ABSTRACT

The human intestine (gut) nurtures the growth of approximately 100 trillion bacteria. In return, most of these bacteria harvest extra energy from the diet and protect against infection. However, a range of factors can trigger the gut immune system to activate an inflammation response and produce anti-microbial molecules that harm beneficial bacteria while leading the a bloom of non-beneficial bacterial. It has become widely accepted the that gut microbiome is important, nevertheless, the understanding how the fluctuations in diet and bacterial composition affect the immune system and how the 'good' bacteria maintain a healthy state remains largely unknown. A major limitation is a lack of technologies for non-invasively measuring the molecules produced by the gut immune system. The investigator seeks to overcome this limitation by engineering harmless, orally ingestible 'sensor bacteria' that specifically detect these molecules and respond by expression of a reporter (that might give rise to a color change of the bacteria, for example) that can be evaluated after passage through the gut. The investigator will use a combination of computational and experimental techniques to evaluate the ability of these sensor bacteria to probe molecular interactions that impact the gut microbiome. This work supports NSFs mission to understand a fundamental complex and poorly understood biological processes at a molecular level. It may also offer down-stream opportunities to reduce or eliminate some of the prevalent bowel diseases. The planned broader impact activities emphasize student education and public outreach to demonstrate how basic research can have profound beneficial impacts on society.

The mammalian gut maintains a large and diverse community of bacteria that performs numerous beneficial functions. The so-called gut microbiota is largely comprised of anaerobic fermenters that digest host- and diet-derived oligosaccharides. However, metabolites produced by minority members can induce a host inflammatory response, which enriches the local environment with reactive oxygen species, leading to the accumulation of oxidized metabolites. These metabolites can be respired by facultative anaerobes leading to blooms of otherwise rare gut members, under certain conditions. The consequence can be long-term microbial imbalance, or dysbiosis. The precise connection between the temporal dynamics of oxidized metabolite production and consumption leading to undesirable microbial blooms remains poorly understood. This project uses a systems and synthetic biology approach to engineer bacteria to sense physiologically-relevant signals in the gut. The sensor bacteria would report on the state of the gut microbiome during its transient passage through the gut, providing a molecular-level understanding of gut physiology and dynamics.

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