Characterizing the Role of the E. Coli Cytochrome Oxidase AppBCX During Intestinal Inflammation
During non-infectious colitis, oral antibiotic treatment, and enteric infection, changes in colonocyte metabolism allow for increased oxygen availability in the gut lumen, supporting the growth of facultative anaerobic bacteria primarily from the family Enterobacteriaceae. Additionally, recruitment of inflammatory cells, especially neutrophils, has also been shown to influence local oxygen levels. The oxidative burst mounted by neutrophils consumes oxygen, which in turn creates a hyper-hypoxic microenvironment. These two seemingly contradictory findings remain to be reconciled. The findings described here delineate an additional mechanism that helps explain these seemingly contradictory observations on oxygen availability and bacterial respiratory processes during non-infectious colitis. The picture emerging from our work is that reactive oxygen species (ROS) generated by the NADPH oxidase 1 (NOX1) at the epithelial interface serve as a local source of oxygen. Specifically, H2O2 deriving from epithelial NOX1, is detoxified via bacterial catalases to molecular oxygen. Facultative anaerobic bacteria can then respire this pool of oxygen. In this work, we have used commensal strains of E. coli as representative members of Enterobacteriaceae, a family of facultative anaerobic bacteria that is observed to outgrow during episodes of inflammation. In particular, we have studied the physiological function of the cytochrome bd oxidase, AppBCX. Using both chemical and genetic models of non-infectious colitis we have shown that it allows E. coli to utilize low levels of oxygen early in inflammation. Additionally, we have characterized the regulation of this enzyme in vivo highlighting the delicate balance between growth and survival during oxidative and nitrosative stress.
Electron Transport Complex IV, Escherichia coli, Inflammation, Intestinal Mucosa, NADPH Oxidase 1, Reactive Oxygen Species
University of Texas Southwestern Medical Center
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