In my last post we found that magnesium enhanced the growth of bifidobacteria and lactobacillus — two groups of bacteria that CFS patients are low in. The majority of PubMed studies found that it also improve symptoms. Yet magnesium levels were found to be normal in blood cells — which raise the issue of “selective rationing of minerals and vitamins to the most critical components”. The blood is far more critical to maintain magnesium levels than incidental bacteria in the gut. Often testing assumes that the body is naive and does not do selective rationing.

In this next re-examination of supplements shown to help CFS/FM/IBS, I will look at Vitamin D. I have written often about the need to take sufficients (Mythology of Vitamin D toxicity,  changes from increasing Vitamin D, Vitamin 25D and 1,25D). A few citations:

• “This study demonstrates for the first time a direct antiviral effect of vitamin D in an in vitro infectious virus production system.”[2011]
• “vitamin D is the environmental factor that most strongly influences autoimmune disease development.”[2015]
• “A significant negative correlation between vitamin D level and widespread pain index was found.”[2012] i.e. FM
• Serum 25-Hydroxyvitamin D3 and BAFF Levels Are Associated with Disease Activity in Primary Sjogren’s Syndrome [2017].  “Female SS patients had significantly lower vit D levels  than controls” [2015]
• “Our findings showed that the high-dose supplementation of vitamin D[9 of 50000 IU cholecalciferol capsules for 3 months taken at weekly intervals] affects measures of systemic inflammation: reductions in High-Sensitivity C-Reactive Protein level and Neutrophil-to-lymphocyte ratio (NLR) distribution.” [2017]
  • “The results of the meta-analysis of 10 trials involving a total of 924 participants showed that vitamin D supplementation significantly decreased the circulating hs-CRP level by 1.08 mg/L” [2014]

A longer quote from this year is beneficial

“Vitamin D was first discovered as the curative agent for nutritional c, and its classical actions are associated with calcium absorption and bone health. However, vitamin D exhibits a number of extra-skeletal effects, particularly in innate immunity. Notably, it stimulates production of pattern recognition receptors, anti-microbial peptides, and cytokines, which are at the forefront of innate immune responses. They play a role in sensing the microbiota, in preventing excessive bacterial overgrowth, and complement the actions of vitamin D signaling in enhancing intestinal barrier function. Vitamin D also favours tolerogenic rather than inflammogenic T cell differentiation and function. Compromised innate immune function and overactive adaptive immunity, as well as defective intestinal barrier function, have been associated with IBD. Importantly, observational and intervention studies support a beneficial role of vitamin D supplementation in patients with Crohn’s disease, a form of IBD. This review summarizes the effects of vitamin D signaling on barrier integrity and innate and adaptive immunity in the gut, as well as on microbial load and composition. Collectively, studies to date reveal that vitamin D signaling has widespread effects on gut homeostasis, and provide a mechanistic basis for potential therapeutic benefit of vitamin D supplementation in IBD.” [2017]

Now for some interesting links:

• Oral supplementation with probiotic L. reuteri NCIMB 30242 increases mean circulating 25-hydroxyvitamin D: a post hoc analysis of a randomized controlled trial.  L.Reuteri is low in CFS patients, thus a decrease would be expected.
• Vitamin D Promotes Pneumococcal Killing and Modulates Inflammatory Responses in Primary Human Neutrophils [2017].
• “Vitamin D intake .. Prevotella was more abundant .., while Haemophilus and Veillonella were less abundant … and abundances of Coprococcus  and Bifdobacterium … were inversely correlated with 25(OH)D.”[2017] in other words, Vitamin D alters the microbiome.
• “As a result of these effects on the intestinal mucosa, maintenance of sufficient vitamin D status may be essential for the development of a healthy gut microbiota, particularly in conditions defined by chronic mucosal inflammation such as CF…additional evidence is needed to establish vitamin D as a therapeutic approach for gut microbiota modification.” [2016]
• Vitamin D deficiency changes the intestinal microbiome reducing B vitamin production in the gut. The resulting lack of pantothenic acid adversely affects the immune system, producing a “pro-inflammatory” state associated with atherosclerosis and autoimmunity[2016]. “1) Seasonal fluctuations in vitamin D levels have normally produced changes in the intestinal microbiome that promoted weight gain in winter. Years of vitamin D deficiency, however, results in a permanently altered intestinal environment that no longer favors the “healthy foursome”. 2) Humans have always had a commensal relationship with their intestinal microbiome. We supplied them vitamin D, they supplied us B vitamins. 3) The four species that make up the normal microbiome are also commensal, each excretes at least one B vitamin that the other three need but cannot make. 4) Improved sleep and more cellular repairs eventually depletes body stores of pantothenic acid, causing reduced cortisol production, increased arthritic pain and widespread “pro-inflammatory” effects on the immune system. 5) Pantothenic acid deficiency also decreases available acetylcholine, the neurotransmitter used by the parasympathetic nervous system.”

Bottom Line

The understanding of what Vitamin D does have changed over the last decades. Originally, it was know to cure rickets (and the recommended dosage became some 50 Iu/day), then it impacted bone loss and the dosage increased.  Today, we find that it is implicated in many areas, impacting the distribution of bacteria in the microbiome, and needed for a healthy gut microbiota.

The biggest problem is that MDs are often behind the times and do not work from the latest literature.  For example a single dosage of 600,000 IU of vitamin D is deemed safe on medscape, or 10,000 IU/day for months [source]. One of the studies above cited an average of 60,000 IU/day for 3 months!  [2017]

I wrote about Magnesium and Malate acid back in 2012. There are sites that takes you thru the pros and cons of different magnesiums such as MAGNESIUM SUPPLEMENTS: DIFFERENT TYPES & DIFFERENT BENEFITS. I wish to do a short revisit by looking only at the pH of each because a hypothesis suggests that those having a higher pH (more alkaline) would likely have additional impact beyond just the magnesium.

• Magnesium Gylcinate  9 – 11 [source] – $1.50/gram
• Magnesium Oxide – 11.2   $ 0.02 /gram
• Magnesium Citrate –  4.0 [source] [source]  $0.85/gram
• Magnesium Malate – 7 – 11 [source]  $0.05/gram
• Magnesium Taurate – 9-10 [source]  $1.00 /gram
• Magnesium Threonate  -5.8 – 7 [source]  $ 0.50 /gram
• Magnesium Carbonate – 10.41   $0.02 /gram
• Magnesium Hydroxide (Milk of Magnesia) –  10.5  [source] $0.03/gram

There are three dimensions to consider:

• Ability for magnesium to get absorbed (instead of just passing thru) — see link at top
• pH of the product (more pH is usually better)
• cost of the product.

Importance of Magnesium

• “Low intake of omega-3 fatty acids, vitamin B6, magnesium, zinc and antioxidants may also play a supporting role in symptom occurrence.” [2016]
• “This pilot study suggests that transdermal magnesium chloride applied on upper and lower limbs may be beneficial to patients with fibromyalgia.” [2015]
• “The number of tender points, tender point index, FIQ and Beck depression scores decreased significantly with the magnesium citrate treatment. The combined amitriptyline + magnesium citrate treatment proved effective on all parameters except numbness. Low magnesium levels in the erythrocyte might be an etiologic factor on fibromyalgia symptoms.” [2013]
• Women with fibromyalgia have lower levels of calcium, magnesium, iron and manganese in hair mineral analysis [2011].
• The relationship between serum antioxidant vitamins, magnesium levels, and clinical parameters in patients with primary fibromyalgia syndrome [2011].
• “Magnesium sulphate, a substance known to cause release of cholecystokinin (CCK) from the small intestinal mucosa, was given by mouth (dose 0.1g/kg in 150 ml water) to 20 patients with the irritable bowel syndrome. …These findings provide further evidence that ;functional’ abdominal pain after food may in some cases be related to an exaggerated intestinal motor response to cholecystokinin.” [1973]
• “The diet of IBS patients was found to consist of a low calcium, magnesium, phosphorus, vitamin B2 and vitamin A content.” [2012]
• Magnesium deficit in a sample of the Belgian population presenting with chronic fatigue [1997].
• “[Chronic Fatigue] Patients treated with magnesium claimed to have improved energy levels, better emotional state, and less pain, as judged by changes in the Nottingham health profile. 12 of the 15 treated patients said that they had benefited from treatment, and in 7 patients energy score improved” [1991]
• Cognitive behaviour therapy for the chronic fatigue syndrome. Evening primrose oil and magnesium have been shown to be effective [1996].
• “magnesium was demonstrated effective on ME/CFS patients’ symptom profiles.” [2012]
• [A case of chronic fatigue syndrome who showed a beneficial effect by intravenous administration of magnesium sulphate] [1992].
• Magnesium status and parameters of the oxidant-antioxidant balance in patients with chronic fatigue: effects of supplementation with magnesium [2000]. “Mg supplementation was followed by an improvement in Mg body stores, in serum vitamin E and its interrelated stage of lipid peroxidation.”
• “Magnesium (p = .002) and support groups (p = .06) were strongly associated with fatigue worsening from 6 months to 2 years.” [2005]
• “Red blood cell magnesium concentrations were measured in samples from 89 patients who fulfilled the diagnostic criteria for chronic fatigue syndrome and the results compared to those found in an age and sex matched group selected from the normal population. No significant difference was found. … There is therefore no indication for the use of magnesium therapy in the management of this condition.” [1994] – note that was confined to red cell analysis only.
• Chronic fatigue syndrome and chronic primary magnesium deficiency (CFS and CPMD) [1992].

Microbiome Dimension

• Changes in intestinal bifidobacteria levels are associated with the inflammatory response in magnesium-deficient mice [2010]. Mg+ and Mg- below indicate deficient or increased. After 4 days, both bifido and lactobacillus increased.
  
• “We conclude that calcium and magnesium fluxes play an important role in the physiology of the bifidobacteria and that several metal growth inhibitors interfere with iron metabolism.” [1984]
• Mg improves the thermotolerance of probiotic Lactobacillus rhamnosus GG, Lactobacillus casei Zhang and Lactobacillus plantarum P-8 [2017].
• Mn(2+) and Mg(2+) synergistically enhanced lactic acid production by Lactobacillus rhamnosus FTDC 8313 via affecting different stages of the hexose monophosphate pathway [2014].
• “Nutritional requirements of Lactobacillus delbrueckii subsp. lactis in a chemically defined medium[2004]. “Magnesium was the only essential oligoelement.”

pH factor

Optimal pH for Bifidobacterium bifidum is 7.0 [source] with other sources saying 6.5 – 7.0. Stomach acid is around 1.0-3.0.  This raise the question whether it may be good to take you bifidobacteria with magnesium instead of at a separate time..

From National Institute of Health site:

• “Diets with higher amounts of magnesium are associated with a significantly lower risk of diabetes,”
• “People who experience migraine headaches have lower levels of serum and tissue magnesium than those who do not.”
• ” taking 300 mg magnesium twice a day, either alone or in combination with medication, can prevent migraines”
• “Forms of magnesium most commonly reported to cause diarrhea include magnesium carbonate, chloride, gluconate, and oxide [11].”

Bottom Line

Magnesium impact on CFS etc may be because it encourages the growth of Lactobacillus and Bifidobacteria

Magnesium oxide/Magnesium Hydroxide are cited as less bioavailable. My conclusions today are still the same as in 2012, Magnesium Malate is the best bang for the buck (and bucks are always sparse for CFS patients!). Dosage should be determined by your MD, the literature indicated that 5000 mg/day can create problems with the young and the elderly, I would question more than 1000 mg/day and suggest that 600 mg/day (used to treat another condition successfully) may be warranted.

Note: Magnesium Malate tablets cited as 1250 mg is not 1250 mg of magnesium, just 425mg for three 1250mg tablets. That is  140 mg or magnesium per tablet, so 7 tablets of 1250mg per day would be needed to reach 1000 mg/day.

A very common mistake that CFS patients make in their brain fog is thinking that their dosage are sufficient. “Yes, I am taking Magnesium — it is in my multivitamin!” (Looking at Centrum multivitamins, I see there is 64 mg, approximately 1/10 of what may be needed to do corrective action for low magnesium).

As always, start with a low dosage and slowly work up.

THIS IS NOT MEDICAL ADVICE — this post is an education summary of what has been reported on PubMed. Always consult with a knowledgeable medical professional before changing diet, supplements and prescription drugs.

Some CFS patients have been found to have high glutamate levels.  There are two possibilities:

• Bacteria or infections producing too much
• Bacteria that normally consumes it are missing — this I suspect is the more common cause of high levels in CFS.

Glutamate pathways are reported impacted in CFS [2017].

• “These findings suggest that dietary glutamate may be contributing to FM symptoms in some patients.” [2012]
• “patients with FM showed higher levels of glutamate/glutamine (Glx) compounds” [2010]
• “CSF concentrations of substance P and glutamate have been repeatedly found to be increased in fibromyalgia patients [32–34].” [2012]

Now we hit the interesting part of this issue:

• “GI-tract-abundant Gram-positive facultative anaerobic or microaerophilic Lactobacillus, and other Bifidobacterium (Actinobacteria) species such as Lactobacillus brevis and Bifidobacterium dentium are capable of metabolizing glutamate to produce gamma-amino butyric acid (GABA),” [2014] [2012]
• “The results revealed that 10 isolates, i.e., Lactobacillus buchneri (2 isolates), Lactobacillus brevis (6 isolates), and Weissella hellenica (2 isolates) had a high GABA–producing ability” out of 53 tested from Japanese foods: aburazushi, narezushi, konkazuke, and ishiru [2016]  10/53 or 19%
• “In this paper, we screened our collection of 135 human-derived Lactobacillus and Bifidobacterium strains for their ability to produce GABA from its precursor monosodium glutamate. Fifty eight [58] strains were able to produce GABA. The most efficient GABA-producers were Bifidobacterium strains (up to 6 g/L)….The genes were found in the following genera of bacteria: Bacteroidetes (Bacteroides, Parabacteroides, Alistipes, Odoribacter, Prevotella), Proteobacterium (Esherichia), Firmicutes (Enterococcus), Actinobacteria (Bifidobacterium). These data indicate that gad genes as well as the ability to produce GABA are widely distributed among lactobacilli and bifidobacteria (mainly in L. plantarum, L. brevis, B. adolescentis, B. angulatum, B. dentium) and other gut-derived bacterial species.” [2016] 58/135 = 43% 

GABA Link

“GABA metabolism is dependent on the activity of three enzymes: glutamic acid decarboxylase, GABA-transaminase and succinic semialdehyde dehydrogenase. Decreased activity of these enzymes may cause many neurological syndromes, such as stiff-person syndrome, chronic fatigue syndrome, anxiety disorders and seizures.” [2007]

Bottom Line

Given any random bifidobacteria or lactobacillus strain, the possibility of it producing GABA from glutamate appears to be between 19% and 43%. The best odds are for

• L. plantarum,
• L. brevis,
• B. adolescentis,
• B. angulatum,
• B. dentium

Given the low levels of bifidobacteria, lactobacillus and E.Coli seen in CFS patients, a high level of glutamate would be expected. It would not effect all because these are not the sole consumers of glutamate.

This model gives a concrete biological process accounting for this shifts seen.

I forwarded an article “Common diabetes drug may work by changing gut bacteria, study finds”  to a reader and he responded:

• “This is fascinating Ken, thank you. I belong to untold numbers of CFS and Lyme Facebook groups, newsletters, forums, etc. Many of them talk of Metformin as being the biggest and best “new thing” out there for treatment. Once again it seems that all roads lead to the microbiome…”

I am opposed to trying random “new things” but very much in favor of trying “new things” that the model that you are using would predict to help.  With the microbiome model, I have had a very good batting average 🙂 .

What do we know about Metformin?

• Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug [2017]. [Full Text]
  • “Earlier studies have shown an association between metformin
    and the abundance of Akkermansia muciniphila and between
    A. muciniphila and improved metabolic features in mice and humans” Very Good! See this post on Akkermansia and this post on Chronic Lyme Microbiome.
  • “After correction for FDR, we found that the PTR of only one bacterial species (Bifidobacterium adolescentis) was significantly increased by metformin”
• Metformin Is Associated With Higher Relative Abundance of Mucin-Degrading Akkermansia muciniphila and Several Short-Chain Fatty Acid-Producing Microbiota in the Gut [2017].
• “Akkermansia muciniphila (12.44%±5.26%) and Clostridium cocleatum (0.10%±0.09%) abundances increased significantly after metformin treatment” [2014]

Bottom Line

The known shifts for metformin appear to be beneficial for CFS/Lyme patients with no reported negative shifts. I suspect that it will likely improve some subset of symptoms (which ones are unknown). It would be nice to see a formal study done and published for CFS/FM/IBS.

It is reported to have some side effects:

“Metformin can rarely cause a serious (sometimes fatal) condition called lactic acidosis. Stop taking metformin and get medical help right away if you develop any of the following symptoms of lactic acidosis: unusual tiredness, dizziness, severe drowsiness, chills, blue/cold skin, muscle pain, fast/difficult breathing, slow/irregular heartbeat, stomach pain with nausea, vomiting, or diarrhea.” — of course, lactic acidosis is suspected to be a significant part of CFS…

On Facebook, a reader wrote ” I took metformin xr for my diabetes and it ripped me up!! Killed me with my IBS, to the point that I had to stop taking it.“

I have mentioned VSL#3 probiotic is passing but have not done an explicit review. I know that it is heavily promoted directly to MDs. In terms of readers’ experience…

• “taking VSL#3 (I hadn’t discovered your website yet).  I switched over to Prescript Assist, and it hasn’t even been a week yet, and yesterday, for the first time in 6 months I went for a 2 mile walk/jog around my neighborhood.  My mono symptoms have disappeared.” [2017]

So what is known about VSL#3 from clinical studies ideally. There are 250+ citations on PubMed, so it is well studied. It is helpful for some conditions and many MDs will suggest it blindly for any issue dealing with the microbiome or digestion.

Not Specific to CFS/IBS/FM

• The Probiotic Compound VSL#3 Modulates Mucosal, Peripheral, and Systemic Immunity Following Murine Broad-Spectrum Antibiotic Treatment [2017].
• Amelioration of intestinal and systemic sequelae of murine Campylobacter jejuni infection by probiotic VSL#3 treatment [2017].
• Possible determinants of VSL#3 probiotic failure in preventing gastrointestinal adverse events associated with dacomitinib in patients with advanced non-small-cell lung cancer enrolled in ARCHER-1042 trial [2016].
• Unexpected improvement in core autism spectrum disorder symptoms after long-term treatment with probiotics [2016]. – single patient
• Probiotic mix VSL#3 is effective adjunctive therapy for mild to moderately active ulcerative colitis: a meta-analysis[2014]. By itself, not significant effect.
• Oral Probiotic VSL#3 Prevents Autoimmune Diabetes by Modulating Microbiota and Promoting Indoleamine 2,3-Dioxygenase-Enriched Tolerogenic Intestinal Environment[2016]. From which I found the chart below. By itself, only a minor effect — but when combined with RA is retinoic acid, a major shift

• Gut microbial diversity is reduced by the probiotic VSL#3 and correlates with decreased TNBS-induced colitis [2011].

Relevant Studies

Research Double Speak:  “Improvement” – may mean that there is only a 2% improvement, shown by statistical analysis which is often indicated by the use of the word “significantly“.

• Probiotics for Irritable Bowel Syndrome: Clinical Data in Children. ” concluded that Lactobacillus GG, Lactobacillus reuteri DSM 17938 and VSL#3 significantly increased treatment success. We recently showed that, in children with IBS, a mixture of Bifidobacterium infantis M-63®, breve M-16V® and longum BB536® is safe and is associated with better AP control and improved quality of life when compared to placebo.” –
• ” clinical trials in children showed an improvement in abdominal pain for Lactobacillus GG, Lactobacillus reuteri DSM 17938, and the probiotic mixture VSL#3. The patients most benefiting from probiotics were those with predominant diarrhea or with a post-infectious IBS.” [2014]
• “Before therapy, intestinal microbiota of IBS subjects differed significantly from that of healthy controls, with less diversity and evenness than controls (n = 9; P < 0.05), increased abundance of Bacteroidetes (P = 0.014) and Synegitestes (P = 0.017), and reduced abundance of Actinobacteria (P = 0.004). The classes Flavobacteria (P = 0.028) and Epsilonproteobacteria (P = 0.017) were less enriched in IBS. Abundance differences were largely consistent from the phylum to genus level. Probiotic treatment in IBS patients was associated with a significant reduction of the genus Bacteroides (all taxonomy levels; P < 0.05) to levels similar to that of controls." [ [2013] The genus bacteroides improved, but not Actinobacteria, Synegistetes, or Epsilonproteobacteria. Flavobacteria was low, and article implies that it went lower.
• Gut microbiota is not modified by Randomized, Double-blind, Placebo-controlled Trial of VSL#3 in Diarrhea-predominant Irritable Bowel Syndrome [2011].
• Does VSL#3 really improve symptoms in children with IBS? [2012] – summarizes some major problems with how earlier studies were done.
• “A randomized controlled trial of a probiotic combination VSL# 3 and placebo in irritable bowel syndrome with bloating[2005]. “VSL# 3 reduces flatulence scores and retards colonic transit without altering bowel function in patients with IBS and bloating.”

No studies with SIBO, Chronic Fatigue Syndrome or Fibromyalgia.

Bottom Line

There is low value (and high costs) to taking VSL#3 for IBS/FM/CFS/SIBO.  While it does reduce one of the groups of bacteria — it does not impact other significant groups.  I greatly favor taking Prescript Assist or General Biotics Equilibrium as a better choice than VSL#3.

• “Conclusion. The probiotic formula[5 g of VSL#3 twice daily] when taken orally over the 12-week period did not significantly alter the microbiota measured in this population. ” [2016]
• VSL#3 Persistance
  “Streptococcal population was detected after 3 days of administration and persisted for 6 days after the treatment suspension.” [2003] — No part of it was detected after a week. It’s benefit requires constant taking.

The use of retinoic acid with probiotics is an interesting aspect.

• “Epithelial cells have also been shown to metabolize vitamin A into retinoic acid (RA) (2)”

On a naive level, it suggests that taking Vitamin A with probiotics may be beneficial — but this is strictly speculation.