The Correlation Between Multiple Sclerosis and Clostridium Toxin

Clostridium perfringens types B and D, which primarily infect ruminants, produce a toxin known as epsilon that causes nerve demyelination and subsequent neurologic signs.

While few reports exist of humans with epsilon toxin—producing Clostridium infection, research shows that approximately 10% of patients with multiple sclerosis (MS) have antibodies to epsilon toxin, a prevalence 10 times that of the general US population. This suggests that epsilon toxin may play a role in MS development.

Researchers at the University of Exeter in the United Kingdom recently performed a study to determine the prevalence of antibodies to epsilon toxin in clinically defined MS (CDMS) patients, as well as patients at high risk for developing MS due to 2 other demyelinating conditions: clinically isolated syndrome (CIS) and optic neuritis (ON).

Study Design

Serum samples were collected from adults in the United Kingdom who were diagnosed with CDMS, CIS, or ON by an MS specialist. Age- and gender-matched sera from the Exeter 10,000 project, a nationwide voluntary medical registry, served as controls.

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Researchers performed a neutralization assay by serially diluting samples in saline containing activated epsilon toxin. Samples were incubated on cultured cells and cellular metabolic activity was measured. Also, 2 forms of enzyme-linked immunosorbent assay (ELISA) were performed to detect serum antibodies to epsilon toxin and synthesized toxin peptides. Western blot was also used to detect antibodies to epsilon toxin, and positive samples were then tested to Bacillus anthracis toxin to rule out nonspecific binding. If samples were positive for both toxins, they were assumed to be false-positive and thus excluded from analysis.

Results

Serum samples were available for 65 patients with CDMS, 20 with CIS, and 44 with ON.

Overall, 23.2% (30/129) of samples from patients with demyelination diseases reacted to epsilon toxin on Western blot, compared with only 10% (13/129) of samples from the age- and gender-matched controls.

Reactive serum samples included:

• 23% (14/65) of patients with CDMS
• 35% (7/20) of patients with CIS
• 20% (9/44) of patients with ON

ELISA performed on a subset of samples determined that 33% (14/43) of CDMS sera reacted with 1 or more epsilon toxin peptides, while 16% (5/32) of control samples were ELISA-positive. Overall, only 3 CDMS samples and 1 control sample were positive via both Western blot and ELISA. None of the positive samples significantly inhibited signal on the serum neutralization assay.

Perhaps most striking of all, the authors noted that 71% (5/7) of the CIS patients with measurable antibody against epsilon toxin eventually developed CDMS.

Take-home Message

Seroreactivity against epsilon toxin was more prevalent in patients with CDMS, CIS, and ON compared with controls, suggesting a link between toxin exposure and demyelination-associated diseases. However, some control samples were also positive, which indicates that epsilon toxin exposure does not universally lead to development of MS.

Dr. Stilwell received her DVM from Auburn University, followed by a MS in fisheries and aquatic sciences and a PhD in veterinary medical sciences from the University of Florida. She provides freelance medical writing and aquatic veterinary consulting services through her business, Seastar Communications and Consulting.