Bacterial Toxin May Trigger Multiple Sclerosis

October 25, 2013

Researchers have identified a bacterial toxin that they believe may be a trigger for multiple sclerosis (MS).

Their study, published in the October issue of PLoS ONE, is the first to identify the culprit bacterium, Clostridium perfringens type B, in humans, and to single out the toxin it produces — known as epsilon toxin — as a probable MS trigger.

The researchers, from the Weill Cornell Medical College and The Rockefeller University in New York, New York, describes discovery of C perfringens type B in a 21-year-old woman who was experiencing a flare-up of her MS.

"That we identified this bacterium in a human is important enough, but the fact that it is present in MS patients is truly significant because the toxin targets the exact tissues damaged during the acute MS disease process," said lead author, Kareem Rashid Rumah, an MD/PhD student at Weill Cornell Medical College.

For the study, the researchers screened serum and spinal fluid from 30 patients with MS and 31 healthy controls. They found that 10% of the patients with MS had antibodies to an epsilon toxin compared with just 1% of controls.

Senior investigator, Timothy Vartanian, MD, Weill Cornell Medical College, commented to Medscape Medical News: "We know from the veterinary literature that if animals are vaccinated against C perfringens type B, their immunity drops off very quickly. So the 10% figure is probably lower than the real incidence. We believe the exposure is much higher than the seroreactivity is telling us."

The team also examined stool samples from both patients with MS and healthy controls enrolled in the HITMS (Harboring the Initial Trigger of Multiple Sclerosis) clinical study and found that 52% of healthy controls carried the A subtype compared with 23% of patients with MS.

"This is important because it is believed that the type A bacterium competes with the other subtypes for resources, so that makes it potentially protective against being colonized by epsilon toxin–secreting subtypes and developing MS," Dr. Vartanian noted. 

Evidence Supporting a Trigger

He says substantial evidence supports the idea of an environmental trigger necessary for MS to begin. "There are many datasets that point to this." He gives the example of the situation in the Faroe Islands.

"The population of the Faroes has the same ancestry as that of the Scandinavian countries, where there has been a high incidence of MS. But there was no case of MS documented in the Faroes until 1943, when British troops occupied the country. This coincided with the first of 4 documented MS epidemics within native Faroe people."

The other piece of information that points to a trigger, Dr. Vartanian explained, is the pathology of the very first lesions at the earliest stages of the disease, which shows disruption of the normal integrity of the blood-brain barrier, oligodendrocyte apoptosis with preservation of myelin, and early microglial activation, but no T cells or B cells. "This suggests that the initial lesions are not formed by an autoimmune response but rather by a toxin or virus targeting oligodendrocytes."

"While it is clear that new MS disease activity requires an environmental trigger, the identity of this trigger has eluded the MS scientific community for decades," Dr. Vartanian says.

He noted that it has previously been suggested that MS may be related in some way to sheep and that organisms commonly found in sheep may be a trigger. C perfringens type B is one such organism, and he is proposing that the toxin it produces could be the trigger.

"C perfringens B is found in soil and is not normally present in humans. It can live the gastrointestinal tract of grass-eating animals, where it can grow fast and make a toxin that causes neurological symptoms. In humans, who have a linear GI [gastrointestinal] tract, it does not grow well. Our hypothesis is that in some environmental conditions, this bacterium takes up residence in the human gut and makes this toxin."

New Treatment Possibilities

The scientists say their study is small and must be expanded before a definitive connection between the pathogen and MS can be made, but they also say their findings are so intriguing that they have already begun to work on new treatments for the disease.

The researchers' next step is to set up collaborations in an attempt to confirm these results in larger populations of patients so that the findings to be independently verified.

Dr. Vartanian suggested that if these findings can be confirmed, it may be possible to vaccinate against the epsilon toxin or to prevent the toxin from getting to the brain. "Another strategy would be to change the gastrointestinal environment with a probiotic cocktail to stop the bacteria from growing. Or alternatively to develop small-molecule drugs to prevent the toxin from interacting with its receptor. Antibiotics may not work as the organism can form spores and avoid their effects," he added.

This work was supported in part by the Laurence Tisch Family Research Fund, the Dr. Mortimer D. Sackler Family Fund for Neuroregenerative Research, the Widgeon Point Charitable Foundation, and the Rockefeller University Funds to the Laboratory of Bacterial Pathogenesis and Immunology.

PLoS ONE. Published online 16 October 2013. Full text


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