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Stable transgene expression using native gut bacteria in mice

Written by Liam Little, Science Writer

A study published in Cell provides a new proof-of-concept for the delivery of live bacterial therapeutics (LBTs) using native E. coli strains. Performed in mice, native E. coli have been isolated, genetically engineered and successfully engrafted back into a murine host. This research can potentially revolutionise the delivery of LBTs across many diseases including diabetes, non-alcoholic fatty liver disease, atherosclerosis and cancer.

Native LBT expression

LBTs can tackle diseases by engrafting in the gut, leading to transgene expression and persistent improvement of host physiology. However, previous attempts to implement LBTs have been unsuccessful due to the hostile environment posed by the host and other microorganisms. To address this, a team of researchers have utilised native host E. coli to improve the engraftment of genetically modified bacteria. The procedure involves the isolation of bacteria from a conventionally raised mouse, modification to express the transgene of interest, and re-introduction of the engineered bacteria back into the host (Figure 1).

Figure 1: Experimental workflow of engineered native bacteria. Undomesticated E. coli is isolated from biopsy or stool sample. The E. coli strain is modified to express a gene of interest and re-introduced back into the conventionally raised host where it readily engrafts.

Maximum transgene delivery

Native bacteria are an ideal chassis for transgene delivery as they are already adapted to the host environment and can therefore bypass any barriers to engraftment. The researchers were able to stably colonise the murine hosts for months, stating this may also be possible “in perpetuity after a single gavage, without the need for pre-treatment for microbiome depletion.”

Transgenic E. coli also exerted persistent physiological effects in their host long after engrafting. Differences were observed in bile acid levels 12 weeks post gavage with a bile salt hydrolase (BSH) transgene. This showed that the BSH gene remained stably expressed and functional in the mice long after a single treatment.

IL-10 expression was also performed to explore the effects of a transgene that could be used to treat disease. IL-10 is a mammalian cytokine that can function as an anti-inflammatory agent. Mice treated with an IL-10 transgene produced IL-10 at much higher levels than controls at a notable 89 days after treatment.

Translating to humans

Progressing this work into humans, the researchers isolated E. coli from human volunteer gastrointestinal biopsies. Several E. coli strains were successfully transformed, an essential first step in the translation of this technology into humans. The researchers hope that native E. coli can be used in the future “to introduce novel, curative biotherapeutics that improve treatment of chronic diseases without relying on patient compliance”.