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Title: "EXPLOITING THE BENEFITS OF PROBIOTICS FOR INTESTINAL DISEASE DIAGNOSIS AND THERAPY" Committee: Prof. Jim Collins, MIT Medical Engineering and Science (Co-Advisor) Prof. Mo Khalil, BU BME (Co-Advisor) Prof. Wilson Wong, BU BME (Chair) Prof. Mary Dunlop, BU BME Prof. Domitilla Del Vecchio, MIT Mechanical and Biological Engineering Abstract: Probiotics are live microorganisms that can confer health benefits to the host. They have long been consumed through fermented foods. While the specific mechanisms of probiotics are largely unclear, there is evidence that their beneficial effects may be attributed to the microbes’ ability to modify the gastrointestinal (GI) environment, to modulate host immune response, or to produce natural products that directly inhibit pathogens in the gut. With the increasing awareness of the important functions that the gut microbiota plays in affecting host heath, probiotics may no longer just stay as simple dietary supplements, but become a promising approach to disease management. With recent advances in synthetic biology, novel functions can be introduced into these “good” microbes to provide additional benefits. Genetically engineered bacteria have been developed to specifically target pathogens or effectively deliver therapeutics to the GI tract. However, there are significant limitations to the existing systems developed. For example, the engineered pathogen sensors largely rely on the similarity between the host and the pathogens, the therapeutics delivery systems are usually constrained by the molecular structures, and the majority of the works have been limited to laboratory settings. In this dissertation, I present a system we have developed based on a food-grade probitoic, Lactococcus lactis, and demonstrate a synthetic biology methodology that could be applied to build biosensors of other pathogens or environmental signals, as well as a generalizable peptide delivery vehicle to the GI tract. I will present my work in three parts. (1) The discovery of an effective antagonistic effect of L. lactis against the infectious diarrheal disease cholera, and elucidation of the mechanism with an infant mouse model. (2) The development of a diagnostic circuit in L. lacits that enables in situ detection of the pathogen and easy readout through fecal sample analysis. (3) The design of a generalizable therapeutic peptide delivery system utilizing the endogenous secretion pathway of L. lacits. Overall, my work exploits the natural and engineered benefits of the probiotic L. lactis and demonstrates its use in the intestinal disease diagnosis and therapy.