UC San Diego

Inflammatory bowel disease (IBD) presents a significant healthcare challenge due to its rising global prevalence and the limitation of current treatments. This thesis investigated the feasibility of an engineered native bacteria (ENB) therapeutic for IBD which aimed to address the limitations of current treatments and offer an alternative for patients who do not respond to existing therapies. Building on the study by Russell et al. (2022) which identified a genetically tractable, colonizable and functional native E. coli chassis, I tested the therapeutic effect of interleukin-10 (IL-10) expressing E. coli (EcAZ-2(IL-10+)) in mice with dextran sulfate sodium (DSS)-induced acute colitis. Recombinant IL-10 molecules expressed by EcAZ-2IL-10+ showed high bioactivity in vitro, reducing tumor necrosis factor-alpha (TNF-α) production by lipopolysaccharide (LPS) stimulated mouse macrophages. In addition, EcAZ-2(IL-10+) stably colonized the gut of C57Bl/6 mice after one single treatment via oral gavage, maintaining colonization after DSS administration. Intestinal delivery of bioactive IL-10 by EcAZ-2(IL-10+) did not show significant amelioration in colitis symptoms reflected by body weight change, colon measurements, and histology, but it was well tolerated by the mice and did not worsen disease severity. My thesis demonstrates that EcAZ-2(IL-10+) has the potential to be optimized for better therapeutic efficacy in managing IBD.