Researchers Develop System That Models Interactions Between Gut and Brain for Studies of Neurodegenerative Diseases

Researchers Develop System That Models Interactions Between Gut and Brain for Studies of Neurodegenerative Diseases

Image Source: MIT

Evidence of the link between the digestive tract and the brain is growing, with some recent studies indicating the makeup of the gut microbiome can have and influence on certain neurological diseases.

One recent study set out to investigate further how the different types of gut bacteria affect organs such as the brain and the liver using human cells, as it is difficult to gain insights using animal models as their physiology is very different.

Researchers at the Massachusetts Institute of Technology (MIT) developed an organs-on-a-chip system to model how the gut microbiome affects both healthy and diseased tissue. According to the researchers, the gut-brain axis has a two-way communication system, integrating the endocrine, metabolic, and immune signaling pathways.

Linda Griffith, PhD, a senior research on the study, has been working on developing microphysiological systems (MPS) for several years as models of different organs. MPS are small devices that are used to grow engineered tissue which serve as models of different organs, with different organ tissues connected by microfluidic channels. Under perfusion, these models mimic certain aspects of physiological organ behavior and they can more accurately mimic human disease than animal models.

A previous study was conducted using an MPS that modeled interactions between the colon and liver and showed that, under certain conditions, the short fatty acids produced by gut bacteria – which are normally beneficial to tissues – caused autoimmune inflammation associated with ulcerative colitis to worsen. The latest study took the research a step further, adding in the brain and circulating immune cells to the model.

Rudolf Jaenisch, PhD, an MIT professor of biology and a member of MIT’s Whitehead Institute for Medical Research, had previously developed a technique for reprogramming fibroblast cells taken from Parkinson’s disease patients into induced pluripotent stem cells, which can subsequently be differentiated into different types of brain cells. The researchers teamed up with Jaenisch’s lab and used cells that carried the A53T mutation that leads to the buildup of alpha synuclein protein that causes inflammation and damage to brain cells and neurons. Cells were also used that were genetically identical but had had the mutation corrected.

First the researchers used their MPS to study the cells when the different organs of the chip were not connected and found that the cells with the mutation showed more inflammation and were less able to metabolize lipids and cholesterol. When the organs on the chip were connected and nutrients and immune cells were allowed to flow, they found that exposure to short chain fatty acids was beneficial to the healthy cells and helped the cells mature, but the benefits were not seen with the cells from Parkinson’s patients. In fact, exposure to short chain fatty acids exacerbated the pathologies of the disease and caused high levels of protein misfolding and cell death. Even when immune cells were removed there were similar effects.

“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, Martin Trapecar, PhD, an MIT postdoc and the lead author of the study.

“We have created a human gut-liver-cerebral physiomimetic system that incorporates cells of both the innate and adaptive immune system,” explained the researchers. “Using this approach and advanced genetic tools, we were able to observe increased maturation of hiPSC-derived neurons, astrocytes, and microglia on the transcriptomic level. Our conceptual and experimental model of continuous and prolonged interactive immune-metabolic cross-talk between organ systems represents a significant advance in modeling the human gut-brain axis in the context of NDs in vitro.”

The researchers are working on further improvements to their organs-on-a-chip system to add micro blood vessels to study the effect of blood flow between tissues.

You can read more about the study in the paper – Human physiomimetic model integrating microphysiological systems of the gut, liver, and brain for studies of neurodegenerative diseases – which was recently published in the Science Advances. DOI: 10.1126/sciadv.abd1707