A specific, toxin-producing gut bacteria may be responsible for both triggering the onset of multiple sclerosis (MS) and ongoing disease activity, according to a new study led by a team of researchers at Weill Cornell Medicine and New York-Presbyterian. The team is working with investigators from Cornell’s Ithaca campus as well as the University of California, San Diego; the University of California, Davis, and the University of Pittsburgh; and has a long-standing collaboration with scientists at the Rockefeller University.
The work, published in the Journal of Clinical Investigation, identifies epsilon toxin-producing Clostridium perfringens in unusually high abundance within the gut microbiome of people with MS. The study goes on to show that in a preclinical model of MS, epsilon toxin opens the blood vessels of the brain allowing inflammatory cells to gain access to the central nervous system and cause demyelination characteristic of MS.
MS is a disabling disease of the central nervous system that commonly has its onset in young adulthood and affects nearly 1 million people in the United States alone. Early in the disease course, MS is characterized by episodic relapses and remissions of neurologic symptoms, including loss of vision, weakness and imbalance. Later in the disease course, despite numerous advancements in treatment, MS tends to progress in approximately 40% of afflicted individuals.
“There are many mysteries to MS,” said co-senior author Dr. Timothy Vartanian, a professor of neuroscience in the Feil Family Brain and Mind Research Institute 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? Clostridium perfringens and epsilon toxin may explain many of these mysteries.”
An environmental trigger is required for MS to occur in a genetically susceptible individual, and the abundance of epsilon toxin-producing Clostridium perfringens in people with MS suggests it could be the culprit. Epsilon toxin-producing strains of Clostridium perfringens live in the small intestine, and epsilon toxin is only produced briefly when the bacterium is in a growth phase, fitting with the relapsing remitting nature of MS. Perhaps most remarkably, epsilon toxin specifically targets brain blood vessels and myelin, providing a clear mechanism of its action.
Despite the mounting evidence that epsilon toxin-producing strains of Clostridium perfringens could be relevant environmental pathogens for MS, modern studies of the gut microbiome in people with the disease failed to detect these strains. In the current study, Yinghua Ma, an assistant professor of research in neuroscience in the Vartanian lab, led work, along with co-lead authors David Sannino and Jennifer Linden in the Brain and Mind Research Institute, showing that more sensitive techniques readily detected these strains in the MS gut microbiome.
“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, a professor of physiology and biophysics and co-director of the WorldQuant Initiative for Quantitative Prediction at Weill Cornell Medicine.
Using highly sensitive DNA detection techniques, Ma found that people with MS are more likely to carry epsilon toxin-producing C. perfringens in their small intestines than healthy controls.
