Abstract PL01-02: Influence of the microbiota on cellular proliferation and survival

Abstract

Abstract The resident prokaryotic microbiota of the mammalian intestine influences diverse homeostatic functions of the gut, including maintenance of barrier function, modulation of immune responses, as well as energy and nutrient extraction. Additionally, through studies of germ free mice, it has become apparent that commensal prokaryotic organisms are involved in the regulation of growth and survival in the intestinal epithelia, and thus may play fundamental roles in the pathogenesis of colon cancers. However, the molecular mechanisms of growth control by prokaryotes in the gut are largely unknown. It is increasingly recognized that physiologically generated reactive oxygen species (ROS) function as signaling secondary messengers that influence cellular proliferation and differentiation in a variety of biological systems. We have shown that commensal bacteria, particularly members of the genus Lactobacillus, can activate NADPH oxidase 1 (Nox1)-dependent ROS generation and modulate multiple cellular pathways, including NF-kB, ERK-MAPK and focal adhesion kinase, that are involved in control of epithelial cellular survival, proliferation, and migration. ROS inducing commensal bacteria can rapidly stimulate consequent cellular proliferation in intestinal stem cells upon initial ingestion into the murine or Drosophila intestine, illustrating the highly conserved nature of this host microbe interaction. Additionally, a well-studied and evolutionarily highly conserved system for transducing exogenous stimuli into eukaryotic host tissues is Nrf2 signaling. Nrf2 pathway activation upregulates a regulon of genes including those involved in xenobiotic and ROS detoxification, as well as pro-restitutive function. This pathway has attracted considerable attention because small molecule inducers of Nrf2 have cytoprotective and growth modulatory effects. We show cellular ROS generated in response to contact with lactobacilli have cytoprotective effects in the intestinal epithelium through the activation of Nrf2 responsive cytoprotective genes. These data suggest that the Nrf2 pathway, and perhaps other highly conserved pathways that respond to environmental alterations, have been adapted as signaling conduits between eukaryotic host and prokaryotic symbiont, and highlight the role the microbiota plays in eukaryotic cytoprotective pathways. Characterization of these pathways may have significant implications in the delineation of a eubiotic microbiota, and in the identification of probiotic microbes with potential to influence epithelial growth and survival. Citation Format: Andrew Scott Neish. Influence of the microbiota on cellular proliferation and survival. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr PL01-02.