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Gut-brain interactions have an influence on diseases

The gut and the brain are connected in many ways, and a growing collection of research suggests that gut-brain interactions are critically important to our health. In a new study from the Massachusetts Institute of Technology, researchers developed an “organ-on-a-chip” system to investigate how microbes living in the gut affect brain health.

Gut-brain interactions can make us irritable when we are hungry, or cause physical pain in the stomach when we are nervous. Recently, experts have determined that gut bacteria may even influence neurological diseases.

In the lab of study senior author Professor Linda Griffith, researchers have worked for several years developing microphysiological systems – small devices that can be used to grow engineered tissue models of different organs, connected by microfluidic channels. In some cases, these models can offer more accurate information on human disease than animal models can, noted Professor Griffith.

The researchers used this system to model the influence of gut microbes on healthy brain tissue compared to tissue samples obtained from patients with Parkinson’s disease. 

The study revealed that short-chain fatty acids (SCFAs), which are produced by microbes in the gut and are transported to the brain, can have very different effects on healthy and diseased brain cells.

“While short-chain fatty acids are largely beneficial to human health, we observed that under certain conditions they can further exacerbate certain brain pathologies, such as protein misfolding and neuronal death, related to Parkinson’s disease,” said study lead author Martin Trapecar.

Previously, Caltech Professor Sarkis Mazmanian discovered a connection between SCFAs and Parkinson’s disease in mice. He showed that SCFAs, which are produced by bacteria as they consume undigested fiber in the gut, sped up the progression of the disease. On the other hand, mice raised in a germ-free environment were slower to develop the disease.

The MIT team set out to expand on these findings using their microphysiological modeling system. For the Parkinson’s model, the experts used cells that carry a mutation that causes the accumulation of a protein called alpha synuclein, which damages neurons and causes inflammation in brain cells. They also used brain cells that have this mutation corrected and are otherwise identical to the diseased cells.

First, the researchers studied these two sets of brain cells in microphysiological systems that were not connected to any other tissues. Under this condition, the Parkinson’s cells showed more inflammation than the healthy, corrected cells. The Parkinson’s cells were also less able to metabolize lipids and cholesterol.

Next, the investigators connected the brain cells to tissue models of the colon and liver, using channels that allow immune cells and nutrients – including SCFAs – to flow between them. The team discovered that for healthy brain cells, being exposed to SCFAs is beneficial, and helps them to mature. However, diseased brain cells did not benefit from exposure to SCFAs. Instead, the cells experienced higher levels of protein misfolding and cell death.

The same effects persisted even when immune cells were removed from the system, indicating that the effects are mediated by changes to lipid metabolism.

“It seems that short-chain fatty acids can be linked to neurodegenerative diseases by affecting lipid metabolism rather than directly affecting a certain immune cell population,” said Trapecar. “Now the goal for us is to try to understand this.”

The researchers plan to model other types of neurological diseases that may be influenced by gut-brain interactions. According to Professor Griffith, the findings offer support for the idea that human tissue models could yield information that animal models cannot. 

“We should be really pushing development of these, because it is important to start bringing more human features into our models,” said Professor Griffith. “We have been able to start getting insights into the human condition that are hard to get from mice.”

The study is published in the journal Science Advances.

By Chrissy Sexton, Staff Writer

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