UCalgary researchers develop new imaging technique for clearer picture of “brain in the gut”

Gastrointestinal disorders, such as irritable bowel syndrome and Crohn’s disease, impact 10 to 20 per cent of North America’s population and cost billions of dollars in health care. Yet because GI disorders are poorly understood, current treatments work for only a fraction of patients, may lose their effectiveness over time, or cause serious side effects.

Gaining a better understanding of the physiology of the human gut is fundamental to being able to understand what happens when it doesn’t work properly, and to developing effective treatments. The digestion of food and elimination of waste afterwards in the GI tract is controlled by a “brain in the gut,” called the enteric nervous system. Neurons, or nerve cells, embedded in the wall of the gut precisely control its movements and the complex processes of digestion and waste elimination.

To study various aspects of this system, scientists have relied on examining dissected pieces of the gut, peeling back layers to see the neurons. But this approach hasn’t yielded a complete, well-understood picture of what is actually happening in the entire gut’s nervous system.

New research provides better picture of gut’s nervous system

Now, a study led by researchers at the Snyder Institute for Chronic Diseases in the Cumming School of Medicine (CSM) at the University of Calgary dramatically improves that picture. The researchers designed a novel imaging and experimental preparation system in mice, that allows them to record the activity of neurons in the gut’s enteric nervous system.

“We found that enteric neurons respond to the mechanical distension or expansion of the gut caused by the presence of gut contents,” such as food introduced into the intestine, says study co-principal investigator Dr. Keith Sharkey, PhD.  “When the gut is distended or enlarged, the nerve circuits respond in ways that are totally different than when the gut is relaxed.”

Co-principal investigator Dr. Wallace MacNaughton, PhD, says: “This completely different way of conducting experiments allows us to better understand the complexity of the nerve interactions that are regulating and coordinating the responses by the gut’s nervous system,” He adds, “It opens up new avenues for us to understand what’s really going on, and that’s going to help us understand GI diseases and disorders a lot better.”

The research team’s study, “Intestinal distension orchestrates neuronal activity in the enteric nervous system of adult mice,” is published in the Journal of Physiology.

Post-docs conducted the experiment

Study co-lead author Dr. Jean-Baptiste Cavin, PhD, a postdoctoral associate in both Sharkey’s research group and MacNaughton’s research group at the time of the study, designed the experimental system and conducted the initial experiments.

“With this novel approach to look inside the gut wall, we have discovered a new way by which the neurons in our gut can sense food-induced chemical and mechanical changes,” says Cavin, who is now a researcher at the Nestlé Institute of Health Sciences in Lausanne, Switzerland.

Study co-lead author Dr. Preedajit Wongkrasant, PhD, a postdoctoral fellow in Sharkey’s and MacNaughton’s research groups, refined the techniques and conducted the final 18 months’ work on the experiments.

“Using our new dynamic calcium tracking set-up in intact intestinal preparations helps us to better understand the complexities of the neuronal world of the gut,” Wongkrasant says. The tracking apparatus measured intracellular calcium as a marker of neuron activity.

Sharkey says the team’s study is the first that shows, in an intact gut preparation, the role of the gut’s physical distention in controlling how the entire neural network in the gut is coordinated. The team used mice genetically encoded with fluorescent labels, so the neurons in the gut’s nervous system would “light up,” glowing green under microscopes, whenever the neurons were activated.

“This wave of excitation around the circumference of the gut, and the change in neuron excitability, have never been seen before,” Sharkey says. Notes MacNaughton: “You can really dramatically change how that nervous system responds, depending on whether there are nutrients in the gut or not.”

While the findings are in an animal model, the populations of neurons, the neural architecture, and the way the gut is arranged is identical in both the mouse gut and the human gut. This makes it highly likely that similar processes occur in the human gut, the researchers say.

Live Cell Imaging Laboratory made research possible

Sharkey and MacNaughton say this transdisciplinary study would have been impossible without their use of state-of-the-art microscopes, optical imaging and 3-D printing technology in the Live Cell Imaging Laboratory at UCalgary’s Snyder Institute for Chronic Diseases, as well as the collaboration of the lab’s personnel. They built specialized chambers, using 3-D printing, that enabled the researchers to image the live gut under the microscope.

“It’s marrying technology with biology and doing so in the environment at the Snyder Institute that fosters that kind of creativity and innovation,” Sharkey notes. He and MacNaughton and their team now plan to investigate how probiotics, inflammation and bacterial infection alter the control and coordination of the gut’s nervous system (in mice).

“This is giving us a model that may help us test new approaches to treating GI diseases in patients at some point in the future,” MacNaughton says.

The study was supported by the Canadian Institutes of Health Research and the Natural Sciences and Engineering Research Council of Canada. Dr. Cavin was supported by the Human Frontiers Science Program and Alberta Innovates. Dr. Wongkrasant was supported by the Triangle Fellowship, a CHIR-Crohn’s and Colitis Canada-funded program.

Other co-authors were Dr. Joel Glover, PhD, (CSM) and Dr. Onesmo Balemba, PhD (University of Idaho).

Keith Sharkey, PhD, is a professor in the Department of Physiology and Pharmacology at the Cumming School of Medicine (CSM) and a member of the Snyder Institute for Chronic Diseases and the Hotchkiss Brain Institute at the CSM.

Wallace MacNaughton, PhD, is a professor in the Department of Physiology and Pharmacology at the Cumming School of Medicine (CSM) and a member of the Snyder Institute and the Alberta Children’s Hospital Research Institute at the CSM.

The Snyder Institute for Chronic Diseases is a team of more than 480 clinician-scientists and basic scientists dedicated to uncovering new knowledge leading to disease prevention, tailored medical applications and ultimately cures for those with chronic and infectious disease. Visit snyder.ucalgary.ca and follow @SnyderInstitute to learn more.

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