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Exploring the gut-brain connection in the quest to solve brain disorders

This collaborative project will develop innovative neurotechnologies to explore the frontiers of the neuro gastrointestinal (NeuroGI) connection towards biomarker discovery and novel therapies for brain disorders.

Gut feeling

The digestive tract is controlled by an extensive network of neurons known as the enteric nervous system (ENS). Comprising more than half a billion neurons, the ENS controls gut motility, nutrient absorption, immune regulation, and defense, and is sometimes thought of as a miniature second brain.

One of the ways the brain communicates with the rest of the body is via the vagus nerve, but messages travel the other way too. In fact, 80 to 90 percent of the nerve fibers in the ENS go from the gut to the brain.

Healthy gut – happy brain?

Colonies of microbes in our gut also affect our brain. These gut microbiota produce over 50 percent of the dopamine in the body and 90 percent of the serotonin – both important neurotransmitters in the brain that influence feelings of pleasure and happiness.

The increasing evidence that brain function is linked to gut health is leading scientists to explore the gut-brain connection in search of biomarkers and new treatment approaches for diseases including Parkinson’s disease, dementia, and depression.

The latest data

Travel down the gut and discover a second brain! New video reveals the gut’s own nervous system. Captured with lightsheet microscopy, the images show a section of mouse colon in 3D with tissue structures (blue) and the neuronal network that surrounds the gut (pink).

3cm long mouse gut segment cleared with iDisco+ protocol. Autofluorescence at 10x magnification acquired with Clarity Optimised Lightsheet Microscopy showing colon architecture with crypts of colonic mucosa on the inside of each slice surrounded by submucosa and a ring of circular and longitudinal muscles. Data processed with Imaris software.

The unmet need
We urgently require a solution to assess the state of the ENS in vivo

Despite the emerging realization of the importance of the ENS for brain and digestive health, there is no single solution to monitor the morphology and function of the ENS and microbiota nor determine how it may change because of disease.

Tackling the technical challenges to allow analysis of the gut-brain connection could pave the way for innovative therapies to solve major brain disorders.

The solution
Harnessing neurotechnologies to explore the frontiers of the microbiota–gut–brain axis

The interdisciplinary team from the Wyss Center is developing innovative minimally invasive micro-endoscopic technology to reveal gut and ENS function in vivo in partnership with the French National Institute of Health and Medical Research (INSERM) and the University of Strasbourg

The miniaturized device will simultaneously evaluate the morphology, functionality and bacterial composition of the digestive system. An intraluminal optrode will use light and electrical signals to stimulate the neurons of the ENS and record their electrical activity from within the gut.

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Monitoring of neurons, blood vessels and microbiota to assess how morphology and function change with disease.
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Activation and recording of the ENS response. Optogenetic activation using light to stimulate genetically modified cells in the mouse gut and electrical recording of the neuronal response with thin, flexible electrodes in vivo.
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Investigation of the connection between the gut and the brain with the aim to induce a brain response through gut activation with confirmation via functional magnetic resonance imaging (fMRI).
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Michalina Gora, PhD, Manager in Neurophotonics
The use of non-invasive optical monitoring and stimulation provides a unique and powerful tool for the investigation of diseases linked to dysfunction of the microbiota-gut-brain axis and could lead to solutions for people with neurological disorders ranging from Parkinson's disease to depression.

Initially developed for pre-clinical investigation, the goal is to deploy the technology and its findings to improve patient management. Critical steps to reach the patient have been integrated into the project from the outset. These include working with tissue samples from Parkinson’s and Alzheimer’s disease patients, as well as ensuring that all materials and procedures are appropriate for translation to people. 

In parallel to the development of the in vivo investigation tool, the team is leveraging the Wyss Center’s advanced imaging capabilities to collect high resolution microscopic images of large sections of intestine to better understand the morphology of gut neurons and to collect design inputs for the device.

One of the challenges in advancing the field of the gut-brain axis research is lack of knowledge about processing gut tissue samples. The team is defining a simplified protocol for handling and preparation of gut samples in both normal and disease conditions. Sharing this knowledge will enable researchers investigating neurodegenerative disorders to include information about gut status in their research.

3D image of intestinal villi in the mouse. Villi are controlled by the enteric nervous system (ENS) our gut’s own little brain. The team is using the three-dimensional microscopic imaging of the intestinal wall to better understand the involvement of enteric neurons in gut function and their connection with the brain. Image acquired with Clarity Optimised Lightsheet Microscope. Gut section cleared with iDisco+ protocol. Data are processed with a depth coding algorithm - the color represents the depth of the 3D image.

This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program.

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