Glowing bacterial sensors detect gut illness in mice before symptoms emerge

UBC researchers have engineered gut bacteria that dim their fluorescent glow in the presence of illness.

Their findings, published in Cell today, could improve how we diagnose problems in the gut by using bacteria that already live there.

“Our biosensors could improve the ability to predict how diseases in the gut progress, identifying early changes that could aid preventative interventions,” said co-first author Juan Camilo Burckhardt (he/him), a doctoral candidate in the department of microbiology and immunology (MBIM).

The current gold standard methods for peering into the gut involve invasive procedures that can only provide a single snapshot of gut health. The UBC-developed biosensor, currently tested in mice, establishes a new technology that can provide non-invasive, continuous monitoring through stool samples.

Utilizing ‘good’ gut bacteria

“Beneficial bacteria that naturally reside in the intestine and support gut health are highly sensitive to local conditions and have evolved to thrive long-term in these environments,” said first co-author Dr. Giselle McCallum (she/her), who worked on the research as a doctoral student. “Building biosensors in these bacteria therefore allows researchers to continuously monitor the gut environment without disturbing it.” 

The team homed in on Bacteroides thetaiotaomicron (B. theta), a native gut bacterium that can be easily modified in the lab. They identified genes in B. theta that are ‘turned on’ in response to gut disruptions common in gastrointestinal diseases such as celiac and inflammatory bowel diseases.

One key disruption is osmotic stress: When the gut can’t absorb food properly, undigested molecules build up and draw water into the bowel. This may lead to diarrhea, inflammation and potential worsening of the original disease.

“Understanding these gut changes is essential for advancing our diagnostic and treatment strategies for gut health,” said senior author Dr. Carolina Tropini (she/her), assistant professor in MBIM and the school of biomedical engineering. “For that, we need highly sensitive measurements as those changes occur, including before symptoms appear.”

Linking glowing proteins

Biosensors are usually made by engineering bacteria to glow when they are stressed. In B. theta, however, this glow is too weak to detect. To solve this, the researchers flipped the system: they engineered the bacteria to glow brightly under normal conditions and dim when stressed. Higher osmotic stress in the gut therefore causes a weaker glow, allowing researchers to measure stress by how much the signal fades.

The team then tested their biosensor in mice, analyzing stool samples to measure the intensity of the glow in individual bacterial cells.

“We found that the biosensor accurately reported osmotic stress in the gut, even picking up subtle changes that didn’t cause clinical symptoms like diarrhea. It remained stable and responsive for weeks, which means it could track the gut environment long-term and potentially detect illness before symptoms develop,” Burckhardt said.

The researchers can now adapt their biosensor to report on other gut conditions and potentially develop sensors that can read multiple changes at once, including oxygen, temperature and pH levels in the gut.

“While early applications will likely focus on monitoring gastrointestinal diseases, the long-term goal is a personalized approach where people can track aspects of their gut health over time and identify early warning signs of imbalance or dysfunction,” said Dr. Tropini.

The researchers hope that their study lays the groundwork for an array of next-generation living biosensors, including bacterial systems that deliver drugs only when specific disease-related changes are detected.