Scientists exploit the microbiome microorganisms’ natural ability to sense and respond to environmental– and disease–related stimuli and the ease of engineering new functions into them. This is particularly beneficial in chronic inflammatory diseases like inflammatory bowel disease (IBD) that remain difficult to monitor non–invasively. However, there are several challenges associated with developing living diagnostics and therapeutics including generating robust sensors that do not crash and are capable of long–term monitoring of biomolecules.

In order to use bacteria of the microbiome as biomarker sensors, their genome needs to be modified with synthetic genetic circuits, or a set of genes that work together to achieve a sensory or response function. Some of these genetic alterations may weaken or break normal signaling circuits and be toxic to these bacteria. Even in cases where the probiotic microbes tolerate the changes, the engineered cells can have growth delays and be outcompeted by other components of the microbiome. As a result, probiotic bacteria and engineered therapeutic microbes are rapidly cleared from the body, which makes them inadequate for long period monitoring and modulation of the organism’s tissue environment.

A team at the Wyss Institute of Biologically Inspired Engineering led by Pamela Silver, PhD, designed a powerful bacterial sensor with a stable gene circuit in a colonizing bacterial strain that can record gut inflammation for six months in mice. This study offers a solution to previous challenges associated with living diagnostics and may bring them closer to use in human patients.

The findings were reported in the journal Nature Biotechnology.

Silver, who is a Core Faculty member at the Wyss Institute and also the Elliot T. and Onie H. Adams Professor of Biochemistry and Systems Biology at Harvard Medical School, thought of the gut as a first application for this system due to its inaccessibility by non–invasive means and its susceptibility to inflammation in patients suffering from chronic diseases like IBD. “We think about the gut as a black box where it is hard to see, but we can use bacteria to illuminate these dark places. There is great interest from patients and doctors that push us to build sensors for biomarkers of gut conditions like IBD and colon cancer,” said Silver, “We believe that our work opens up enormous possibilities that can exploit the flexibility and modularity of our diagnostic tool and expand the use of engineered organisms to a wide variety of applications.”

Key to the team’s work is the introduction of a memory module to the circuit that is able to detect a molecule of interest and respond to this exposure long after the stimulus is gone. As bacteria can be rapidly cleared from the intestinal tract, the team used a strain of bacteria that is part of the microbiome of mice, and engineered it to contain the sensory and memory elements capable of detecting tetrathionate. Tetrathionate is a transient metabolic molecule produced in the inflamed mouse intestine as a result of either infection with pathogenic bacteria like Salmonella typhimurium and Yersinia enterocolitica or genetic defects affecting inflammation.