Gender-specific changes of the gut microbiome correlate with tumor development in murine models of pancreatic cancer

Background: Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with dismal outcome. Recently, microbiome signatures were demonstrated to influence disease progression or to correlate with PDAC development. To improve understanding of sequential microbiome changes during PDAC development we comprehensively and longitudinally analyzed appropriate mouse models of murine pancreatic carcinogenesis (KC mice recapitulating preinvasive PanIN formation, as well as KPC mice recapitulating invasive PDAC) during early tumor development and subsequent tumor progression. Results Diversity and community composition were analyzed depending on factors genotype, age, and gender. All three analyzed factors significantly influenced the overall community composition and diversity. Most prevalent genera (59 of 74) were affected by at least one factor. Bacteroidales were typically affected by all three factors whereas Erysipelotrichiaceae were prone to be influenced by gender and Proteobacteria were mainly affected by genotype. Concerning genotype effects, communities in cancer models differed substantially from communities in Pdx-1-Cre control mice, with KC mice harboring preinvasive PanIN lesions often adopting intermediate stages. Genotype clearly influenced microbiota composition at the genus, but to a lesser extent at higher phylogenetic levels. Ten genera/genus level taxa were influenced by all three factors. Here, Bacteroides, Prevotella and Parabacteroides showed similar effects with increasing abundances during ageing, from Pdx1-Cre over KC to KPC mice and, higher levels were observed in female compared to male mice. In few cases, a significant interaction between factors were observed. A genotype effect on the abundance of Parabacteroides and Prevotella was depicted mainly in female mice. Analysis of species level taxa indicated Bacteroides spp to behave similarly, however, species of other genera displayed very distinct characteristics. Conclusion Both mouse models demonstrated concordant abundance changes of several genera influenced by one or more of the investigated factors. Abundance was significantly impacted by gender, highlighting the need to further elucidate the impact of gender differences. Distinct behavior on species level probably enabled to react differently to environmental changes. The findings underline the importance of the microbiome in PDAC development and indicate that microbiological screening of patients at risk and targeting the microbiome in PDAC development may be feasible in future.