The native ecosystem of the intestinal microbiome provides an excellent setting to deploy engineered, probiotic bacteria for a variety of therapeutic cases. In this proposal, we suggest the production of therapeutic butyrate by the engineering of synthetic Nissle 1917 E.coli inside in vivo intestines. Butyrate, when administered in high doses mice, helps regulate the immune system and suppress food-based allergic reactions (R. Wang et al., 2023). While native microbial fauna do produce butyrate in low levels (Daskova et al., 2021), an express, engineered focus on butyrate production holds great potential.
In order to create a population of stable, nascent bacteria within the microbiome, as well as maintain high butyrate dosages, our strategy involves engineering regular oscillatory cycles of cellular lysis that release a concentrated butyrate payload. In their default state, the engineered probiotic strain will populate the intestines and produce high concentrations of butyrate within themselves. When population density becomes high enough, the bacteria will autonomously lyse, releasing their butyrate into the surrounding intestines. The small percentage that survive can continue the cycle as they begin to re-populate. Microbial ecosystems are delicate balances, and introducing synthetic organisms creates stability issues in terms of competition with native species. Our oscillatory lysing strategy should mitigate this issue by inherently self-limiting the bacterial population (Scott et al., 2017), allowing us to maintain a stable consortia within the microbiome of metabolically competitive, engineered E. coli while simultaneously delivering regular, high doses of butyrate directly to the intestines.
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