Introduction
Since there is currently no human vaccine available against ETX and it is estimated that it could take up to 10 years to develop one for human use, are there any existing treatments or supplements that might help MS patients in the meantime if ETX is the trigger?
There are two possible routes either:
- Treating the bacterial infection of C. perfringens; or
- Treating epsilon toxin itself
Treating the bacteria – existing Oral MS Drugs
Firstly, do any of the existing oral disease modifying drugs (DMDs) have antibacterial properties against C. perfringens in particular? The answer is yes!
These antibacterial properties were demonstrated by Rumah et al (35) in 2017 – the three most accepted oral medications approved for the treatment of MS, Fingolimod, Dimethyl Fumarate (DMF) and Teriflunomide (BG12) all inhibited C. perfringens growth, of which Fingolimod was the most successful.
Two of these medications, Fingolimod (bacteriocidal properties) and Teriflunomide (bacteriostatic properties), are considered to be anti-inflammatory agents, while DMF (bacteriostatic properties) is thought to trigger a robust antioxidant response, protecting vulnerable cells during an MS attack.
It seems therefore that these drugs may inhibit the growth of C. perfringens and this may contribute to their clinical efficacy. It should be pointed out that these DMDs will most likely be active against other biological processes and microorganisms, so no link is proven by this research – rather it is an interesting correlation and one that you would not be surprised to find if ETX was a trigger for MS.
Treating the bacteria – existing Antibiotics
It may be that a course of a recognised antibiotic medication, would be effective against the bacterial infection.
Three of the most effective antibiotics against C. perfringens are Metronidazole, Clindamycin and Penicillin G. Research indicates that Metronidazole is particularly effective against C. perfringens. One disadvantage of Metronidazole is that it is contra-indicated with alcohol!
It should be recognised that any course of antibiotics would have an impact on the gut flora generally, therefore systematic research would need to be undertaken to work out the right dose and length of this medication.
Treating the bacteria – existing Probiotics
Lactobacillus plantarum strain ATCC 8014
There are a number of articles covering probiotics including “In Vitro Antimicrobial Activity and Probiotic Potential of Bifidobacterium and Lactobacillus against Species of Clostridium” (44). The conclusion states:
“Our findings allow us to conclude that L. plantarum strain ATCC 8014 has probiotic potential, with antimicrobial activity against C. butyricum ATCC 860, C. difficile ATCC 9689, and C. perfringens ATCC 12924. Additionally, this microorganism fulfills essential criteria to survive the harsh conditions of the gastrointestinal tract, as well as to colonize it.”
Treating ETX – Glycoside-4
There is some interesting new research: “A small bioactive glycoside inhibits epsilon toxin and protects host cell death” (47) about a sugar derivative, which was recently published https://dmm.biologists.org/content/early/2019/09/05/dmm.040410 has shown: “Glycoside-4 effectively blocks cell death of ETX treated cultured primary cells and maintained cellular homeostasis; via disrupting oligomerization, blocking pore formation, restoring calcium homeostasis, stabilizing mitochondrial membrane and impairing HMGB1 translocation from nucleus–to-cytoplasm.
Furthermore, a single dosage of Glycoside-4 protected the Etx-challenged mice and restored normal function to multiple organs. This work for the first-time reports a potent, nontoxic glycoside with strong ability to occlude toxin lethality representing it as bio-arm therapeutics against Etx-based biological threat.”
Treating ETX – Antibodies to ETX
Antibodies against ETX may also ameliorate an MS episode, however, there are no known antibodies to ETX available for human use. There is one antibody (C4D7) known to be highly effective against ETX in mice but it has certainly not been tested in humans.
Vaccines
ETX is known to be highly toxic, pore-forming toxin and somewhat surprisingly, there is currently no human vaccine. There is a crude, formaldehyde-inactivated vaccine for sheep, which are routinely inoculated against ETX as lambs and this vaccine has provided effective protection for sheep for the past 50 years.
If ETX is the trigger for MS, then it is proposed that the disease would, in the long term, be treated by a vaccine in much in the same way as humans are inoculated against the tetanus toxin and sheep are currently vaccinated against ETX. As mentioned the current sheep vaccine is crude and not suitable for human use. Therefore, it is likely that any new vaccine is 5-10 years away.
The vaccine is discussed in more detail in the section entitled “Human Vaccine against ETX”.
A Note on Experimental Mice
Many studies have been undertaken and articles published based on experimenting with mice. There is an article (7), which raises doubts about the value of something Calle Experimental Allergic Encephalomyelitis (EAE). Given that the immune system f a mouse and human differs significantly in terms of MAL sensitivity and expression in different cell lines, there seems to be a dubious value of results in EAE mice.
There now seems to be an opportunity to develop a mouse model of MS based on expressing human MAL in the same cell lines as humans (if possible). In addition, there seems to be a need to develop a mouse model of infection using regular and low doses of ETX.
Conclusion
In the short term, there will be little option to change any treatments recommended by the medical experts so the best advice would be “to keep taking the meds, if they work for you”.
The other main option for MS patients would be to include probiotics and other supplements in their diets. Again, the doses, frequency and impact could only be worked out by trial and error over time.
Whilst the vaccine might inhibit further infections and damage from ETX, for those MS patients already with “auto-immune” symptoms, the immune system would need treatment. This would need to be the subject of future research and proposed solutions. Something would need to be given to MS patients to try and eliminate the faulty memory B and T cells. Perhaps a drug like Cladribine or Alemtuzumab in the appropriate minimum dose might be effective as a once off treatment to reset the immune system?