The gastrointestinal tract is host to a dense microbial community, known as the gut microbiota, which is dominated by obligate anaerobic bacteria belonging to the phyla Bacteroidetes (class Bacteroidia) and Firmicutes (class Clostridia). This microbial community offers benefit by conferring niche protection against facultative anaerobic Proteobacteria (e.g. Escherichia coli), a property known as 'colonization resistance'. However, the precise mechanisms by which the gut microbiota confers colonization resistance remain obscure. The objectives of this application are to study how the gut microbiota influences colonization resistance against Proteobacteria, using E. coli as a prototypical representative. Our central hypothesis is that obligate anaerobic bacteria mediate colonization resistance against E. coli through microbe-host interactions that suppress inflammation. Disruption of these microbe-host interactions by antibiotic treatment (dysbiosis) increases the inflammatory tone of the intestinal mucosa and the concomitant production of radicals by the host response generates respiratory electron acceptors, which support growth of E. coli by anaerobic respiration.
In Aim 1 we will determine whether a reduction in short-chain fatty acid (SCFA) concentrations after antibiotic treatment is responsible for lowering colonization resistance against E. coli.
In Aim 2 we will develop approaches to treat dysbiosis induced by antibiotic therapy. Successful completion of our study will provide innovation by establishing a novel mechanism for colonization resistance (Aim 1) and facilitating the development of approaches to treat a loss of colonization resistance when a balanced community has been disrupted (Aim 2). This outcome will be significant because conceptual advances resulting from the proposed work are expected to establish a new paradigm that will influence research by others in the field.
Over 90% of the cells in the human body are microbes, the majority of which reside in the large intestine, where they provide benefit to the host by educating the immune system and by providing niche protection against colonization with potentially harmful bacteria, a property known as colonization resistance. Antibiotic therapy is accompanied by a microbial imbalance that leads to a loss of colonization resistance. Here we will study the mechanism underlying colonization resistance and develop a potential treatment strategy for restoring it, which will usher in important conceptual advances that have a strong potential to exert a high impact on this field of science.
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