Engineered bacteria monitor inflammation in murine gut

Last Updated: 2017-06-07

By David Douglas

NEW YORK (Reuters Health) - A commensal murine Escherichia coli strain engineered to detect tetrathionate, a product of inflammation, shows long term viability in murine gut, according to Massachusetts-based researchers

"Our inflammation sensing bacteria hold promise for more sensitive and versatile diagnostics," Dr. Pamela A Silver of Harvard University and Harvard Medical School in Boston told Reuters Health by email. "They also open up huge possibilities for discovering new disease and diet related biomarkers as well as more specific localized delivery of therapeutics in the gut."

In a May 29 online paper in Nature Biotechnology, Dr. Silver and colleagues note that in particular, "Live, engineered bacteria can be used as non-invasive diagnostics to detect transient (or highly localized) molecules in the gut."

However, they point out, "commercial translation of technologies to accomplish this has been hindered by the susceptibility of synthetic genetic circuits to mutation and unpredictable function during extended gut colonization."

However, several bacterial strains have been engineered to detect transient gene expression in the laboratory and in vivo for up to 12 days. In earlier work, the team successfully employed engineered E. coli to record exposure to tetracycline and its analogs.

This engineered E. coli detected anhydrotetracycline and retained memory of exposure for up to 7 days following removal of the signal. However, it also responded to tetracycline derivatives which might compromise meaningful long-term analysis of strain stability and function.

In the current study, the researchers developed an E. coli strain (PAS638) that could detect and respond to tetrathionate, a transient product of reactive oxygen species (ROS) produced during inflammation.

The investigators note that increased ROS levels are associated with inflammatory bowel disease (IBD) in humans and may be present even during subclinical inflammation.

Using fecal samples, the team successfully tested the approach in various scenarios including a mouse model of colitis and genetic mouse models of inflammation.

In fact, they were able to show that the engineered bacteria detected tetrathionate in a model of subclinical inflammation using interleukin-10-deficient mice which have features of human IBD, but not in control mice.

Further studies showed that "PAS638 can colonize the mouse gut and retain the ability to respond to inflammation in vivo for at least 6 months."

"Our results," they conclude, "confirm the association of increased tetrathionate concentrations with inflammation both in the presence and absence of pathogen infection" and "that synthetic bacterial devices can colonize the complex host mammalian gut and be used to monitor and analyze the course of a disease over an extended timeframe."

Commenting by email, Dr. Christopher Voigt, a professor of bioengineering at the Massachusetts Institute of Technology, Cambridge who was not involved in the study, told Reuters Health, "It is incredibly challenging to build organisms that can operate robustly in complex, real-world environments, like the gut of an animal."

Dr. Voigt said, "This is a beautiful example that moves us towards the vision of living therapeutic bacteria that can navigate the human body and report on or fix underlying disease."

SOURCE: http://go.nature.com/2qvEqtz

Nature Biotechnology 2017.