Oncobiosis and Microbial Metabolite Signaling in Pancreatic Adenocarcinoma

Abstract

Pancreatic adenocarcinoma is one of the most lethal cancers in both men and women, with a median five-year survival of around 5%. Therefore, pancreatic adenocarcinoma represents an unmet medical need. Neoplastic diseases, such as pancreatic adenocarcinoma, often are associated with microbiome dysbiosis, termed oncobiosis. In pancreatic adenocarcinoma, the oral, duodenal, ductal, and fecal microbiome become dysbiotic. Furthermore, the pancreas frequently becomes colonized (by Helicobacter pylori and Malassezia, among others). The oncobiomes from long- and short-term survivors of pancreatic adenocarcinoma are different and transplantation of the microbiome from long-term survivors into animal models of pancreatic adenocarcinoma prolongs survival. The oncobiome in pancreatic adenocarcinoma modulates the inflammatory processes that drive carcinogenesis. In this review, we point out that bacterial metabolites (short chain fatty acids, secondary bile acids, polyamines, indole-derivatives, etc.) also have a role in the microbiome-driven pathogenesis of pancreatic adenocarcinoma. Finally, we show that bacterial metabolism and the bacterial metabolome is largely dysregulated in pancreatic adenocarcinoma. The pathogenic role of additional metabolites and metabolic pathways will be identified in the near future, widening the scope of this therapeutically and diagnostically exploitable pathogenic pathway in pancreatic adenocarcinoma.

Keywords: LPS; amino acid metabolites; bacterial metabolite; bile acids; microbiome; oncobiome; pancreatic adenocarcinoma; polyamines; short chain fatty acid.

Figure 1

Known bacterial metabolite-elicited signaling pathways in pancreatic adenocarcinoma. Pro-proliferative metabolites are shown in red; antiproliferative metabolites are shown in green. Abbreviations: SCFA—short chain fatty acid, DCA—deoxycholic acid, LPS—lipopolysaccharide, FFAR—free fatty acid receptor, TGR5—Takeda G Protein-Coupled Receptor 5/ G-protein-coupled bile acid receptor, EGFR—Epidermal growth factor receptor, TLR—Toll-like receptor, MAPK—mitogen activated protein kinase, STAT—Signal transducer and activator of transcription.

Figure 2

Schematic representation of the role of oncobiosis in pancreatic adenocarcinoma. Rows represent the spillover of the dysbiotic microbiome of the oral cavity, stomach, and bowels to the pancreas and feces. Antineoplastic processes are shown in green and neoplastic processes are shown in red. Abbreviations: UDCA—ursodeoxycholic acid, DCA—deoxycholic acid, LPS—lipopolysaccharide.