New Class of Minimally Invasive
Biosensors Demonstrated at Rice
April 10, 2017
Synthetic biologists at Rice University have engineered gut bacteria
capable of sensing colitis, an inflammation of the colon, in mice. The
research points the way to new experiments for studying how gut bacteria
and human hosts interact at a molecular level and could eventually lead
to orally ingestible bacteria for monitoring gut health and disease.
The research, published in a new study in Molecular Systems Biology,
involved a series of breakthroughs in the lab of Jeffrey Tabor,
assistant professor of bioengineering and of biosciences at Rice, and
key contributions from collaborators Robert Britton and Noah Shroyer at
Baylor College of Medicine. Tabor's team, including lead co-author and
postdoctoral researcher Kristina Daeffler, identified the first
genetically encoded sensor of a novel biomarker linked to inflammation,
inserted the genes for the sensor into a well-studied gut bacterium and
collaborated with Shroyer and Britton to use the engineered bacteria to
detect colon inflammation in mice.
Synthetic biologists at Rice
University have engineered orally ingestible gut bacteria capable of
sensing colitis in mice.
"The gut harbors trillions of
microorganisms that play key roles in health and disease," Tabor said.
"However, it is a dark and relatively inaccessible place, and few
technologies have been developed to study these processes in detail. On
the other hand, bacteria have evolved tens of thousands of genetically
encoded sensors, many of which sense gut-linked molecules. Thus,
genetically engineered sensor bacteria have tremendous potential for
studying gut pathways and diagnosing gut diseases."
Synthetic biologists like Tabor specialize in programming single-celled
organisms like bacteria in much the same way an engineer might program a
robot. In particular, Tabor's team is working to develop bacterial
sensors that can detect disease signals in the gut. Like electrical
engineers who build circuits from wires and electronic components,
Tabor's team uses genetic circuits to program single-celled creatures to
carry out complex information processing.
Previous work has suggested that alterations to the gut microbiota,
genetic predisposition and other environmental factors may play key
roles in inflammatory bowel disease, a condition that includes Crohn's
disease and ulcerative colitis and which affects as many as 1.6 million
"Based on a number of previous studies, we hypothesized that the
molecule thiosulfate may be elevated during colitis," Daeffler said. "It
has been difficult for scientists to study this link because there
aren't tools for reliably measuring thiosulfate in living animals. Our
first goal in this project was to engineer such a tool."
From the outset of the project in 2015, Daeffler said, the idea was to
use sensor bacteria, in this case an engineered form of Escherichia
coli, to sense thiosulfate and related sulfur-containing compounds that
may also be biomarkers of colitis. There were well-understood methods
for programming E. coli to produce a fluorescent green protein in
response to specific stimuli, but there were no known genes -- in any
organism -- that were used to sense thiosulfate, and few for the other
"There's a link between gut sulfur metabolism and inflammation, and we
knew that we needed to be able to measure sulfur metabolites accurately
to diagnose colon inflammation," she said.
Tabor said study co-author Ravi Sheth, an undergraduate researcher in
the group in 2015, used a computer program to identify potential sensors
of thiosulfate and other sulfur compounds in the genome of Shewanella, a
type of bacteria that live in marine sediment. Tabor's group believes
that Shewanella likely breathe these molecules and use the sensors to
turn on the proper enzymes in their presence.
Daeffler spent one year engineering E. coli to express the sensor genes,
validate their function and optimize them to respond to the potential
biomarkers by producing a green fluorescent protein signal. It took
another year to prove that the system worked and detected colon
inflammation in mice.
The researchers administered orally two drops containing about a billion
sensor bacteria to both healthy mice and to mice with colitis. They
measured the activity of the sensor bacteria in each group six hours
later. The tell-tale green fluorescent protein showed up in the feces of
the mice. Though it was not visible to the unaided eye, it could easily
be measured with a standard laboratory instrument called a flow
The team found that the thiosulfate sensor was activated in the mice
with inflammation, and was not activated in the healthy mice.
Furthermore, the researchers found that the more inflammation the mouse
had, the more the sensor was activated.
Tabor said the study shows that gut bacteria can be outfitted with
engineered sensors and used to noninvasively measure specific
metabolites and that this result could open the door to many new studies
that could help elucidate a wide range of gut processes.
it would likely take several additional years of development, and it
remains unknown if thiosulfate is a biomarker of human colitis, the
sensor bacteria might eventually be re-engineered to function as a
diagnostic of human colitis, Tabor said. In particular, the green
fluorescent protein could be replaced with an enzyme that makes a
"We'd like to develop a home inflammation test where a person prone to
colitis flare-ups would eat yogurt that contained the engineered
bacteria and see blue pigment in the toilet if they were sick," he said.
Tabor said such a test could reduce unneeded and costly trips to the
doctor and unneeded colonoscopy procedures, which are both expensive and
invasive. He said his team has begun collaborations with
gastroenterologists at Baylor to achieve this goal.