Microbes that colonize the gut following extreme medical interventions such as major organ transplantation Crenolanib cell line are under an unprecedented level of

pressure to adapt to an highly abnormal environment in which pH is shifted, nutrient resources are limited, and the normal microbial flora is dramatically altered by the combined effects of extreme physiologic stress and antibiotic treatment. In this regard, the human opportunistic pathogen P. aeruginosa has been shown to rapidly colonize such patients and be a major primary source of infection and sepsis [34]. In many cases of severe sepsis the primary pathogen remains unidentified. In this regard, intestinal P. aeruginosa is particularly Gefitinib research buy suited to use the intestinal tract as a privileged site with its unique ability to survive, persist, and mount a toxic offensive without extraintestinal dissemination (gut-derived sepsis) [35]. The emergence of pan-resistant strains of P. aeruginosa that often colonize the gut of the most critically ill patients begs the development of a non- antibiotic based approach that can suppress virulence activation of P. aeruginosa through the course of surgery or

immuno-suppression as a containment rather than elimination strategy. To achieve this, a more complete understanding of the physico-chemical cues that characterize colonization sites of intestinal pathogens in critically ill patients is needed.

Our previous work suggests that a major environmental cue that shifts P. aeruginosa to Sinomenine express a lethal phenotype within the intestinal tract of surgically injured mice is the mucosal phosphate. During surgical injury, phosphate becomes depleted within the intestinal mucus and signals P. aeruginosa to express a lethal phenotype via pathways that triangulate three global virulence subsystems: phosphate signaling and acquisition, MvfR-PQS of quorum sensing, and pyoverdin production [9]. Importantly, maintenance of phosphate abundance/sufficiency via oral supplementation prevents activation of these pathways and attenuates mortality in mice and C. elegans. Results from the present study emphasize the importance of pH on the ability of phosphate to protect mice and C. elegans from the lethal effect of intestinal P. aeruginosa. This is particularly important given the observation that pH in the distal intestinal tract is increased in response to surgical injury. We focused on pH changes in the proximal colon (cecum) as it is the densest site of microbial colonization and the site of greatest immune activation in response to intestinal pathogens [36–40]. In addition, various reports confirm that experimental injury or human critical illness results in a similar shift in distal intestinal pH from a normal value of 6 to > 7 in both animals and humans [1, 11, 16]. Therefore the transcriptional response of P.