Gut-liver-brain axis in a lab model

Gut-liver-brain axis in a lab model


In many ways, our brain and our digestive tract are deeply connected. Feeling nervous may lead to physical pain in the stomach, while hunger signals from the gut make us feel irritable. Recent studies have even suggested that the bacteria living in our gut can influence some neurological diseases.

Modeling these complex interactions in animals such as mice is difficult to do, because their physiology is very different from humans'. To help researchers better understa nd the gut-brain axis, researchers have developed an "organs-on-a-chip" system that replicates interactions between the brain, liver, and colon.

Using that system, the researchers were able to model the influence that microbes living in the gut have on both healthy brain tissue 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 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," says the lead author of the study published in Science Advances.

For several years, the lab has been 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, the author says.

In a paper published last year, the authors used a microphysiological 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 worsen autoimmune inflammation associated with ulcerative colitis under certain conditions. SCFAs, which include butyrate, propionate, and acetate, can also have beneficial effects on tissues, including increased immune tolerance, and they account for about 10 percent of the energy that we get from food.

In the new study, the team decided to add the brain and circulating immune cells to their multiorgan system. The brain has many interactions with the digestive tract, which can occur via the enteric nervous system or through the circulation of immune cells, nutrients, and hormones between organs.

More than 80 percent of Parkinson's cases cannot be linked to a specific gene mutation, but the rest do have a genetic cause. The cells that the researchers used for their Parkinson's model carry a mutation that causes accumulation of a protein called alpha synuclein, which damages neurons and causes inflammation in brain cells. The lab has also generated brain cells that have this mutation corrected but are otherwise genetically identical and from the same patient as the diseased cells.

The authors first studied these two sets of brain cells in microphysiological systems that were not connected to any other tissues, and found that the Parkinson's cells showed more inflammation than the healthy, corrected cells. The Parkinson's cells also had impairments in their ability to metabolize lipids and cholesterol.

The researchers then 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. They found that for healthy brain cells, being exposed 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 misfolding and cell death.

These effects were seen even when immune cells were removed from the system, leading the researchers to hypothesize 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," the author says. "Now the goal for us is to try to understand this."

The researchers also plan to model other types of neurological diseases that may be influenced by the gut microbiome. The findings offer support for the idea that human tissue models could yield information that animal models cannot, the senior author says.

https://news.mit.edu/2021/gut-brain-chip-0129

https://advances.sciencemag.org/content/7/5/eabd1707

http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Fhuman-physiomimetic&filter=22

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