Vitamin D & Probiotic Supplementation Halt the Progression of Multiple Sclerosis
Margo R. Flanagan
American College of Healthcare Sciences
Multiple Sclerosis is a chronic, incurable, neurologically debilitating disease of the central nervous system. Recent research shows dysbiosis of the gut microbiome and Vitamin D insufficiency are linked to the progression and onset of the disease. This paper assesses the ability of supplementation with probiotics and Vitamin D to halt the progression of Multiple Sclerosis.
Keywords: Vitamin D, Multiple Sclerosis, gut-brain axis, microbiome, microbiota, autoimmune disease
Multiple Sclerosis (MS) is a T-cell mediated, chronic, neurodegenerative disorder that’s pathogenesis causes destruction of the myelin sheath surrounding the axon of neurons in a process called inflammatory demyelination (Perez-Cerda, Gomes & Matute, 2016). As with many other autoimmune diseases, the etiology is unknown, the disease is incurable, medications typically are ineffective, it is progressively debilitating and the chronic inflammatory immune status destroys targeted healthy tissue. Factors contributing to disease onset include northern latitudes and subsequent vitamin D deficiency, birth month, antibiotic exposure, vaccinations, stress, smoking, alcohol abuse and obesity( Joscelyn & Kasper, 2014). Prevention of disease is the ultimate goal however preventing the onset necessitates a better understanding of the disease etiology.
It has long been established that humans and the bacteria that exist on and within the body have a symbiotic relationship. The existing microbes and their corresponding genes make up the “microbiome”. Emerging research and evidence links disruption of the normal gut microbiota (dysbiosis) with etiology of MS and other immune mediated inflammatory diseases (IMID) (Forbes, Domselaar & Bernstein, 2016). The gastrointestinal tract houses gut flora with genetic coding for immune function and immunomodulatory effects comprising 80% of the body’s immune system (Stetka, 2014). Probiotics, as defined by the World Health Organization are living micro-organisms that provide health benefits specifically for the digestive system when taken in appropriate amounts (Hemarajata & Versalovic, 2013). Probiotics affect intestinal immunity through mucin, beta-defensin and Immunoglobulin A production, proliferation and differentiation of immune and epithelial cells and stabilization of the microbial communities (Hemarajata & Versalovic, 2013).
The link between vitamin D deficiency and the onset of MS was suggested a few decades ago when it was noted that northern latitudes with less sunlight had a higher prevalence of MS. Vitamin D’s role in immune function has recently become an area of intense research in the hopes of developing treatment options and preventing disease onset (Jahromi et al, 2016).
This paper seeks to uncover research that shows repopulation of normal gut flora through the use of probiotics will repair the disruption of the microbiota and that the immunomodulatory effects of vitamin D supplementation and eubiosis can restore proper immune function and halt the disease progression of MS.
Classification of MS into four phenotypes based off of activity, progression and lesion development help establish an insight to disease state and possible treatment options. Relapsing-Remitting MS (RRMS) is the initial phenotype characterized by episodes of neurological attacks followed by remission (Perez-Cerda, Gomes & Matute, 2016) that accounts for 85% of all cases of MS (naturally-proven.com) with up to 70% transitioning into Secondary Progressive MS (SPMS) an advanced stage of RRMS (Perez-Cerda, Gomes & Matute, 2016). Primary Progressive MS (PPMS) cases do not have periods of relapse and remission as seen in RRMS, instead showing a steady decline in function from onset of disease (naturally-proven.com). Progressive/Relapsing MS (PRMS) affects 5% of those with MS and experience a steady deterioration with occasional attacks (naturally-proven.com). It is important to try and halt the progression of MS as there are virtually no treatment options once this stage of disease is reached.
A better understanding of the pathological processes that lead to MS disease progression will help to develop new treatments and may also prevent onset. Although the pathological processes that lead to destruction of the myelin sheath are not clear, the following hypotheses have been proposed.
• Outside-In Hypothesis: suggests the immune system becomes activated in the periphery and crosses the blood brain barrier resulting in neurodegeneration (Perez-Cerda, Sanchez-Gomez & Matute, 2016)
• Inside-Out Hypothesis: suggests inflammation occurs within the central nervous system at the site of the myelinating unit and deduces this is a degenerative rather than autoimmune process (Perez-Cerda, Sanchez-Gomez & Matute, 2016)
• Diet Microbiota Hypothesis: suggests that diet is the contributing factor to pathogenesis of autoimmunity and chronic diseases (Joscelyn & Kaspar, 2014). Fiber is fermented by gut microbes producing large amounts of short chain fatty acids (SCFAs) which play a vital role in the immunoregulation of B and T cells and macrophages (Joscelyn & Kaspar 2014) The low fiber intake in the Western diet changes the intestinal microbiota increasing Firmicutes phylum and decreasing Bacteroides (Joscelyn & Kaspar 2014).
• Molecular Mimicry Hypothesis: suggests that the body produces an antibody against a specific infectious agent that has a similar makeup to the protein of the myelin sheath (Joscelyn & Kaspar, 2014).
• Hygiene Hypothesis: suggests that the lack of childhood exposure to pathogens, infections and symbiotic microorganisms results in improper development of protective immunity (Joscelyn & Kaspar, 2014) Without normal functioning immunity, the risk for development and incidence of MS increases. Interleukin 10 is an anti-inflammatory cytokine that has the ability to regulate the immune system in response to an infection (Clemente, Ursell, Parfrey & Knight, 2012). Upregulation of IL-10 suppresses inflammation in a typical healthy immune system but is purported to have improper function in situations where the immune system has not been exposed to pathogens (Clemente, Ursell, Parfrey & Knight, 2012).
• Luminal Conversion Concept: suggests that diet effects the distribution of the dominant phyla, Bacteroides and Firmicutes within the gastrointestinal tract (Hemarajat & Versalovic, 2013). Germ-free mice subjected to the Western high fat/low fiber diet showed increased numbers of Firmicutes within a very short period of time and were able to return to normal state within a week of changing diet. Beneficial microbes in the gut, such as Bacteroides are able to break down sugars into SCFAs. SCFAs interact with the immune system, causing proliferation and production of immune supporting compounds such as mucosal immune cells and cytokines (Hemarajata & Versalovic, 2013). Without Bacteroides in high quantities, there is a decrease in SCFAs and subsequent immune dysfunction.
Vitamin D the Immunomodulator
Vitamin D deficiency is a risk factor for development of MS while high levels of Vitamin D at the time of the first incidence of demyelination indicate a lower risk (Simon, Munger & Ascherio, 2012). MS risk for children is lower if the mother had high levels of vitamin D while pregnant. Levels of Vitamin D in children of mothers with MS should be evaluated and supplemented if found to be low in order to reduce chance of onset (Jahromi et al., 2016).
When skin is exposed to the sun, vitamin D3 is produced and converted to 25-hydroxy-vitamin D3 and the bioactive, calcium and phosphorus regulating 1,25-dihydroxy-vitamin D3 (Yadav, Shinto & Bourdette, 2010). Further metabolism of 1,25-dihydroxy-vitamin D3 in the kidneys produces 1,25-dihydroxycholecalciferol-vitamin D2 (calcitriol) which mediates signaling and binding to the vitamin D receptor (VDR) (Alharbi, 2015). Functionality of the VDR and VDR polymorphism, specifically genotypes AA ApaI and FF FokI may interfere with increasing vitamin D plasma levels through supplementation (Jahromi et al., 2016). The genes CYP27B1 and CYP24A1 are involved in the metabolism of vitamin D and are believed to increase risk of MS by interfering with bioactive vitamin D (Alharbi, 2015). Food provides another source of vitamin D but exposure to the sun and conversion of vitamin D through the skin provides the highest levels of bioavailable hormone.
Vitamin D’s immunomodulatory functions include inhibiting production of Type 1 helper T cell cytokines, T and B cell proliferation, B cell differentiation, immunoglobulin secretion and surface expression of histocompatability complex II-complexed antigens which are mediators of inflammation and heightened immune response (Alharbi, 2015). Vitamin D modulates calcium hemostasis and gene expression exerting rapid cellular level responses (Alharbi,, 2015). Deficiency in Vitamin D causes an underproduction of regulatory T cells that help the immune system protect target tissues such as the myelin sheath (Alharbi, 2015).
Systematic reviews and studies showed decreased risk of MS for babies born in October and November and also with intake of fatty fish, 41% decreased risk for every 50 nmol/L increase of 25-hydroxy-vitamin D, 61% decreased risk for MS when serum levels of 25-hydroxy-vitamin D were >75 nmol/L, 41% lower incidence when intake of vitamin D was >400 IU/day and significant decreased risk with maternal intake of milk and dietary vitamin D during pregnancy (Alharbi, 2015).
Gut-Brain Axis and the Immune System
The gut, considered the 2nd brain with its layer of epithelium functions like the blood brain barrier keeping pathogens from entering the lymphatic and circulatory system (Joscelyn & Kaspar, 2014). Gut Associated Lymphoid Tissue (GALT) comprises 70% of the body’s lymph tissue and has multidirectional communication through metabolic, endocrine, neural and immune pathways (Joscelyn & Kaspar, 2014). Dysbiosis results in inflammation, altered immune function and perturbations in the communication system between the gut and brain (Hemarajata & Versalovic, 2013). Key mediators of inflammation are able to cross the blood brain barrier and are able to attack the myelin sheath.
Effect of Diet on the Gut
The increasing incidence of IMID and metabolic diseases seen after the Industrial Revolution point to antibiotics and vaccinations as the likely culprit but the most prominent change is the Western diet with its low fiber/high fat/high carbohydrate content (Joscelyn & Kaspar, 2014). Consumption of animal fat leads to dysbiosis of the gut flora and increases in the inflammatory mediators C-reactive protein and Tumor Necrosis Factor-alpha (Riccio, 2011) Gut permeability or “Leaky Gut Syndrome” occurs as a result of changes in mucosal wall of the intestines leading to production of IgA and IgG antibodies against gluten and increases in proinflammatory cytokines and endotoxin/lipopolysaccharides (Riccio, 2011). As the plasma levels of endotoxins and lipopolysaccharides increase so do the symptoms of MS (Riccio, 2011).
Probiotics and the gut
Probiotics are able to modulate the immune system of the gastrointestinal tract, reduce passage of bacteria through the intestinal mucosa, alter bacterial populations by suppressing growth of certain microbes and stabilize the microbial environment ( Hemarajata & Versalovic, 2013). Supplementation with probiotics will improve intestinal health and immune function.
A study performed on animals showed that probiotics were able to globally affect metabolic functions of the intestinal microbiome specifically carbohydrate metabolism (Hemarajata & Versalovic, 2013). This study correlates with the “Luminal Conversion Concept” and the importance of SCFAs in modulating immune function.
Levels of vitamin D play a large role in the immune function, onset and progression of MS. Proper function of VDR and genes responsible for metabolism of vitamin D into its active forms are necessary when supplementing with vitamin D for amelioration of symptoms. The best chance of decreasing risk of developing MS is to receive adequate amounts of bioactive vitamin D through sun exposure and to keep serum levels high by supplementing with food and vitamins.
Dysbiosis of the gut flora is known to cause endotoxin release from bacteria which in turn causes an inflammatory immune response and subsequent progression of disease state (Riccio et al., 2016). In order to thwart the mounting immune reaction, balance of the gut microbiota needs to be achieved through proper diet and repopulation of normal gut flora. A diet rich in polyphenols to increase antioxidants, carotenoids, plant fiber from fruits and vegetables, probiotics and vitamin D may bring about eubiosis leading to lowered inflammatory processes and amelioration of disease symptoms (Riccio, 2011).
Recommendations and Conclusions
• Prenatal testing should include a vitamin D level and supplementation provided for women living in northern latitudes or those at risk for onset of MS due to genetic factors.
• Levels of Vitamin D in children of mothers with MS should be evaluated and supplemented if found to be low in order to reduce chance of onset (Jahromi et al., 2016).
• Children at risk of developing MS can decrease their risk with appropriate sun exposure during childhood and teenage years.
• Dosing of Vitamin D supplementation needs to be evaluated and reviewed as the necessary amounts to be beneficial can cause hypercalcemia.
Diet has the largest impact on reducing the progression of disease symptoms of MS, improving immune status and decreasing chronic inflammation. Probiotics help to stabilize the microbial environment leading to better immune function overall. Increasing plant fiber that is able to break down into SCFAs along with supplementation probiotics and vitamin D will promote proliferation of anti inflammatory mediators.
Well designed clinical studies on the use of probiotics, vitamin D supplementation and a diet rich in compounds that promote intestinal health and a stable microbiome would be beneficial in determining direct impact on halting disease progression of MS.
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