IMAGE: MIT researchers have developed an “organ-on-a-chip” system that reproduces interactions between the brain, liver and colon. view more
Credit: Martin Trapecar, MIT
CAMBRIDGE, MA – In many ways, our brain is closely linked to our digestive tract. Feeling nervous may cause physical pain in the stomach, and hunger symptoms from the sprain make us feel humbled. Recent studies have even suggested that some of the neurological diseases can be affected by the bacteria that live in our gut.
It is difficult to model these complex interactions in animals such as mice, because their biology is very different from humans’. To help researchers better support the gut-brain axis, MIT researchers have developed an “organ-on-a-chip” system that reproduces interactions between the brain , the liver and colon.
Using that system, the researchers were able to model the effect of microbes living in the gut on both healthy brain bones and tissue samples derived from patients with Parkinson’s disease. They found that short-chain fatty acids, which are produced by microbes in the gut and transported to the brain, can have a different effect on healthy and diseased brain cells.
“While short-chain fatty acids are largely beneficial to human health, we have found that, in certain conditions, they can eliminate some brain pathologies, such as protein synthesis and neuronal death, associated with Parkinson’s disease. , “said Martin Trapecar, MIT ‘s postdoc and lead author of the study.
The paper’s lead authors are Linda Griffith, Professor of Teaching Innovation and biological engineering and mechanical engineering, and Rudolf Jaenisch, professor of MIT biology and member of the MIT Whitehead Institute for Medical Research, lead authors of the paper, which appears today in Advances in science.
The gut-brain connection
For several years, Griffith ‘s laboratory has been developing microphysiologic systems – small devices that can be used to grow engineered tissue models of various organs, connected by microfluidic channels. In some cases, these models can offer more accurate information about human disease than animal models can, Griffith says.
In a paper published last year, Griffith and Trapecar used a microphysiologic system to model interactions between the liver and the colon. In that study, they found that short-chain fatty acids (SCFAs), molecules produced by microbes in the gut, can exacerbate autoimmune inflammation associated with ulcerative colitis. SCFAs, which include butyrate, propionate, and acetate, can have a beneficial effect on joints, increase immune tolerance, and make up about 10 percent of the energy received. us from food.
In the new study, the MIT team decided to circulate the brain and immune cells to their multiorgan system. The brain has many interactions with the digestive tract, which can occur through the enteric nervous system or through the circulation of immune cells, nutrients, and hormones between organs.
Several years ago, Sarkis Mazmanian, professor of microbiology at Caltech, discovered a link between SCFAs and Parkinson’s disease in mice. He showed that SCFAs, which are produced by bacteria while eating undigested fiber in the gut, eradicated the progression of the disease, while mice raised in a non-growth environment -slower mechanism to improve the disease.
Griffith and Trapecar decided to further study the Mazmanian results, using their microbiological model. To do so, they teamed up with the Jaenisch laboratory at the Whitehead Institute. Jaenisch had previously developed a method to convert fibroblast cells from Parkinson’s patients to pluripotent stem cells, which can then be stimulated to differentiate into different types of brain cells – neurons, astrocytes, and microglia .
More than 80 percent of Parkinson’s cases cannot be linked to a specific gene mutation, but the rest have a genetic cause. The cells used by the MIT researchers for their Parkinson’s model carry a mutation that causes an accumulation of a protein called alpha synuclein, which damages neurons and causes inflammation in brain cells. The Jaenisch laboratory has also created brain cells that have corrected this conversion but are genetically similar and from the same patient to the diseased cells.
Griffith and Trapecar first studied the two sets of brain cells in microphysiologic systems that were not linked to any other cigarettes, and found that Parkinson’s cells showed more inflammation than the healthy, corrected cells. Deficiencies in the Parkinson’s cells were also their ability to metabolize lipids and cholesterol.
Adverse effects
The researchers then connected the brain cells to tight models of the colon and liver, using channels that allow immune cells and nutrients, including SCFAs, to flow between them. They have found that, for healthy brain cells, exposure to SCFAs is beneficial, and helps them to mature. However, when brain cells derived from Parkinson’s patients were exposed to SCFAs, the beneficial effects disappeared. Instead, the cells experienced higher levels of protein malformation and cell death.
These effects were observed even when immune cells were removed from the system, prompting the researchers to assume that the effects are mediated by changes in lipid metabolism.
“It seems that short-chain fatty acids can be linked to neurodegenerative diseases by affecting lipid metabolism rather than directly affecting a specific number of immune cells,” Trapecar says. “Now the goal is for us to try to understand this.”
The researchers also plan to model other types of neurological diseases that may be under the influence of gut midges. The findings support the notion that human weaving models could provide information that animal models cannot, Griffith says. She is now working on a new version of the model that incorporates blood vessels linking different types of tissue, allowing researchers to study how blood flow between nappies is affected. orra.
“We should be pushing hard to improve on those, because it’s important to start incorporating more human features into our models,” says Griffith. “We’ve been able to start gaining insights into a difficult human condition for mice. “
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The research was funded by DARPA, the National Institutes of Health, the National Institute of Biomedical Imaging and Bioengineering, the National Institute of Environmental Health Sciences, the Koch Institute (Heart) Support Grant from the National Cancer Institute, and the Army Research Office Institute for Biology. -Cooperative technologies.