Gut Check


New evidence shows that a bacterium found in the gut of livestock could be a trigger of multiple sclerosis in humans.

By Michael Eisenstein

Cow overlaid with microbes
Illustration: Anatomy Blue

The first time Dr. Timothy Vartanian tried to advance the hypothesis linking the neurological disorder multiple sclerosis (MS) to a bacterium best known for causing fatal disease in livestock, he faced an uphill battle.

In 2013, his team had directly isolated the pathogen in question, Clostridium perfringens type B, from a young woman with MS, and found signatures of a tissue-damaging toxin produced by this bacterium in samples from other patients. But most clinical journals showed little interest, and he struggled to win the grants needed to generate more robust clinical evidence. “It was really hard to get funding at this point,” says Dr. Vartanian, a neurologist and neuroscientist. “It was very much an idea that was not mainstream in MS.”

But his team persevered, building out an extensive portfolio of experimental evidence supporting the hypothesis that C. perfringens can help fuel onset and progression of MS. And in 2023, Dr. Vartanian and collaborators published their most compelling results to date — revealing a strong link between the presence of this pathogen and MS in humans, as well as insights into the biological mechanism by which it inflicts damage on the nervous system. Now, the experts are paying attention.

“I think it’s a fascinating story,” says Dr. Sergio Baranzini, who studies the role of the gut microbiome in MS at the University of California at San Francisco. He notes that many flashy findings linking the bacteria residing within our digestive tract to major diseases have ultimately fizzled out under closer scrutiny. “The most strict studies are the ones that will really pave the field moving forward,” says Dr. Baranzini, “and I think Tim’s study is one of those.”

A bug in the system

MS is a product of abnormal immune activity, wherein white blood cells mount an attack on the myelin sheaths that insulate neurons and allow them to efficiently relay electrical signals. This degeneration leads to the gradual decline of neurological function.

The initiating events behind this disease are shrouded in mystery, but many lines of evidence indicate that environmental factors can contribute to MS by shaping the composition of the gut microbiome. These diverse microbial communities interact closely with the immune system of their human hosts, notes Dr. Gregory Sonnenberg, a collaborator of Dr. Vartanian’s. “Recent evidence indicates that the gut microbiome functionally contributes to MS pathogenesis, as fecal transplant from MS patients can exacerbate mouse models of MS,” he says.

Dr. Vartanian was not the first to look into C. perfringens. A harmless form of this bacteria, known as type A, is commonly found in the human gut. But its pathogenic counterparts, types B and D, have traditionally been associated with disease in goats, sheep and other animals. And almost 40 years ago, researchers led by Dr. Timothy Murrell at the University of Adelaide suggested that the type D bacteria could play a role in MS. However, Dr. Murrell was unable to confirm this at the time. “He didn’t have modern tools, so that theory just kind of sat there,” says Dr. Vartanian.

In their 2013 paper, Dr. Vartanian’s team employed modern molecular biology techniques to establish a tentative link between C. perfringens and MS. Using a method known as the polymerase chain reaction (PCR), Dr. Kareem Rashid Rumah (M.D. ’15, Ph.D.) detected traces of DNA encoding Epsilon toxin — the tissue-damaging molecule produced by pathogenic forms of C. perfringens — in a stool sample from a patient with MS. Dr. Jennifer Linden, now assistant professor of research in neuroscience at the Feil Family Brain and Mind Research Institute, subsequently isolated and cultured this bacterium, and confirmed that it was the harmful type B form of the microbe. In parallel, Dr. Rumah screened serum samples from over 200 patients with MS and healthy controls and found that the former group were more likely to contain antibodies against Epsilon toxin, providing evidence of exposure to C. perfringens. “The numbers weren’t huge — 10% versus 1% — and it was antibodies to the toxin, not detection of the toxin itself,” says Dr. Vartanian. “But it was enough to get a foothold.”

With support from the National Multiple Sclerosis Society, his group embarked on a series of cell culture and animal studies that allowed them to begin teasing out a possible mechanism by which Epsilon toxin might facilitate MS progression. Among other findings, they learned that this molecule can bind to and perforate the walls of the capillaries that form the so-called blood-brain barrier, which normally keeps the nervous system sequestered from the immune system. They further found that Epsilon toxin damages the cells that maintain neuronal myelin sheaths, leading to the erosion of that insulating layer. These preclinical studies culminated in a 2023 article in the Journal of Clinical Investigation, in which Dr. Vartanian and collaborators including Dr. Sonnenberg and Dr. Christopher Mason, professor of physiology and biophysics, demonstrated that pathogenic C. perfringens is a distinctive feature of the gut microbiome in many patients with MS.

Dr. Vartanian notes that this bacterium has proven challenging to detect due to the limited sensitivity of standard PCR methods, and Dr. Yinghua Ma, assistant professor of research in neuroscience in the Brain and Mind Research Institute, developed an optimized PCR protocol that was better suited for finding and quantifying C. perfringens. Nonpathogenic type A bacteria were commonly observed in stool samples from both healthy controls and patients with MS, but the latter were far more likely to also have a thriving community of pathogenic strains. In these patients, Epsilon toxin-producing strains comprised 32% of the C. perfringens population versus just 0.002% in samples from unaffected individuals. This suggests that epsilon toxin-producing strains of C. perfringens may need to outcompete their harmless counterparts and establish a meaningful presence in the gut to induce a pathogenic effect. And importantly, when the researchers isolated Epsilon toxin from these bacteria and administered it to mice, these animals developed inflammation and demyelination in the brain that mirrored the pathology of advanced MS.

Closing in on causality

Dr. Baranzini says that this work provides compelling evidence for a potential causative role of this pathogen in MS. “The team has been very persistent on this hypothesis and has been able to provide more and more evidence that this might be one of the mechanisms that may trigger the disease,” he says. However, he adds that “most likely, it’s not the only one.”    

There are a variety of aspects of MS pathology that could be parsimoniously explained by a contribution from C. perfringens, according to Dr. Vartanian. For example, the disease is typically episodic, with flare-ups and progression interrupted by extended periods of remission, and C. perfringens is known to exhibit similar patterns of sporadic Epsilon toxin production in infected animals. This hypothesis is also compatible with recent work linking MS to an abnormal immune reaction to infection with the Epstein-Barr virus (EBV), and nervous system lesions initially inflicted by Epsilon toxin could be exacerbated by the anti-EBV immune response. And although C. perfringens is not conventionally contagious, it can persist in the feces of animals — and subsequently, in the soil — in a long-lived spore form that offers a ready route of exposure for humans.

Patients with MS currently rely on immunosuppressive drugs to keep their disease in check, but the mechanism uncovered by Dr. Vartanian’s group could offer more direct opportunities to thwart progression. For example, it should be feasible to generate therapeutic antibodies that bind to and inactivate Epsilon toxin in the bloodstream before it can access and injure the nervous system. Additionally, the manifestations of MS exhibited by Epsilon toxin-treated mice seem to be more representative of human disease than traditional laboratory models, giving scientists a better tool for exploring disease pathology and possible avenues for treatment. “We don’t want to cure mouse MS — we want to cure human MS,” says Dr. Sonnenberg. “Anything you can do to make it more accurately model human disease is very important, and this is another key advance in the paper.”

But this hypothesis still requires additional rigorous testing. Dr. Vartanian points out that his analyses of MS patients have been from individual patient samples at single clinical centers, and he hopes to conduct a multi-city — and potentially multinational — study that will analyze many patients for extended periods of time. This longitudinal analysis would provide a better means to assess the influence of Epsilon toxin over the long-term course of disease progression.

Dr. Baranzini also points out the need for more direct proof that C. perfringens itself — as opposed to purified Epsilon toxin — can induce MS pathology in animal models. This is amongst Dr. Vartanian’s top priorities, although transplanting this pathogen from humans to rodents is easier said than done. “Mice aren’t natural hosts to C. perfringens, so we have to figure out a strategy to optimize colonization,” he says. “But we’re working on it.”

Dr. Timothy Vartanian, Dr. Yinghua Ma and Dr. Jennifer Linden are co-founders of and equity stakeholders in Astoria Biologica. Dr. Vartanian and Dr. Ma are also inventors on a patent application for a method used to diagnose and treat multiple sclerosis.

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