Understanding redox-regulated mechanisms of environmental adaptation in gastrointestinal symbionts

Yale University, New Haven CT

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Abstract

Project Summary Bacteria that chronically colonize the host, such as members of the gut microbiota, must adapt to various forms of stress in the host environment. The molecular mechanisms bacteria use to sense and respond to these environmental signals are crucial for maintaining symbiotic associations with host cells. Oxidative stress is a hallmark of host–microbe interaction best known for its role in the host immune response; however, reactive oxygen species (ROS) are also generated by epithelial barriers in response to microbial contact and as byproducts of cellular respiration. My laboratory uses chemical and genetic tools to define molecular mechanisms of bacterial adaptation to oxidative stress. We use the common gastric symbiont Helicobacter pylori to model bacterial responses to physiological ROS. H. pylori is a normal member of the gastric flora that has co-evolved with humans for at least 60,000 years and, like many commensal microbes, can persist for decades in the host despite constant exposure to ROS-generating immune and epithelial cells. Through studies in H. pylori, we recently discovered a highly specific and widely conserved microbial transporter of the dietary antioxidant ergothioneine (EGT) that fortifies bacterial resistance to oxidative stress. EGT belongs to a class of sulfur-containing small molecules known as the low-molecular-weight (LMW) thiols, which are required to maintain reducing conditions within cells. Although LMW thiols are synthesized by nearly all life forms, certain bacteria that colonize animal hosts, including H. pylori, lack the canonical enzymes required for LMW- thiol biosynthesis. Thus, EGT uptake represents a novel mechanism by which certain bacterial symbionts can maintain redox homeostasis in the host. Furthermore, our data strongly suggest that host-derived EGT and glutathione (GSH), another major LMW thiol, can serve as nutrient sources for bacteria in the gastrointestinal tract, inspiring new questions regarding the role of antioxidant metabolism in microbial physiology. In the current proposal, we will build on these findings by providing mechanistic insights into how microbial import and metabolism of host-derived antioxidants shape homeostasis at the host–microbe interface. By using EGT as a model to discover antioxidant-associated proteins and metabolites that regulate bacterial physiology, we expect to build fundamental understanding of how exogenous LMW thiols influence microbial adaptation to the host environment and thereby establish a framework for investigating the roles of other host-derived antioxidants in microbial redox biology and metabolism.