Understanding a neurological disease via the drugs that treat it

Novel antibacterial properties in existing multiple sclerosis treatments hint at a possible cause of the disease.

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Multiple sclerosis (MS) is a debilitating condition affecting the central nervous system, causing weakness, stiffness, and sensory and cognitive problems. Traditionally, MS is considered an autoimmune disease, where the body’s own immune system attacks the fatty myelin sheaths that protect nerves. However, recent research suggests microbial pathogens may also be involved. 

Medical microbiologist K. Rashid Rumah of Rockefeller University and colleagues from elsewhere in the US investigated the mechanism of MS drugs, in the hope of shedding light on what causes the condition. They focused on three ‘disease-modifying drugs’ (DMDs): fingolimod, teriflunomide and dimethyl fumarate. These slow MS progression by suppressing the immune system. They are taken orally, meaning they could also influence the digestive system. 

The research was sparked by the observation that some bacteria produce potent neurotoxins. In particular, Clostridium perfringens, commonly found in livestock, produces an ‘epsilon toxin,’ which localizes to sites — the blood-brain barrier and central nervous system myelin — implicated in MS.  

Clostridium perfringens’ epsilon toxin is known to damage the blood-brain barrier of dairy animals. Coincidentally, the blood-brain barrier is compromised in MS … I am yet to see another toxin that so specifically targets the exact tissues damaged in MS,” says Rumah. 

Remarkably, the DMDs all disrupted the growth of C. perfringens and showed significant antibacterial activity at concentrations similar to those found in the human gut under normal recommended dosages. 

The researchers then searched for compounds related to these DMDs that might match or even exceed their antibacterial activity whilst minimizing side-effects. They found that gambogic acid, a natural compound used in Chinese medicine that is related to dimethyl fumarate, was particularly effective against C. perfringens. Similarly, compounds related to fingolimod were antibacterial, yet likely to cause fewer side-effects since they lack fingolimod’s immunosuppressive properties. 

The research provides intriguing insights, not only into the potential underlying causes of MS, but also into possible new treatments based on neurotoxin-producing microbes. However, at present, the results can only be considered as circumstantial.

“What we have shown is very provocative,” says Rumah, “but it is a small piece of the puzzle.” He and his team are now investigating whether the epsilon toxin is present in MS patients. “If the epsilon toxin is identified as the cause,” Rumah continues, “current anti-inflammatory treatments may become a thing of the past. We would know exactly which molecule and organism to target … We could both prevent people from developing MS and halt progression in those already diagnosed.”

References

  1.  Rumah, K. R., Vartanian, T. K. & Fischetti, V. A. Oral multiple sclerosis drugs inhibit the in vitro growth of epsilon toxin producing gut bacterium Clostridium perfringens. Frontiers in Cellular and Infection Microbiology  (2017). | article

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