Fasting-Mimicking Diet Prevents Pancreatic Carcinogenesis via Gut Microbiota and Metabolites

The incidence of pancreatic cancer has been increasing globally in recent years and dietary is a well-defined factor contributing to its carcinogenesis. In this study, we showed that in a cerulein-induced KC (Pdx1-cre; LSL-Kras G12D/+) mouse model, a fasting-mimicking diet (FMD)─comprising fasting for 3 days followed by 4 days of refeeding, repeated over three 1-week cycles─significantly retards the progression of pancreatic carcinogenesis. FMD treatment altered gut microbiota, notably boosting butyrate-producing bacteria and elevating butyric acid levels in pancreatic tissues. Furthermore, lysine pan-crotonylation (pan-Kcr) expression was markedly upregulated in pancreatic intraepithelial neoplasia (PanIN) tissues from FMD-treated mice. Treatment of normal pancreatic duct and pancreatic cancer cells with sodium butyrate also upregulated pan-Kcr expression while reducing cell proliferation. Our findings reveal the pivotal role of dietary factors in the carcinogenesis of the pancreas and support further clinical studies of FMD as an antineoplastic therapeutic measure.