In the past decade, research has shown that the enormous community of microbes that live in the gut, known as the gut microbiota, are closely linked to human health and disease. This relationship is primarily due to the gut microbiota’s impact on systemic immune responses. There is growing evidence that these impacts on immune function are significant in neuroinflammatory illnesses like Multiple Sclerosis (MS) and that therapeutic microbiome modification may be helpful in these diseases.
Multiple sclerosis is a chronic immune-mediated disease of the central nervous system characterized by adaptive and innate immune system dysregulation, including inflammation, demyelination, and axonal and neuronal loss. Clinically, MS is characterized by recurrent relapses or progression, ultimately leading to severe neurological disability. The limited effectiveness of approved treatments for Multiple Sclerosis and reports of adverse events and toxicity emphasize the need to develop new therapies with improved efficacy and fewer side effects. Microbiome manipulations have been proposed as a novel strategy for preventing and treating Multiple Sclerosis. Here we explore the microbiome signature of Multiple Sclerosis and its involvement in the etiology, pathology, and potential for offering targets for the treatment of the disease.
1. The Microbiome Signature of Multiple Sclerosis
1.1 A Primer on Zinc
The presynaptic vesicles of neurons contain the majority of zinc, which is a common metal in the brain. Since high amounts of zinc can be neurotoxic and zinc deficiency can cause death in neural cells, it is evident that maintaining effective zinc homeostasis in the brain is crucial to neurological health.
The result of the meta-analysis and systematic review investigating the role of zinc in the pathogenesis of Multiple Sclerosis found an overall reduction of serum or plasma zinc levels, but whole blood and erythrocyte zinc levels were several times higher in MS patients compared with healthy controls. Thus, it is hypothesized that local zinc alterations are involved in MS’s pathogenesis [x].
1.2 Microbiome Signature of MS Reveals Pathological Associations with Zinc Homeostasis
The ability of several pathogens to withstand the antimicrobial activity of the many metal-chelating proteins of the innate immune system depends on their genetic adaptations to acquire the ions.
The strong association between bacteria and viruses represented that express genetic components that enable them to resist calprotectin or glutathione-mediated zinc chelation and sequestration suggests a strong association between the Microbiome signature of Multiple Sclerosis and the zinc homeostasis of the host and may play a role in localized zinc deficiency and hyperzincemia discussed in the above meta-analysis and systematic review.
| SPECIES/PHYLA | NOTES |
|---|---|
| Akkermansia muciniphila (Verrucomicrobia) | Akkermansia muciniphila utilizes colonic mucin as its substrate [x]. Thus, the pro-inflammatory functions of Akkermansia in MS may stem from its ability to induce thinning of the intestinal mucosa. Studies suggest that A. muciniphila triggers demyelination in MS patients [x]. Several studies report that A. muciniphila is significantly increased in MS patients. [x, x, x] |
| Acinetobacter baumanii (Proteobacteria) | Acinetobacter baumannii is a significant nosocomial pathogen that is responsible for up to 20% of infections in intensive care units worldwide [x], and has been proposed as the most likely etiological agent for the onset and development of Multiple Sclerosis based on nine Popper sequences [x]. Acinetobacter baumannii, Acinetobacter calcoaceticus, and Acinetobacter lwoffii all have homologous genomes, and are all extremely uncommon in the healthy human gut [x, x]. Acinetobacter all have a genetic zinc acquisition and transport system that enables resistance to calprotectin-mediated zinc chelation and sequestration [x]. |
| Acinetobacter calcoaceticus (Proteobacteria) | Like Acinetobacter baumannii above, Acinetobacter calcoaceticus are a gram-negative species whose pervasiveness has also made them significant causes of nosocomial pneumonia and systemic infections [x]. Acinetobacter calcoaceticus is increased in MS patients [x, x]. Computer analysis of myelin shows molecular mimicry with sequences found in Acinetobacter [x], and higher numbers of antibodies to Acinetobacter bacteria are found in MS patients [x]. |
| Haemophilus influenzae (Proteobacteria) | Like Acinetobacter baumannii above, Acinetobacter calcoaceticus are a gram-negative species whose pervasiveness has also made them significant causes of nosocomial pneumonia and systemic infections [x]. Acinetobacter calcoaceticus is increased in MS patients [x, x]. Computer analysis of myelin shows molecular mimicry with sequences found in Acinetobacter [x], and higher numbers of antibodies to Acinetobacter bacteria are found in MS patients [x]. |
| Mycoplana (Proteobacteria) | Molecular mimicry is a putative mechanism for the activation of autoreactive T cells in MS. A naturally occurring Haemophilus influenzae-encoded molecular mimic was found to induce a rapid-onset demyelinating disease[x], indicating that a bacterial protein could be one of the native antigens leading to the development of MS. H. influenzae has been shown in several studies to be increased in MS patients compared to healthy controls [x,x,x]. Studies in a murine lung infection model have discovered that a novel zinc-binding system, ZevAB, is critical for survival of Haemophilus influenzae [x] . |
| Pseudomonas aeruginosa (Proteobacteria) | Polyamines (PA) putrescine, cadaverine, spermidine, and spermine are bioactive amines widely distributed among both eukaryotic and prokaryotic cells. Polyamines and their metabolites are essential for a wide array of biological functions including gene regulation, stress resistance, cell proliferation and differentiation [x]. By regulating the expression of numerous growth-related genes, cellular polyamine availability, in particular, supports tissue homeostasis of the gastrointestinal mucosa, the rates of epithelial cell division, and apoptosis. Polyamines are generally involved in a number of critical cellular activities. Thus, their dysregulation can have an impact on development of a number of diseases including cancer, metabolic disorders, and neurodegeneration [x]. The role of Mycoplana in health or disease is largely unknown, but it is found to be increased in MS patients relative to controls [x, x] . However, studies have found that Mycoplana can utilize putrescine, spermidine, or spermine as its sole carbon source, and that its enzyme, acetylpolyamine amidohydrolase, plays a major role in the retroconversion of polyamines to acetylspermidine, acetylspermine, and acetylputrescine [x]. The gene encoding the acetylpolyamine amidohydrolase enzyme of Mycoplana was found to have one zinc atom per subunit. Metal substitution analyses further revealed that zinc was necessary for the catalytic reaction of the acetylpolyamine amidohydrolase enzyme [x]. |
| Desulfovibrio (Proteobacteria) | Desulfovibrio is a genus of Gram-negative sulfate-reducing bacteria. Studies have indicated that Desulfovibrio is increased in MS patients. [x] In engineering studies, Desulfovibrio vulgaris forms biofilms on zinc and zinc-coated galvanized steel resulting in severe microbiologically influenced corrosion (MIC) [x], which is a significant issue that results in a loss of billions of dollars annually for many industries [x] . |
| Clostridium perfringens (Firmicutes) | Clostridium perfringens bacteria are one of the most common causes of foodborne illness (food poisoning). Data suggests that epsilon toxin from the gut bacterium Clostridium perfringens may initiate newly forming MS lesions [x]. A few studies have found that Clostridium perfringens is increased in MS patients. [x, x] Clostridium perfringens alpha toxin displays lethal, hemolytic, and phospholipase activity and is responsible for gas gangrene and myonecrosis in infected tissues [x]. Alpha toxin is also an enzyme, a lecithinase, and evidence suggests that it is the most important factor in infections caused by C. perfringens [x]. In a 1960s study investigating zinc on the production of clostridium perfringens toxins, toxin production was found to be decreased in the presence of iron and magnesium, but significantly increased in the presence of zinc [x]. Ethylenediaminetetraacetic Acid (EDTA) is a potent chelating agent used in the management and treatment of heavy metal toxicity [x]. In a 1950s study, EDTA consistently protected mice against lethal doses of C. Perfringens alpha toxin. However, when an addition of Zinc, Cobalt, and Manganese were injected into the mice, the protective effect of EDTA against C.perfringens alpha toxin was reversed [x]. Epsilon Toxin [x] |
| Blautia (Firmicutes) | Studies found a high relative abundance of the Blautia genus and its variants were associated with higher relapse risk in MS cases. [x, x]. Blautia stercoris has been linked to disease activity in other immune-mediated diseases such as systemic lupus erythematosus.[x]. |
| Dorea (Firmicutes) | While Dorea is thought to be a constituent of healthy gut microflora, its higher abundance in MS and IBD patients suggests a pro-inflammatory role for this bacterium [x], most likely due to its ability to degrade mucin and thin the intestinal mucosa [x]. |
| Atopobium vaginae (Actinobacteria) | The recently described anaerobic bacterium, Atopobium vaginae is associated with bacterial vaginosis [x], and has been found to trigger demyelination[x]. |
| Methanobrevibacter (Archaea) | Methane-producing Methanobrevibacter is associated with constipation and irritable bowel syndrome and are shown to be increased in MS patients [x, x]. |
| Epstein-Barr Virus (Virus) | The link between Epstein-Barr Virus (EBV) and MS is supported by a higher prevalence of EBV infection and elevated EBV-specific antibody levels in MS patients compared to healthy controls [x, x]. |
| Caulobacteraceae (Proteobacteria) | |
| Pseudomonadaceae (Proteobacteria) | Differentially abundant taxa between MS and control samples found a 5-fold increase in the prevalence of Caulobacteracea compared to control in stool sample analyses [x] . |
Erysipelotrichaceae (Firmicutes) | Erysipelotrichaceae is a beneficial commensal bacteria that have been shown to induce regulatory T cells [x], which is lower in MS patients than healthy controls [x, x, x]. |
| Parabacteroides distasonis (Parabacteroides) | Differentially abundant taxa between MS and control samples found a 7-fold increase in the prevalence of Pseudomonadaceae compared to control in stool sample analyses [x] . |
| Butyricimonas virosa (Bacteroidetes) | Butyrate is a short-chain fatty acid (SCFA) that preserves the integrity of your gut lining. However, studies have indicated that Butyricimonas virosa, a butyrate-producing genus, is reduced in MS patients [x][x][x]. |
| Prevotella histicola (Bacteroidetes) | P. histicola is a commensal species. Several studies have found that MS patients have a lower abundance of P. histicola compared to healthy controls. Data suggests that P. histicola can suppress disease in a preclinical model of MS [x]. In mice treated with P. histicola, the permeability of the blood-brain barrier is reduced along with relatively reduced activation of immune cells [x]. |
| Clostridia clusters XIVa (Firmicutes) | Parabacteroides distasonis is an obligate anaerobe known for mitigating metabolic dysfunction by producing succinate and secondary bile acids. Several studies have indicated that Parabacteroides distasonis is reduced in MS patients. |
| Veillonellaceae (Firmicutes) | Veillonellaceae is a beneficial bacteria that play an important role in bile acid metabolism [x], and was also found to be lower in MS patients than healthy controls [x, x]. |
1.3 Microbiome Differences in relapsing-remitting MS (RRMS) and Progressive MS patients
While microbiota diversity did not differ between RRMS and progressive MS or differ based on disease-modifying therapies, elevated Enterobacteriaceae and Clostridium, and decreased unclassified Blautia, and Agathobaculum
DQ795333 was unique to progressive MS [x]. Blautia species are also well recognized as part of the butyrate-producing bacteria of the intestinal microbiota [x], and Agathobaculum are butyrate-producing beneficial gut bacteria that aid in the intestinal epithelium’s integrity [x]. In short, the progressive MS has an increased number of Clostridium bacterium and a decreased population of the butyrate-producing bacterium.
As such, targets for enhanced butyrate production may improve progressive MS. In animal models of MS, exogenous butyrate suppresses demyelination and enhances remyelination [x]. These results, although preliminary, further enhance our understanding of the association between gut microbiome metabolites, the central nervous system (CNS), and offers clues to controlling demyelination and remyelination in MS.
2. Effective Microbiome Manipulations for Multiple Sclerosis
An increasing body of evidence reveals gut microbiota dysbiosis in Multiple Sclerosis [x, x, x, x]. For this reason, rebuilding gut microbiota has been proposed as an innovative approach to treatment.
| INTERVENTIONS | NOTES |
|---|---|
| Fecal microbiota transplantation (FMT) | Fecal microbiota transplantation (FMT) is an ancient treatment dating back to 1700 years ago [x], and appears to be the most direct way to reconstruct the gut microbiota [x, x]. Data reveal a tendency for the gut microbiota structure to change towards normal after FMT treatment in animal models of Multiple Sclerosis [x]. |
| Schistosoma mansoni Helminthic Therapy | Experimental autoimmune encephalomyelitis (EAE) is an animal model for multiple sclerosis (MS) characterized by chronic inflammatory demyelination of the central nervous system (CNS). In EAE models, S. mansoni ovum can attenuate the clinical course of EAE, and significantly delay the development of clinical symptoms. [x] In other studies, it was described that colonization by S. mansoni was associated with overall changes in the gut microbiota, including increases in Parabacteroides and decreases in spore-forming Clostridiales [x], which would likely confer benefit to the microbiome of an MS patient. |
3. Potential Dietary Considerations for Multiple Sclerosis
Various therapies for MS have been approved by the food and drug administration (FDA) and European Medicine Agency (EMA). However, these therapies are marked by high cost and toxicity in neurological disorders. Therefore, naturally isolated compounds and foods may overcome some limitations.
| DIETARY CONSIDERATIONS | NOTES |
|---|---|
| Aronia Melanocarpa | Ursolic acid found in Aronia melanocarpa has been found to prevent and repair neurons in animal models of Multiple Sclerosis, reduce further damage, rebuild myelin, and have anti-inflammatory properties [x]. |
| Aloe | Preliminary data in animal models of MS suggests that Aloe vera is capable of suppressing a preactivated immune system in the late effector phase [x]. Of note, Akkermansia muciniphila is a mucin-degrading bacteria that thins the intestinal mucosa, while aloe is a mucilaginous polysaccharide [x]that might offer substrate to Akkermansia muciniphila preferentially over human intestinal mucosa. |
| High-fat diet and alcohol | Preliminary data in animal models of MS suggests that Aloe vera can suppress a preactivated immune system in the late effector phase [x]. Of note, Akkermansia muciniphila is a mucin-degrading bacteria that thins the intestinal mucosa, while aloe is a mucilaginous polysaccharide [x]that might offer substrate to Akkermansia muciniphila preferentially over human intestinal mucosa. |
| Ketogenic diet | In a phase II study of ketogenic diets for relapsing multiple sclerosis, body composition, fatigue, depression, neurological disability, adipose-related inflammation and overall quality of life improved [x]. One randomized-controlled trial aims to determine if a ketogenic diet will show a reduction in lesions over an 18-month period. [x] However, the study has not yet been concluded. |
4. Potential Supplements for Multiple Sclerosis
| INTERVENTIONS | NOTES |
|---|---|
| Zinc Aspartate | It is known that common components of daily dietary habits, such as salt and zinc, can influence the severity of experimental autoimmune encephalomyelitis (EAE), a disease used to model MS in laboratory settings. However, when combined with aspartate, the treatment with zinc reduced MS severity [x]. |
| Bile Acid | Due to the decrease in Veillonellaceae, bile acid metabolism is altered in multiple sclerosis patients. Supplementation with bile acid has been found to ameliorate neuroinflammation. In studies, bile acid supplementation prevented the polarization of astrocytes and microglia to neurotoxic phenotypes and ameliorated neuropathology in an animal model of MS [x]. |
| Isoflavones | P. histicola can modulate host immunity through the metabolism of phytoestrogens[x], and estrogen is recognized for its immunomodulatory properties in animal models of MS [x]. A hallmark of MS and the animal model of MS is proinflammatory cellular infiltration into the CNS [x]. One study found that the animal model of MS could be suppressed by a diet supplemented with isoflavones [x]. |
| Guar gum | Studies demonstrate that standard fiber diets (5%) do not offer protection against animal models of MS when compared to zero-fiber diets, whereas a diet high in the soluble fiber guar gum (30%), inhibited disease progression and prevented lymphocytic CNS infiltration [x]. Of note, pectin, resistant starch, and inulin did not offer the same protection – providing evidence that the types of dietary fiber have differential effects on the immune system and neuroinflammation. |
| D-Mannose | D-Mannose The use of D-mannose in MS patients reporting recurrent UTIs is associated with reducing the number of UTIs and antibiotic prescriptions without safety concerns [x]. Treatment of Pseudomonas aeruginosa with 1 to 3% d-mannose reduced cell activity and motility [x]. |
| Curcumin | Multiple mechanisms, including zinc neurotoxicity, calcium excitotoxicity, and oxidative injury, have been implicated in the pathological role of neuronal death. Before the onset of neuronal damage, a high zinc concentration depletes glutathione. Glutathione is the brain’s most abundant antioxidant and is crucial in eliminating reactive oxidants [x]. However, data indicates that the glutathione levels in the cerebrospinal fluid of patients with multiple sclerosis were significantly lower compared to those of healthy controls [x]. Glutathione lessens the neurotoxicity of zinc [x], is a potent chelator involved in cellular response, transport, and excretion of metal cations, and is a biomarker for toxic metal overload [x]. N-acetylcysteine (NAC) is an immediate glutathione precursor [x]. In clinical studies, multiple sclerosis patients treated with N-acetylcysteine had significantly improved metabolic activity in certain brain regions, cerebral glucose metabolism [x], and improved fatigue and antioxidant status [x]. N-acetylcysteine was tolerated at doses of 1250 mg thrice daily in clinical studies of progressive MS patients [x]. |
| Exogenous Butyrate | Studies suggest that curcumin is a potent anti-inflammatory and antioxidant agent that could modulate cell cycle regulatory proteins, enzymes, cytokines, and transcription factors in CNS-related disorders, including MS [x]. Curcumin can also prevent the adhesion of P. aeruginosa biofilm [x]. |
| Ganoderma Lucidum (Reishi) | In the central nervous system (CNS), microglia are the resident macrophage-like cells that play a crucial role in host defense and tissue repair [x]. Under pathological conditions, however, microglia are stimulated by bacterial toxins called lipopolysaccharides (LPS), and release neurotoxic and pro-inflammatory mediators, such as nitric oxide, prostaglandin E2, reactive oxygen species, and pro-inflammatory cytokines such as interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF) [x,x]. These inflammatory mediators and cytokines cause severe neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, cerebral ischemia, and multiple sclerosis [x, x, x]. While Ganoderma Lucidum (reishi) has not been studied in MS patients, Ganoderma lucidum inhibits the excessive production of nitric oxide, prostaglandin E2, and pro-inflammatory cytokines without causing cytotoxicity [x]. By inhibiting inflammatory mediator responses in activated microglia, Ganoderma lucidum may be advantageous for treating Multiple Sclerosis. In animal models of Multiple Sclerosis, at peak demyelination, Ganoderma lucidum treatments significantly improved motor dysfunction and effectively suppressed Cuprazone-induced demyelination [x]. |
| Piwep Extract ( Phellinus igniarius) | Piwep is a mushroom extract derived from the mushroom Phellinus igniarius that ameliorates multiple sclerosis symptoms in animal models and inhibits immune cell infiltration in the spinal cord [x, x]. |
| Copper | CNS demyelination is associated with copper deficiency and hyperzincemia [x]. Excess zinc levels cause an upregulation of metallothionein production, This effectively decreases intestinal absorption of copper and zinc, resulting in copper deficiency [x]. To study multiple sclerosis in an animal model, animals are given Cuprizone [oxalic acid bis(cyclohexylidene hydrazide)], which is a high-affinity, copper-chelating agent that induces demyelination [x]. |
| NAC (N-acetylcysteine) | Multiple mechanisms, including zinc neurotoxicity, calcium excitotoxicity, and oxidative injury, have been implicated in the pathological role of neuronal death. Before the onset of neuronal damage, a high zinc concentration depletes glutathione. Glutathione is the brain’s most abundant antioxidant and is crucial in eliminating reactive oxidants [x]. However, data indicates that the glutathione levels in patients with multiple sclerosis cerebrospinal fluid were significantly lower compared to healthy controls [x]. Glutathione lessens the neurotoxicity of zinc [x], is a potent chelator involved in cellular response, transport, and excretion of metal cations, and is a biomarker for toxic metal overload [x]. N-acetylcysteine (NAC) is an immediate glutathione precursor [x]. In clinical studies, multiple sclerosis patients treated with N-acetylcysteine had significantly improved metabolic activity in certain brain regions, cerebral glucose metabolism [x], and improved fatigue and antioxidant status [x]. N-acetylcysteine was tolerated at doses of 1250 mg thrice daily in clinical studies of progressive MS patients [x]. |
| GlcNAc (N-acetylglucosamine) | A Meta-Analysis of Clinical Research in Patients with MS published in Frontiers in Neurology looked at 11 randomized controlled trials that studied different cannabis-based treatments for MS patients. The study found that when using Sativex—a pharmaceutical drug made from cannabis extracts—patients experienced reduced muscle spasms and pain in their extremities. However, there was no clear evidence that it affected MS symptoms overall [x]. Similarly, a separate study on oral cannabis extract also found that it helped reduce muscle spasms and pain in extremities but did not impact overall MS symptoms. In addition to helping with spasticity and pain relief, this study also found that smoking marijuana could help reduce tremors associated with MS [x]. Despite some promising results from the studies discussed above, more research must be done before any firm conclusions can be drawn about the effects of smoking cannabis on MS symptoms. While evidence suggests it can help reduce muscle spasms, pain in extremities, and tremors associated with MS [x], more research is needed to determine if it has any long-term beneficial effects on overall disease progression. |
| Cannabis | A Meta-Analysis of Clinical Research in Patients with MS published in Frontiers in Neurology looked at 11 randomized controlled trials that studied different cannabis-based treatments for MS patients. The study found that when using Sativex—a pharmaceutical drug made from cannabis extracts—patients experienced reduced muscle spasms and pain in their extremities. However, there was no clear evidence that it affected MS symptoms overall [x]. Similarly, a separate study looking at oral cannabis extract also found that it helped reduce muscle spasms and pain in extremities but did not impact overall MS symptoms. In addition to helping with spasticity and pain relief, this study also found that smoking marijuana could help reduce tremors associated with MS [x]. Despite some promising results from the studies discussed above, more research must be done before any firm conclusions can be drawn about the effects of smoking cannabis on MS symptoms. While evidence suggests it can help reduce muscle spasms, pain in extremities, and tremors associated with MS [x], more research is needed to determine if it has any long-term beneficial effects on overall disease progression. |
| Panax Ginseng | A Meta-Analysis of Clinical Research in Patients with MS published in Frontiers in Neurology looked at 11 randomized controlled trials that studied different cannabis-based treatments for MS patients. The study found that when using Sativex—a pharmaceutical drug made from cannabis extracts—patients experienced a reduction in muscle spasms and pain in their extremities. However, there was no clear evidence that it affected MS symptoms overall [x]. Similarly, a separate study looking at oral cannabis extract also found that it helped reduce muscle spasms and pain in extremities, but did not impact overall MS symptoms. In addition to helping with spasticity and pain relief, this study also found that smoking marijuana could help reduce tremors associated with MS [x]. Despite some promising results from the studies discussed above, more research needs to be done before any firm conclusions can be drawn about the effects of smoking cannabis on MS symptoms. While evidence suggests it can help reduce muscle spasms, pain in extremities, and tremors associated with MS [x], more research is needed to determine if it has any long-term beneficial effects on overall disease progression. |
| Apocynin/ Picrorhiza kurroa | Compared to placebo, clinical studies suggest that taking Panax ginseng 250 mg twice daily for three months benefits female patients with relapsing-remitting multiple sclerosis tiredness symptoms and quality of life (RRMS) scores. Women taking Panax ginseng reported a 75% reduction in fatigue, and their quality of life increased by 19.9 points as opposed to just 4.2 in the group receiving a placebo [x]. |
5. Potential Non-Pharmacological Adjunct Therapies
| Photobiomodulation | Low-level laser therapy (LLLT) or photobiomodulation (PBM) is a therapy that applies low-level lasers or light-emitting diodes to the body’s surface. In vitro and in vivo studies have shown that photobiomodulation can be an effective non-pharmacological treatment for inflammatory diseases such as MS [X]. Photobiomodulation results in the regeneration of cells, the stimulation of Schwann cell growth, a decrease in spasticity, functional improvements, a decrease in nitric oxide levels, and the upregulation of the cytokine IL10, demonstrating that this therapeutic modality can provide neuroprotection X. Clinical trials investigating the efficacy of administering low-level laser light therapy in the sublingual region, radial artery, and along the spinal cord in Multiple Sclerosis, patients were successful in slowing the progression of the disease and is a promising adjunct therapy [x]. |
6. Microbiome Activity of Multiple Sclerosis Drugs
6.1 Immunomodulating Medication
Few oral medications are currently approved for treating multiple sclerosis (MS). Two approved medications, Fingolimod and Teriflunomide are considered to be anti-inflammatory agents. At the same time, dimethyl fumarate (DMF) is thought to trigger a robust antioxidant response, protecting vulnerable cells during an MS attack.
Data suggests that epsilon toxin from the gut bacterium Clostridium perfringens may initiate newly forming MS lesions. Recent studies suggest that Fingolimod, Teriflunomide, and DMF inhibit Clostridium perfringens growth[x]. These data suggest that the approved oral MS therapies may owe their efficacy to an antibiotic mechanism that reduces these bacteria.
6.2 Antifungal Medication
A study using the anti-fungal itraconazole in an animal model of MS found that itraconazole restored dysregulated gene expression networks involved in stress responses and cell apoptosis [x].
Dimethyl fumarate, another inexpensive fungicide, was repurposed to treat MS in the US in 2013 [x]. In a randomized, double-blind, placebo-controlled phase 3 study involving patients with relapsing-remitting multiple sclerosis (RMSS), the anti-fungal significantly reduced the proportion of patients who had a relapse, the annualized relapse rate, the rate of disability progression, and the number of lesions on MRI [x]. These results may be due to the known inhibition of Epstein-Barr virus by dimethyl fumarate [x] or the above-cited inhibition of Clostridium perfringens.
6.2 Immunosuppressants
Copaxone® (Glatiramer acetate-GA) is an analog of myelin basic protein that is comprised of a heterogeneous mixture of polypeptides that is used as a first-line disease-modifying therapy (DMTs) for the treatment of MS. Unfortunately, Copaxone® alone is not always efficacious in suppressing the inflammatory response in MS patients [x, x]. Nevertheless, preliminary data suggest that P. histicola is as effective as Copaxone® in suppressing the disease in a preclinical mouse model of MS [x], and that Copaxone® has modest antimicrobial activity against multi-drug resistant Pseudomonas aeruginosa [x], which is found in higher relative abundance in MS patients.
6.3 Promising MS Drugs
P. aeruginosa is an opportunistic pathogenic bacterium responsible for acute and chronic infections. Beyond its natural resistance to many drugs, its ability to form a biofilm, a complex biological system, renders most antibiotics and immune defense systems ineffective. However, metformin markedly decreased biofilm formation, swimming, and twitching motilities and increased the sensitivity to oxidative stress [x]. Polyethylene glycol, a constituent of Metformin, is known to reduce biofilm formation and virulence of P. aeruginosa [x].
6.4 Repurposing Drugs for Multiple Sclerosis
Minocycline is a second-generation tetracycline antibiotic, and it is bacteriostatic. Minocycline works by inhibiting protein synthesis in bacteria, thereby blocking the elongation of polypeptide chains. This ultimately leads to the inhibition of bacterial growth and replication. In addition to anti-microbial activity, minocycline demonstrates neuroprotective action in multiple sclerosis [x].
Initially indicated for psoriasis, dimethyl fumarate is an oral medication used for treating multiple sclerosis. It is believed to work by activating a protein called nuclear factor erythroid 2–related factor 2 (Nrf2), which has anti-inflammatory and antioxidant effects in the body.
Clemastine is a first-generation antihistamine primarily used to treat allergies such as allergic rhinitis. However, there is growing interest in its potential as a repurposed drug for treating multiple sclerosis as a remyelinating therapy [x].
Quetiapine is an atypical antipsychotic medication that is primarily used for the treatment of schizophrenia and bipolar disorder. There is evidence to suggest that it may also have the potential as a repurposed drug for treating multiple sclerosis [x].
7. Potentially Detrimental Interventions for Multiple Sclerosis
| POTENTIALLY DETRIMENTAL | NOTES |
|---|---|
| Excessive Vitamin D Supplementation | The administration of cranberry to prevent UTIs in MS appears to be inefficient, as no significant reduction in UTIs happened after a one-year multicenter, randomized, placebo-controlled, double-blind trial [x]. However, in another study, a cranberry extract-supplemented diet dramatically increased Akkermansia muciniphila [x], which is already disproportionately high relative to controls in MS patients [x, x, x]. |
| Low-fat, plant-based diet | In a randomized controlled trial found that while a low-fat plant-based diet was well adhered to, the diet resulted in no significant improvement on brain MRI, relapse rate, or disability as assessed by EDSS scores in subjects with relapsing-remitting multiple sclerosis (RRMS) over one year. [x] |
| Cranberry Juice for UTI prophylaxis | The administration of cranberry to prevent UTIs in MS appears to be inefficient, as no significant reduction in UTIs happened after a one-year multicenter, randomized, placebo-controlled, double-blind trial [x]. However, in another study, a cranberry extract-supplemented diet dramatically increased Akkermansia muciniphila [x], which is already disproportionately high relative to controls in MS patients [x, x, x]. |
| Zinc Supplementation / Zinc oxide exposure | A recent randomized controlled study (RCT) found no neurological improvement in patients with multiple sclerosis compared with a placebo group after 12 weeks of zinc supplementation [x]. Demyelination is a key pathogenic feature of multiple sclerosis (MS). CNS demyelination is associated with hyperzincemia [x]. The abundance of zinc is implicated in the pathogenesis of Multiple Sclerosis [x]. Evidence suggests that intracellular zinc release plays a role in the death of oligodendroglia in Multiple Sclerosis, and intracellular zinc release is a key mediator of glutamate-induced excitotoxic damage to oligodendrocytes [x]. Abnormal zinc release and intracellular zinc accumulation may mediate multiple steps in the pathophysiology of Multiple Sclerosis, including matrix metalloproteinase 9 (MMP-9) activation, blood-brain barrier disruption, and subsequent immune cell infiltration in peripheral systems. Oral administration of zinc chelators TPEN and Clioquinol (CQ) decreased the blood-brain-barrier disruption, immune cell infiltration, and the destruction of myelin [x, x] in Multiple Sclerosis models. In the Multiple Sclerosis (experimental autoimmune encephalomyelitis EAE) animal model, vesicular zinc depletion showed protective effects on white matter damage and motor deficits by suppressing inflammation and demyelination in the spinal cord. Zinc chelation also decreased blood-brain-barrier disruption, immune cell infiltration, spinal white matter myelin destruction, MMP-9 activation, and the formation of aberrant synaptic zinc patches [x]. |
8. Regional Variability in the Distribution of MS
From 2013 to 2020, the estimated global prevalence of multiple sclerosis has increased to 2.8 million and has risen worldwide. with only 14% (11/81) of countries reporting either a decline or stabilization of prevalence [x]. As it is currently understood, multiple sclerosis is a disease caused by the interaction of genetic and environmental factors. Some chronic infections and living in ecologically hazardous areas are risk factors associated with the disease. Studies aimed at determining the ecological risk factors examine the effects of zinc, cadmium, lead, and copper on the progression of multiple sclerosis [x]
| The number of countries included a | 2013 prevalence per 100,000 population [95% CI] | 2020 prevalence per 100,000 population [95% CI] | Increase; absolute (%) |
| Global | 29.26 [29.21, 29.30] | 43.95 [43.90, 44.01] | 14.69 (50%) |
| African | 5.52 [5.41, 5.62] | 8.76 [8.64, 8.89] | 3.24 (59%) |
| Americas | 62.89 [62.72, 63.05] | 117.49 [117.27, 117.71] | 3.24 (59%) |
| E. Mediterranean | 23.91 [23.77, 24.04] | 33.00 [32.85, 33.15] | 9.09 (38%) |
| European | 108.25 [108.01, 108.49] | 142.81 [142.53, 143.08] | 34.56 (32%) |
| South East Asia | 5.44 [5.41, 5.48] | 8.62 [8.58, 8.66] | 3.18 (58%) |
| Western Pacific | 3.64 [3.61, 3.67] | 34.79 [4.75, 4.82] | 1.15 (32%) |
aOnly countries providing data for 2013 and 2020 editions of the Atlas of MS are included in the analysis.Global and WHO regional totals reported. Reported MS prevalence increased in every WHO region between the 2013 and 2020 versions of the Atlas of MS [x]
8.1 Regional Variability in the Distribution of MS in the United States
9. Occupational or Regional Factors of MS
While there are roughly 30 cases of Multiple Sclerosis per 100,000 individuals worldwide, there are clusters of MS that are statistically significant that may offer further clues into the disease.
Death rates from MS vary with social class, highest in social class IIIN (skilled non-manual) and lowest in social class II (intermediate). These different rates may be due to MS causing health-related occupational mobility [x]. Data has also indicated an association between multiple sclerosis and environmental factors, especially occupational exposure to solvents [x, x].
| Occupation | |
| Zinc-Related Manufacturing Plant | Eleven cases of MS occurred within 10 years in a zinc-related manufacturing plant. The observed disease incidence was greater than expected from population data, using multiple approaches to statistical analysis (p less than or equal to 0.01). The case-control study, performed to examine several zinc parameters in blood, failed to indicate specific abnormalities among MS patients. Still, all subjects (both MS and controls) working in the plant demonstrated higher serum zinc levels than all subjects (MS and controls) not working there [x]. |
| Nurses | In 1990, a cluster of multiple sclerosis (MS) patients was reported in 7 of 307 nurses in Key West, Florida [x]. In other words, 2.3% of the nurses in this group in 1990 had multiple sclerosis, when the prevalence in 1990 was 0.02% [20.8 of 100,000], representing an 11,400.00% increase from baseline. [x]. |
| Female Nurse Anaesthetists | Data from a register-based study found that the cumulative incidence rate ratio of MS in female teachers from middle and upper compulsory school levels was significantly greater relative to other occupations [x]. In the advent of dustless chalk, zinc oxide (ZnO) was used to give it its dustless property [x]. Data suggests trace element particulate matter affects classroom air quality and poses a health hazard to teachers [x]. |
| Leather Shoe Workers | The observation of many multiple sclerosis cases among shoe and leather workers prompted a survey of the risk of MS in this working population. In 1976, patients with MS were interviewed regarding their occupation at the onset of the disease. 5 of the 41 patients working at the time had worked in shoe leather factories. This survey indicates an increased risk of MS among shoe and leather workers. Organic solvents, contained in large quantities in the glues used, may be involved in the pathogenic mechanism of multiple sclerosis [x]. Flexible rubber is commonly used as a leather adhesive in shoe-making [x]. Adding zinc oxide to rubber compounds activates sulfur vulcanization and shortens the vulcanization time. In addition to its influence on the curing process, zinc oxide has numerous positive effects on the physical properties of rubber and is ubiquitous in rubber manufacturing [x]. |
| Teachers | Data from a register-based study found that the cumulative incidence rate ratio of MS in female teachers from middle and upper compulsory school levels was significantly greater relative to other occupations [x]. In the advent of dustless chalk, zinc oxide (ZnO) was used to give it its dustless property [x]. Data suggests trace element particulate matter affects the air quality in classrooms and poses a health hazard to teachers [x]. |
10. Multiple Sclerosis: Sticky Notes
Sticky notes are data points that are currently not well understood that require further investigation and hypothesis generation.
STICKY NOTES
The frequency of MS increases with latitudes in the Northern Hemisphere, and the reverse is found in the Southern Hemisphere. This data is not currently understood.
Analysis of data on the incidence of multiple sclerosis in different soil-climatic zones of Ukraine (steppe, forest-steppe, woodlands) in relation to the content of cobalt, boron, manganese, zinc, and molybdenum in arable lands led to the conclusion that inhabitants of semi-arid steppes are less likely to suffer from multiple sclerosis than individuals who inhabit more forested lands [x]. It has been hypothesized that the high-risk regions are associated with the local soil’s capacity to obtain and fix molybdenum over copper preferentially. This type of partitioning is prevalent in cool temperate zones [x].
STICKY NOTES
Vancomycin Antibiotic treatments modulate gut microbiota in animal models of Multiple Sclerosis. Vancomycin treatments administered 1 week before the induction of the animal model of Multiple Sclerosis significantly reduces disease scores [x].
The glycopeptide antibiotic vancomycin induces a zinc starvation response in bacteria by chelating zinc, highlighting this activity as a new biologically relevant chemical property of vancomycin [x] .
STICKY NOTES
Urinary tract infections (UTIs) are prevalent among patients with multiple sclerosis (MS) and are associated with an increased risk of morbidity and mortality [x], effecting 70-90% of MS patients [x].
A key feature of the host response to bacterial infections is activating strategies aimed at sequestrating transition metals, such as iron, zinc, and manganese, to starve microorganisms from nutrients essential for their growth [x]. Calprotectin is one such strategy and is an abundant protein that comes from leukocytes (white blood cells) that inhibits microbial growth by sequestering zinc and manganese ions at infection sites [x].
Studies investigating the prevalence of calprotectin levels in the cerebral spinal fluid of multiple sclerosis patients at the onset of symptoms found significant elevations relative to controls [x]. The ability of several pathogens to withstand the antimicrobial activity of calprotectin depends on their ability to produce metal transporters with a high affinity for zinc or manganese [x].
Proteus mirabilis (P. mirabilis) is a Gram-negative bacterium of the Enterobacteriaceae family, which are in disproportionately high abundance in the MS Microbiome signature [x]. Clinically, this organism is most frequently a pathogen of the urinary tract and is associated with pyelonephritis, particularly in patients undergoing long-term catheterization with nitrofurazone/silicone or latex catheters [x].
The zinc uptake of P. mirabilis contributes to motility and provides a competitive advantage in experimental urinary tract infections [x]. Further, genes associated with P. mirabilis include P-type ATPase zinc transporter and high-affinity zinc uptake system ATP-binding protein [x].
As previously mentioned, pseudomonas aeruginosa is another opportunistic pathogen known to cause severe urinary tract infections (UTIs) [x] and worsen MS symptoms. Like P. mirabilis, P. aeruginosa also acquires zinc via an ATP-binding cassette (ABC) permease containing ZnuA, a high-affinity, zinc-specific binding protein that does not affect other transient or essential metal ions [x].
In studies evaluating P. aeuroginosa, zinc eluted from siliconized urinary catheters resulted in Carbapenem resistance [x]. Clinically, human urinary copper content becomes elevated during urinary tract infections as a protective mechanism against pathogen colonization of the urinary tract [x].
This further underscores the potential role of copper and zinc in the pathogenicity of Multiple Sclerosis and the critical role that the Microbiome Signature of MS plays in finding targets for pharmacological and non-pharmacological interventions.
STICKY NOTES
Female gender is considered an independent risk factor for multiple sclerosis, at a commonly reported ratio of 4:1 over men. However, the gender gap has increasingly widened in the past 50 years.
In 1940 the female-to-male ratio of multiple sclerosis was 2:1, and 3:1 in 1980 [x]. Data also indicates that the ratio increased in all age groups, but there was a larger increase for younger ages at onset of the disease [x].
Trace quantities of heavy metals can be intentionally added to cosmetics or present as impurities in the raw materials. In a study evaluating the contamination of cosmetic products, zinc was detected in the range of 1.73–488.31 mg/kg in all samples, leading the study authors to conclude that control of heavy metals in lipsticks, powders, and other cosmetic products should be “seriously considered [x]” .
11. Final Thoughts
Though research into how changes in gut microbiota contribute to Multiple Sclerosis is still at an early stage, this is a promising area of investigation for future research. Microbiome studies continue to uncover new information about the human body, and this field will no doubt help us understand more about how devising therapies that target microbiome activity can alleviate, treat, or help us understand MS.
