Scientists investigate neurotoxin migrations from gut to brain using organ-on-chip technology

Scientists have developed a multiple organ-on-chip system to help study how neurotoxins move from the gut to the brain. The model system simulated how a neurotoxin found in the gut can trigger the brain cell death seen in Parkinson’s disease in a proof-of-concept study from the UK Quadram Institute, University of Hull, University of Essex and the UK Health Security Agency (UKHSA).

Published in the journal Biomicrofluidics, the study shows how their system recreates the gut-brain axis. This bidirectional communication network links the gastrointestinal tract to the nervous system of the brain, influencing everything from digestion to mood and neurodegenerative diseases.

The scientists say the study of human-derived cells and tissues of the gut-brain axis in an interconnected model system will be a valuable tool to advance the understanding of Parkinsons’ disease and other neurodegenerative conditions.

“Following the protracted illness and death of my mother from Parkinson’s disease, I made a commitment to try to contribute toward innovative research that aims to assist the development of new drugs, therapeutics or treatments to prevent or protect the public from the threat of early-onset neurological decline,” says Dr. Simon Funnell, group leader at the Quadram Institute and scientific leader at the UKHSA.

“This collaborative research has applications outside of Parkinson’s disease and UKHSA is working to use this tool to better understand the impact of infectious diseases on the body and evaluate treatments and vaccines.”

Parkinson’s and the gut microbiome

Research into Parkinson’s disease is much needed, stress the study authors. At least 10 million people globally live with the condition, which attacks and destroys nerve cells in the brain, causing tremors, stiffness and other movement-related symptoms.

But the disease also triggers non-motor symptoms elsewhere, including in the gut, they underscore. Some research indicates that gut problems like constipation and protein accumulations characteristic of Parkinson’s disease brain cell damage appear in the gut years before a diagnosis of the condition.

People with Parkinson’s disease also have changes in their gut microbiome, which has prompted researchers to look at the gut-brain axis.

“But studying the way these two organ systems interact is difficult. Scientists can grow individual human cells in the laboratory, but these don’t necessarily reflect what happens in the body, due to the complex connectivity networks linking the gut and brain. Research can be carried out in animals to provide more holistic insights, but this raises questions of how well findings translate to humans as well as having ethical concerns,” says the research team.

To fill this gap, miniature microphysiological systems (MPS) have been developed. Also known as organ-on-chip technology, MPS allows researchers to grow human cells or tissues in appropriate conditions to mimic how they look, behave and communicate in our bodies.

Linking devices

After receiving a seed start-up grant from the University of Essex, the team created the gut-brain MPS, two devices combined via tubing representing the blood flow.

In the first device, a layer of cells representing the gut lining forms a selectively permeable barrier between the contents of the gut and the rest of the body. In the second connected device, the researchers cultured human-derived brain neuronal cells of a type susceptible to neurotoxins.

The MPS can simulate not just how neurotoxins cross the gut lining, but also how they travel to the brain and interact with cells there. “In this proof-of-concept study, the neurotoxin was introduced into the gut and was seen to kill off the brain cells without affecting the cells of the gut lining as it passed across them,” the researchers highlight.

“This is a very exciting development and really shows the power of innovation and collaboration between scientists from across the country,” says Dr. Ben Skinner at the University of Essex.

“This project was sparked after a chance meeting between Dr. Funnell and I at a University of Essex lab challenge day and it is incredible to see how it has developed. The paper has been the culmination of more than five year’s work, and I hope this technology can make a real difference in fighting Parkinson’s disease.”

Adapting model for broader applications

The simplified MPS designed by the University of Hull makes it easier to use without specialist training and adaptable to study a range of disorders. The researchers believe this will help reduce the reliance on the use of animals in this type of research.

The model can also be deployed in high-containment laboratory settings, which would allow its use in tracking the course of dangerous infections.

“We hope this new multi-organ MPS will provide a valuable tool for unravelling the complex interactions between the gut and brain,” says Dr. Emily Jones from the Quadram Institute.

“By allowing us to study human-derived cells in an interconnected model, we aim to gain deeper insights into disease mechanisms and potentially identify new therapeutic targets that can protect against neuronal inflammation and cell death,” she continues.

“This approach could revolutionize our understanding of neurological disorders, paving the way for more effective treatments and ultimately improving the lives of millions affected by these conditions.”

Professor John Greenman from the Centre for Biomedicine at the University of Hull comments: “Each time our devices are used by colleagues to answer different clinical questions we learn how to improve and adapt them in terms of capabilities, robustness and ease of use; we haven’t finished yet.”

Professor Isabel Oliver, chief scientific officer at the UKHSA, adds: “We are using Organ-on-Chip technology to better understand the impact of viruses on the human body, allowing us to evaluate and predict the effectiveness of vaccines and treatments.”

“We’ve already developed this technique to look at the impact of COVID-19 on the lungs and we are now working to expand this tool to study other organs and how they are impacted by COVID-19 and other infections.”

The research was funded by the Economic and Social Research Council (UKHSA and University of Essex, Public Health Challenge Lab) and the Biotechnology and Biological Sciences Research Council, both part of the UK’s Research and Innovation government department.

Over the summer, Quadram Institute partnered with India’s Skan Research Trust to leverage the high-resolution whole-genome assay TraDIS-Xpress platform to study the effects of traditional medical compounds on bacteria.

In other Parkinson’s disease research, scientists at Osaka Metropolitan University’s Graduate School of Human Life and Ecology, Japan, have verified the physiological effect of the polyphenols and antioxidants in the Ecklonia cava variety of seaweed to prevent Parkinson’s disease.

Elsewhere, scientists are drawing attention to Chinese herbal medicine for preventing neurodegenerative diseases. A recent mouse model study in eLife found that Zizyphi spinosi semen — the dried seeds of a type of jujube — have the potential to reverse cognitive and motor function loss associated with Parkinson’s and other degenerative diseases.