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Gut Bacteria Toxin Linked to Onset and Relapse of Multiple Sclerosis

Under a magnification 1000X, this photomicrograph reveals numbers of rod-shaped, darkly-stained, Clostridium perfringens bacteria.
Under a magnification 1000X, this photomicrograph reveals numbers of rod-shaped, darkly-stained, Clostridium perfringens bacteria. Credit: CDC/Don Stalons
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A new study suggests that the onset and relapse of multiple sclerosis (MS) may be initiated by a toxin from gut bacteria. The research is published in the Journal of Clinical Investigation.

The effects of MS

MS is a chronic and disabling disease of the central nervous system. It is characterized by the destruction and loss of myelin – the fatty layer that protects neurons – that impairs the conduction of electrical impulses to and from the brain. Neurologic symptoms include vision loss, weakness and imbalance.

MS is estimated to affect nearly 1 million US adults and commonly develops in young adulthood – however, the disease is unpredictable and its effects on different individuals can vary.

Early MS is characterized by relapses and remissions of neurologic symptoms, whereas later in the disease course, MS typically progresses in approximately 40% of patients.

Correlation with toxin-producing bacteria

The study was a collaboration between researchers from Weill Cornell Medicine, University of California San Diego, University of California Davis, the University of Pittsburgh and Rockefeller University.

The research team observed that the gut microbiome of MS patients – the collection of bacteria, viruses and fungi in our intestines – featured remarkably high levels of the bacterium Clostridium perfringens, which produces a toxin known as epsilon toxin.

People who are genetically predisposed to develop MS require an environmental signal to trigger the disease – could epsilon toxin-producing C. perfringens be responsible? Epsilon toxin production may fit with the pattern of relapse and remission, as it is only produced during the growth phase of the bacteria.

Researchers demonstrated in animal models of MS that the toxin was able to open the brain’s blood vessels, allowing inflammatory cells to enter the central nervous system and demyelinate neurons – a key characteristic of MS.

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“There are many mysteries to MS,” explained Dr. Timothy Vartanian, co-senior author of the study and professor of neuroscience at Weill Cornell Medicine. “Why do some people get MS and others don’t, despite similar or identical genetics? What accounts for the episodic nature of relapses and remissions? How is the central nervous system targeted and why myelin specifically? C. perfringens and epsilon toxin may explain many of these mysteries.”

Epsilon toxin in mouse models

Previous studies were unable to detect toxin-producing C. perfringens strains, despite growing evidence supporting its role in MS – however, researchers in the current study employed more sensitive techniques. These enabled them to demonstrate there are increased levels of these strains in the microbiomes of MS patients compared to healthy controls.

“Previous studies would use a method where you could see the bacterial species that are there, but you couldn’t actually see the toxin or some of the more functionally relevant parts of the species,” said co-senior author Christopher Mason, professor of physiology and biophysics and co-director of the WorldQuant Initiative for Quantitative Prediction at Weill Cornell Medicine.

Now they had established a link between epsilon-producing strains of C. perfringens and MS, the team set out to investigate if the toxin alone could trigger the disease in a mouse model. The mice were predisposed to autoimmunity, but only developed MS-like disease when they were also administered pertussis toxin. The researchers found that giving them epsilon toxin instead of pertussis toxin also resulted in mice developing a similar MS-like disease.

“The finding that epsilon toxin can replace pertussis toxin in a mouse model of MS is very exciting,” said co-author Dr. Gregory F. Sonnenberg. “It not only advances a more relevant model to study MS, but critically defines a new microbial-derived determinant that provokes a breakdown of immune privilege in the central nervous system to initiate demyelinating disease.”

“A treatment that neutralizes epsilon toxin may halt our patients’ new disease activity, far more effectively than current treatment modalities that suppress or modulate the immune system,” Vartanian said.

Reference: Ma Y, Sannino D, Linden JR, et al. Epsilon toxin-producing Clostridium perfringens colonize the MS gut and epsilon toxin overcomes immune privilege. J Clin Invest. 2023. doi: 10.1172/JCI163239

This article is a rework of a press release issued by Cornell University. Material has been edited for length and content.