Inflammatory Stimuli and Fecal Microbiota Transplantation Accelerate Pancreatic Carcinogenesis in Transgenic Mice, Accompanied by Changes in the Microbiota Composition

An association between gut microbiota and the development of pancreatic ductal adenocarcinoma (PDAC) has been previously described. To better understand the bacterial microbiota changes accompanying PDAC promotion and progression stimulated by inflammation and fecal microbiota transplantation (FMT), we investigated stool and pancreatic microbiota by 16s RNA-based metagenomic analysis in mice with inducible acinar transgenic expressions of KrasG12D, and age- and sex-matched control mice that were exposed to inflammatory stimuli and fecal microbiota obtained from mice with PDAC. Time- and inflammatory-dependent stool and pancreatic bacterial composition alterations and stool alpha microbiota diversity reduction were observed only in mice with a Kras mutation that developed advanced pancreatic changes. Stool <i>Actinobacteriota</i> abundance and pancreatic <i>Actinobacteriota</i> and <i>Bifidobacterium</i> abundances increased. In contrast, stool abundance of <i>Firmicutes</i>, <i>Verrucomicrobiota</i>, <i>Spirochaetota</i>, <i>Desulfobacterota</i>, <i>Butyricicoccus</i>, <i>Roseburia</i>, <i>Lachnospiraceae A2</i>, <i>Lachnospiraceae unclassified</i>, and <i>Oscillospiraceae unclassified</i> decreased, and pancreatic detection of <i>Alloprevotella</i> and <i>Oscillospiraceae uncultured</i> was not observed. Furthermore, FMT accelerated tumorigenesis, gradually decreased the stool alpha diversity, and changed the pancreatic and stool microbial composition in mice with a Kras mutation. Specifically, the abundance of <i>Actinobacteriota</i>, <i>Bifidobacterium</i> and <i>Faecalibaculum</i> increased, while the abundance of genera such as <i>Lachnospiraceace A2</i> and <i>ASF356</i>, <i>Desulfovibrionaceace</i> uncultured, and <i>Roseburia</i> has decreased. In conclusion, pancreatic carcinogenesis in the presence of an oncogenic Kras mutation stimulated by chronic inflammation and FMT dynamically changes the stool and pancreas microbiota. In particular, a decrease in stool microbiota diversity and abundance of bacteria known to be involved in short-fatty acids production were observed. PDAC mouse model can be used for further research on microbiota-PDAC interactions and towards more personalized and effective cancer therapies.