Multiple Sclerosis Onset Can Be Triggered By Bacterial Toxin

According to a recent study led by a group of scientists at Weill Cornell Medicine and NewYork-Presbyterian, both the beginning of multiple sclerosis (MS) and ongoing disease activity may be caused by a unique toxin-producing gut bacteria.
The team has a long-standing partnership with researchers at Rockefeller University and is currently working with researchers from Cornell’s Ithaca campus as well as the Universities of California, San Diego, Davis, and Pittsburgh.
The study, which was published in the Journal of Clinical Investigation, shows that the gut microbiota of MS patients has an extremely high number of Clostridium perfringens, which produce the epsilon toxin.

The study goes on to demonstrate that epsilon toxin opens the blood arteries of the brain in a preclinical MS model, allowing inflammatory cells to enter the central nervous system and cause demyelination, a hallmark of MS.

Nearly 1 million people in the United States alone are affected with MS, a central nervous system illness that typically manifests in young adulthood. MS is characterized by periodic relapses and remissions of neurologic symptoms, such as visual loss, weakness, and imbalance, early in the course of the disease. Despite major medical improvements, MS tends to worsen in about 40% of patients later in the disease’s course.

“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.”

The prevalence of epsilon toxin-producing Clostridium perfringens in MS patients raises the possibility that environmental factors, rather than genetic predisposition, maybe the cause of the disease. The small intestine is home to strains of Clostridium perfringens that manufacture epsilon toxin. Epsilon toxin is only produced momentarily during the bacterium’s development phase, which is consistent with the relapsing-remitting aspect of MS. Epsilon toxin precisely targets brain blood arteries and myelin, offering a clear mechanism of action. This is perhaps most remarkable.

Modern analyses of the gut microbiome in MS patients failed to find these strains despite accumulating evidence that epsilon toxin-producing Clostridium perfringens strains may be important environmental pathogens for the disease. The current study demonstrated that more sensitive techniques easily detected these strains in the MS gut microbiome. It was led by Yinghua Ma, an assistant professor of neuroscience research in the Vartanian lab, as well as co-lead authors David Sannino and Jennifer Linden.

“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.

“The team brought the full armamentarium of modern molecular biology to address the question of pathogenesis and possible drivers of multiple sclerosis,” said Mason, who is also a professor of neuroscience in the Brain and Mind Research Institute at Weill Cornell Medicine. Having established this correlation, the investigators tested whether the toxin alone could cause the disease.

For that, they turned to a standard mouse model of MS in which animals are predisposed to autoimmunity, but MS-like disease only occurs if mice are also given pertussis toxin. Ma substituted epsilon toxin for pertussis toxin and animals developed a disease that more closely resembled MS compared to previous models.

“The finding that epsilon toxin can replace pertussis toxin in a mouse model of Multiple Sclerosis is very exciting,” said co-author Gregory F. Sonnenberg, the Henry R. Erle, M.D.-Roberts Family Associate Professor of Medicine and a member of the Jill Roberts Institute for Research in Inflammatory Bowel Disease at Weill Cornell Medicine.

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.

Epsilon toxin functions at the very earliest stage of MS lesion formation,” said Vartanian, who is also chief of the Multiple Sclerosis and Neuro-Immunology Division in the Department of Neurology at Weill Cornell Medicine and a neurologist at NewYork-Presbyterian/Weill Cornell Medical Center. “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.”

“In the immediate term, we’re driven by a sense of urgency to get more effective and safer therapeutics to people with MS,” Vartanian said.

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