Intestinal transgene delivery with native E. coli chassis allows persistent physiological changes.

TitleIntestinal transgene delivery with native E. coli chassis allows persistent physiological changes.
Publication TypeJournal Article
Year of Publication2022
AuthorsRussell BJ, Brown SD, Siguenza N, Mai I, Saran AR, Lingaraju A, Maissy ES, Machado ACDantas, Pinto AFM, Sanchez C, Rossitto L-A, Miyamoto Y, R Richter A, Ho SB, Eckmann L, Hasty J, Gonzalez DJ, Saghatelian A, Knight R, Zarrinpar A
Date Published2022 Aug 18
KeywordsAnimals, Bacteria, Escherichia coli, Gastrointestinal Microbiome, Mice, Microbiota, Transgenes

Live bacterial therapeutics (LBTs) could reverse diseases by engrafting in the gut and providing persistent beneficial functions in the host. However, attempts to functionally manipulate the gut microbiome of conventionally raised (CR) hosts have been unsuccessful because engineered microbial organisms (i.e., chassis) have difficulty in colonizing the hostile luminal environment. In this proof-of-concept study, we use native bacteria as chassis for transgene delivery to impact CR host physiology. Native Escherichia coli bacteria isolated from the stool cultures of CR mice were modified to express functional genes. The reintroduction of these strains induces perpetual engraftment in the intestine. In addition, engineered native E. coli can induce functional changes that affect physiology of and reverse pathology in CR hosts months after administration. Thus, using native bacteria as chassis to "knock in" specific functions allows mechanistic studies of specific microbial activities in the microbiome of CR hosts and enables LBT with curative intent.

Alternate JournalCell
PubMed ID35931082
Grant ListP30 DK120515 / DK / NIDDK NIH HHS / United States
T32 AR064194 / AR / NIAMS NIH HHS / United States
IRG Funded