, including PDAC. This study aimed to evaluate the anticancer effects of cannabinoids, individually and in combination, and to elucidate their mechanisms of action in a murine PDAC model (KPC mice, KRASWT/G12D/TP53WT/R172H/Pdx1-Cre+/+) that mimics human disease. Additionally, the study explored the potential link between cannabinoid action, gut microbiota modulation, and bile acid (BA) metabolism. PDAC cell lines and KPC mice were treated with delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), either as monotherapy or in combination. Faecal pellets, caecal contents, plasma, and tissues were collected at the survival endpoint for analysis. BA profiling was performed using mass spectrometry, and the faecal microbiota was characterised by sequencing the V3-V4 region of the 16S rRNA gene. While CBD and THC synergistically reduced cell viability in PDAC cell lines, only CBD monotherapy improved survival in KPC mice. Extended survival with CBD was accompanied by changes in gut microbiota composition and BA metabolism, suggesting a possible association. Notably, the effects of CBD were different from those observed with THC alone or in combination with CBD. The study highlights a distinct role for CBD in altering BA profiles, suggesting these changes may predict responses to cannabidiol in PDAC models. Furthermore, the findings propose that targeting BA metabolism could offer a novel therapeutic strategy for PDAC.