Bacterial toxin epsilon in gut may be environmental driver of MS

A bacterial toxin in the gut — specifically, the epsilon toxin produced by Clostridium perfringens bacteria in the intestinal tract — may be a key environmental driver of multiple sclerosis (MS), according to a recent study.

After finding the toxin at a higher abundance in the fecal samples of MS patients compared with healthy people, scientists determined that epsilon was capable of producing MS symptoms in mice predisposed to the disease.

Indeed, according to Timothy Vartanian, MD, PhD, chief of the multiple sclerosis and neuro-immunology division in the department of neurology at NewYork-Presbyterian/Weill Cornell Medical Center, “epsilon toxin functions at the very earliest stage of MS lesion formation.”

“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, also one of the study’s co-senior authors, said in a Weill Cornell press release, adding, “In the immediate term, we’re driven by a sense of urgency to get more effective and safer therapeutics to people with MS.”

The study, “Epsilon toxin-producing Clostridium perfringens colonize the MS gut and epsilon toxin overcomes immune privilege,” was published in The Journal of Clinical Investigation.

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The gut microbiome, comprised of the collection of microbes living in the intestinal tract, has been increasingly linked to MS in recent years. An imbalance of these microbes — called gut dysbiosis — is often observed in MS patients and has been associated with more severe disease in preclinical models.

For patients with an underlying genetic susceptibility to MS, it’s possible that changes in the gut microbiome could be the environmental trigger that prompts the disease to ultimately develop. Yet, the particular bacteria that might drive this association haven’t been uncovered, and have been a focus of recent research studies.

C. perfringens is a gut bacteria that humans are widely exposed to through pets and food sources. It releases epsilon toxin, known as ETX, a neurotoxin that targets the cells of the selective blood-brain-barrier (BBB).

The BBB works to prevent the passage of potentially harmful substances from the bloodstream into the brain. By targeting its cells, ETX reduces the integrity of that barrier, making it more like to leak substances it wouldn’t normally let through, like the immune cells that drive MS.

As such, having a higher abundance of ETX-producing C. perfringens in the gut might be an environmental MS trigger, according to the U.S.-based research team.

While other studies of the human microbiome failed to find this link, it is possible previous techniques weren’t sensitive enough to detect the toxin-producing bacteria, they noted.

“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 Christopher Mason, PhD, a professor and co-director of the WorldQuaint Initiative for Quantitative Prediction at Weill Cornell, and one of the study’s co-senior authors.

Now, the team examined fecal samples from MS patients and healthy people using more sensitive DNA detection techniques.

Doing so, they found that MS patients were significantly more likely to carry ETX-producing C. perfringens than their healthy counterparts — and at a greater abundance.

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Clinical trials needed to examine ETX in MS patients

The researchers next turned to a preclinical model in which the immune system of mice is modified to make them predisposed to MS, but the animals only develop symptoms if they are also treated with a toxin called pertussis — which also targets the BBB and allows immune cells to infiltrate the brain.

When the scientists swapped out pertussis for ETX, they found that the toxin induced clinical signs of disease and led to demyelination in the brain and spinal cord that was more widespread than when pertussis was used, better matching the lesion distribution normally seen in MS patients.

Demyelination, a progressive loss of the substance (myelin) that surrounds and protects nerve cells, is the hallmark of MS.

ETX led to the infiltration of immune cells that normally remain in circulation and don’t enter the brain unless the BBB is compromised. It also induced the activity of genes involved in BBB dysfunction.

According to co-author Gregory F. Sonnenberg, PhD, also of Weill Cornell, the study “advances a more relevant model to study MS,” but also “defines a new microbial-derived determinant,” that could inform MS development.

There are many mysteries to MS. … Clostridium perfringens and epsilon toxin may explain many of these mysteries.

In addition to a role for ETX at MS onset, it also could be involved throughout the disease course.

ETX is produced episodically when C. perfringens is in a phase of high growth. Those episodes might correlate with periods of disease activity in relapsing-remitting MS, the researchers noted.

“There are many mysteries to MS,” Vartanian said. “Clostridium perfringens and epsilon toxin may explain many of these mysteries.”

Still, a clinical trial will be required to examine their role in MS patients, “as would be the case for any environmental factor,” the team concluded.