不良研究所

Gastrointestinal disorders, such as irritable bowel syndrome and Crohn鈥檚 disease, impact 10 to 20 per cent of North America鈥檚 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鈥檛 work properly, and to developing effective treatments. The digestion of food and elimination of waste afterward in the GI tract is controlled by a 鈥渂rain in the gut,鈥� 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鈥檛 yielded a complete, well-understood picture of what is actually happening in the entire gut鈥檚 nervous system.

New research provides better picture of gut鈥檚 nervous system

Now, a led by researchers in the (CSM) at the University of 不良研究所 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鈥檚 enteric nervous system.

鈥淲e found that enteric neurons respond to the mechanical distension or expansion of the gut caused by the presence of gut contents,鈥� such as food introduced into the intestine, says study co-principal investigator Dr. Keith Sharkey, PhD.

 鈥淲hen the gut is distended or enlarged, the nerve circuits respond in ways that are totally different than when the gut is relaxed.鈥�

Co-principal investigator Dr. Wallace MacNaughton, PhD, says, 鈥淭his completely different way of conducting experiments allows us to better understand the complexity of the nerve interactions that are regulating and co-ordinating the responses by the gut鈥檚 nervous system,鈥�

He adds, 鈥淚t opens up new avenues for us to understand what鈥檚 really going on, and that鈥檚 going to help us understand GI diseases and disorders a lot better.鈥�

The research team鈥檚 study, 鈥淚ntestinal Distension Orchestrates Neuronal Activity in the Enteric Nervous System of Adult Mice,鈥� is .

Postdocs conducted the experiment

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

鈥�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,鈥� says Cavin, who is now a researcher at the Nestl茅 Institute of Health Sciences in Lausanne, Switzerland.

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

鈥淯sing our new dynamic calcium tracking setup in intact intestinal preparations helps us to better understand the complexities of the neuronal world of the gut,鈥� Wongkrasant says. The tracking apparatus measured intracellular calcium as a marker of neuron activity.

Sharkey says the team鈥檚 study is the first that shows, in an intact gut preparation, the role of the gut鈥檚 physical distention in controlling how the entire neural network in the gut is co-ordinated. The team used mice genetically encoded with fluorescent labels, so the neurons in the gut鈥檚 nervous system would 鈥渓ight up,鈥� glowing green under microscopes, whenever the neurons were activated.

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

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 at U不良研究所鈥檚 Snyder Institute for Chronic Diseases, as well as the collaboration of the lab鈥檚 personnel. They built specialized chambers, using 3D printing, that enabled the researchers to image the live gut under the microscope.

鈥淚t鈥檚 marrying technology with biology and doing so in the environment at the Snyder Institute that fosters that kind of creativity and innovation,鈥� Sharkey notes. He and MacNaughton and their team now plan to investigate how probiotics, inflammation and bacterial infection alter the control and co-ordination of the gut鈥檚 nervous system (in mice).

鈥淭his is giving us a model that may help us test new approaches to treating GI diseases in patients at some point in the future,鈥� MacNaughton says.