While researching this post, I found a 2015 study where the microbiome of healthy controls were significantly altered by consuming a liter of mineral water each day. This was unexpected, but in reflection totally reasonable. The minerals in the water would likely have significant impact on some bacteria.

• “Additionally, microbiomeanalysis demonstrated that composition of lean-inducible bacteria was increased after bicarbonate-rich mineral water consumption. Our results suggested that consumption of BMW has the possible potential to prevent and/or improve type 2 diabetes through the alterations of host metabolism and gut microbiotacomposition.” [2015]

While I was shopping today, I tried some mineral water (Gerolsteiner from Germany) and found that my body responded strongly (feeling good/better) after 8 oz. I selected this brand at the co-op because it listed the contents, the level of bicarbonate was below that of the water used in the study, but it is at the top of the brands available in the US.

This post is for anyone else that is intrigued about the use of mineral water. Dosage is always important — in talking with people about the positive results of Vitamin B1, I found most people were taking lower dosages than the threshold to see results in the study that I cited (i.e. 1500 mg/day). Yes, “Vitamin B1 had no effect” because the dosage was too low (which the study reported too!). For mineral water, it is important to see how any supplier compare to the study cited above. For example, with Acquaua Panna, you would need to drink 18 liters of water a day!

If you have an Android phone, there is a sweet application available https://play.google.com/store/apps/details?id=de.gerolsteiner.meinwasser that provide over 500 waters.

The following is a report using the common mineral waters in the US, and an “electrolyte water” which many would believe is equivalent. They are not. Gerolsteiner  looks by far to be the closest to the water used in the study.

• “Among the natural mineral waters available on the market, only a few feature the optimum calcium-magnesium proportion (2:1).” [2016]

Mineral Supplements Help with CFS

I believe that minerals already dissolved in water is more easily absorbed than mineral supplements. Part of this is basic chemistry — stomach pH and volume of liquid determines how much gets dissolved and how fast. If the minerals are already in solution, then they can be readily absorbed with the water without any additional processing.

• “This study is only the second study done on multivitamin mineral supplementation in CFS that used both biochemical and subjective markers of treatment success…Treatment with a vitamin and mineral supplement could be a safe and easy way to improve symptoms and quality of life in patients with CFS.”[2014]

Further Readings

• http://www.dailymail.co.uk/health/article-17725/Which-water-gives-best-minerals.html
• http://www.quickanddirtytips.com/health-fitness/healthy-eating/is-mineral-water-good-for-you

My last post dealt with a patient with both diabetes and CFS.  There are likely more patients with that combination. Today, I am going to try to assemble what I can from PubMed on diabetes and the microbiome (without CFS — I suspect studies of that combination are none existent). This is an area of growing interest in the last few years:

• 
• “Oral microbiota is also correlated with many systemic diseases, including cancer, diabetes mellitus, rheumatoid arthritis, cardiovascular diseases, and preterm birth. ” [2015]  See  Oral Probiotics post as well an hydrogen peroxide, etc mouth rinses
  • Typically, I waterpic my teeth at night, rinse with a germ killing mouth wash and then go to sleep with a oral probiotic in the mouth…
• “The co-occurrence of the three disease entities, inflammatory bowel disease (IBD), colorectal cancer (CRC), type 2 diabetes mellitus (T2DM) along with inflammation and dismicrobism has been frequently reported.” [2015]
• “Type 2 diabetes (T2D) is associated with dysbiosis of the gut microbiota, though diabetes treatment regimens, including metformin, may confound the results.” [2016]
• “The present analysis showed, for the first time, a limited association between Functional gastrointestinal disorders and T2D risk in a large prospective cohort, and supports the hypothesis of a relationship between gastrointestinal function and diabetes” [2015]
• Clostridium butyricum attenuates cerebral ischemia/reperfusion injury in diabetic mice via modulation of gut microbiota. [2016] – thumbs up for Miyarisan!
• ” L. brevis DPC 6108 attenuated hyperglycaemia induced by diabetes” [2016]
• “S. aureus was isolated in 72 % of culture-positive samples, whereas the most commonly detected bacteria in all ulcers were Peptoniphilus spp., Anaerococcus spp. and Corynebacterium spp., with the addition of Staphylococcus spp. in new ulcers.”[diabetic foot ulcers, 2016]
• “We found changes both in composition and in function of the sub-clinical gut microbiome, including a decrease in Akkermansia muciniphila suggesting a role prior to the onset of [diabetes] disease,” [2016]
• “. Additionally, microbiomeanalysis demonstrated that composition of lean-inducible bacteria was increased after bicarbonate-rich mineral water consumption. Our results suggested that consumption of BMW has the possible potential to prevent and/or improve type 2 diabetes through the alterations of host metabolism and gut microbiota composition.” [2015]
• “The five most abundant phyla identified were: Bacteroidetes, Firmicutes, Proteobacteria, Verrucomicrobia, and Actinobacteria. Class Chloracido bacteria was increased in preDM compared to T2DM (p = 0.04). An unknown genus from family Pseudonocardiaceae was significantly present in preDM group compared to the others (p = 0.04). Genus Collinsella, and an unknown genus belonging to familyEnterobacteriaceae were both found to be” [2015]
• ” The gut microbiota in individuals with preclinical Type 1 diabetes mellitus is characterized by Bacteroidetes dominating at the phylum level, a dearth of butyrate-producing bacteria, reduced bacterial and functional diversity and low community stability.” [2016]
• Gut microbiota: Antidiabetic drug treatment confounds gut dysbiosis associated with type 2diabetes mellitus. [2016]
• “Specifically, lower stool Bacteroidaceae, Clostridiales XIV, Lachnospiraceae, Ruminococcacae and higher Enterococcaceae and Enterobacteriaceae were seen in hospitalized patients.” [2015]
• ” We provide support for microbial mediation of the therapeutic effects of metformin through short-chain fatty acid production, as well as for potential microbiota-mediated mechanisms behind known intestinal adverse effects in the form of a relative increase in abundance of Escherichia species. Controlling for metformin treatment, we report a unified signature of gut microbiome shifts in T2D with a depletion of butyrate-producing taxa. These in turn cause functional microbiome shifts, in part alleviated by metformin-induced changes. Overall, the present study emphasizes the need to disentangle gut microbiota signatures of specific human diseases from those of medication.” [2015] again Miyarisan is implied.
• ” Microbiota in the samples was predominantly represented by Firmicutes, in a less degree by Bacteroidetes. Blautia was a dominant genus in all samples. The representation of Blautia, Serratia was lower in preD than in T2D patients, and even lower in those with normal glucose tolerance.”[2016] Blautia was formerly part of Ruminococcus until DNA analysis found that they were different see this 2008 article or this 2013 PDF

Take Aways

The most interesting take-away was the use of bicarbonate-rich mineral water. This is actual clinical study confirmation of the health-loosing aspect of using soft water (see this post). The details of the water (from Japan) (Bicarbonate ion, 2485 mg/kg (i.e. per litter) – roughly 100x higher than in tap water. Second, CFS/FM/IBS has an increase diabetes risk (and likely also cancer risk – the latter may be connected with low Vitamin D levels). Third, the typical medication used for diabetes increases E.Coli and alters the microbiome, but not necessarily the right strains.

Last, there appear to be specific families (for example Blautia) that may be strongly associated with diabetes risk.

In today’s email I got this comment on my older post on Lactobacillus Acidophilus:

“When I eat alkaline vegetables (which are most vegetables), my urine smells badly of bacteria, like a dirty urinal, I get bladder discomfort and I constantly have to urinate (almost to the point of incontinence). Taking apple cider vinegar alleviates the situation but I have to stop eating veggies. Thus it’s been hard for me to take probiotics while eating a diet diverse in plant fiber …. It’s really frustrating because it seems impossible for me to do a probiotic regimen without lactobacillus….My CFS became really bad years ago after a high dosage of Levaquin so maybe I have some crazy dysbiosis. What do you think?”

I will not give advice of what to do — I am willing to assemble notes from my usual resources (which is hard to do for the brain fogged). I will attempt to create a model that fits the information.

Any conclusions from my notes should be discussed with your knowledgeable medical professional before starting.

Input Data

Simple question: What bacteria may be involved?

• Levaquin (levofloxacin) is a fluoroquinolones [see this earlier post]
  • Not effective against Staphylococcus aureus, bifidobacterium
  • Effective against some E. Coli (per wikipedia)
  • Effective against Lactobacillus
  • greater activity towards Gram-positive bacteria( but lesser activity toward Gram-negative bacteria
• Urine smell,
  • “The presence of bacteria in the urine, such as with a urinary tract infection (UTI), can affect the appearance and smell of urine. When there is an infection in the urinary tract, the urine may take on a foul-smelling odor as well as appear cloudy or bloody.” [medicinenet]
  • “The E. coli strains causing recurrent UTI were identified in the periurethra of at least 75% of the women and in the urine of at least 35% 1 week prior to the onset of a new UTI.” [2007]

Possible Model

The Levaquin killed off what was left of good E.Coli and you happen to have antibiotic resistant bad E.Coli. When you eat green vegetables, you are providing sulfoquinovose   (see this post), which the bad bacteria thank you for and quickly multiple. Vinegar does inhibit pathogenic E.Coli [1998]. This same study found that vinegar and salt worked better than vinegar alone (hmmm…. Salt and vinegar — just add fish and chips 😉 .  Glucose reduced the effectiveness of vinegar.

Possible Approach

There are two ways of fighting E.Coli — antibiotics to kill it, or E.Coli probiotics to displace the bad E.Coli. I strongly favor the latter — the reader had tried various probiotics but did not list any of the following in the list:

• Symbioflor-2 : 6 E.Coli strains, one of which is documented to colonize and last for many weeks after a single dose.
  • There have been no studies on it’s impact on UTI
• Mutafor – E.Coli Nissle 1917. There are several studies on PubMed
• Miyarisan – Clostridium butyricum
  • “t dietary supplementation with C. butyricum promotes immune response, improves intestinal barrier function, and digestive enzyme activities in broiler chickens challenged with E. coli K88. There is no significant difference between the C. butyricum probiotic treatment and the colistin sulfate antibiotic treatment.” [2016] [2014]
  • Ability of Clostridium butyricum to inhibit Escherichia coli-induced apoptosis in chicken embryo intestinal cells. [2012]

Now, Lactobacillus also inhibits E.Coli.

The apparent issue is that you can control the bad E.Coli with Lactobacillus. The challenge of needing to replace them with good E.Coli. You can kill off some of the bad E.Coli with antibiotics, but there are two issues to consider:

• antibiotic resistant E.Coli
• what will replace them

Going the route of good E.Coli probiotics overwhelming them seem a better approach. First, use Miyarisan in increasingly large dosages (watch out for herx!) and then stopping, and 24 hrs later start with Symbioflor-2, again ramping off the dosage.

Further readings:

Effects of antibiotics on bacterial species composition and metabolic activities in chemostats containing defined populations of human gut microorganisms.[2013] – full text

A reader emailed me “Can you do a PubMed breakdown of CoQ10 and how it might relate to gut bacteria? I’m struggling so much with energy, but things that are supposed to give me energy like Coq10, pretty much all the B vitamins, etc. often make me drowsy and spacey. Any thoughts?”

As a preamble: Many things have been found low in CFS which leads to an inference that supplementation of the low items could help. This happens sometimes, but more often it has little impact — often because of “co-factors” or some other process not being there. Studies finding low levels are not included, rather studies that tried supplementation..

First, the known results from studies on PubMed.

• Effect of coenzyme Q₁₀ plus nicotinamide adenine dinucleotide supplementation on maximum heart rate after exercise testing in chronic fatigue syndrome – A randomized, controlled, double-blind trial.[2015] “The CoQ₁₀ plus NADH group showed a significant reduction in max Heart Rate during a cycle ergometer test at week 8 versus baseline (P = 0.022). Perception of fatigue also showed a decrease through all follow-up visits in active group versus placebo (P = 0.03). However, pain and sleep did not improve in the active group.”
• Does oral coenzyme Q10 plus NADH supplementation improve fatigue and biochemical parameters in chronic fatigue syndrome? [2015] “oralCoQ10 (200 mg/day) plus NADH (20 mg/day)..  A significant improvement of fatigue showing a reduction in fatigue impact scale total score … could confer potential therapeutic benefits on fatigue and biochemical parameters” — remember the word “significant” can mean a very very small change on average….
• “76 ME/CFS patients with initially abnormal autoimmune responses were treated with care-as-usual, including nutraceuticals with anti-IO&NS effects (NAIOS), such as L-carnitine, coenzyme Q10, taurine + lipoic acid, with or without curcumine + quercitine or N-acetyl-cysteine, zinc + glutamine. …. Although hypernitrosylation and nitrosative stress play a role in ME/CFS, reductions in these pathways are not associated with lowered severity of illness.”
• “Coenzyme Q10 deficiency in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is related to fatigue, autonomic and neurocognitive symptoms and is another risk factor explaining the early mortality in ME/CFS due to cardiovascular disorder.[2009] “lowered levels of CoQ10 play a role in the pathophysiology of ME/CFS and that symptoms, such as fatigue, and autonomic and neurocognitive symptoms may be caused by CoQ10 depletion. Our results suggest that patients with ME/CFS would benefit fromCoQ10 supplementation in order to normalize the low CoQ10 syndrome and the IO&NS disorders.”
• “A daily dose of 100 mg coenzyme Q(10) for 60 days does not alleviate the fatigue of the late-onset sequelae of poliomyelitis.”[2015] – this is not CFS, but a different illness with fatgiue being a strong characteristic.

CFS and FM both have low levels but do have differences

“Peripheral blood mononuclear cell showed decreased levels of Coenzyme Q10 from CFS patients (p<0.001 compared with controls) and from FM subjects (p<0.001 compared with controls) and ATP levels for CFS patients (p<0.001 compared with controls) and for FM subjects (p<0.001 compared with controls). On the contrary, CFS/FM patients had significantly increased levels of lipid peroxidation, respectively (p<0.001 for both CFS and FM patients with regard to controls) that were indicative of oxidative stress-induced damage. Mitochondrial citrate synthase activity was significantly lower in FM patients (p<0.001) and, however, in CFS, it resulted in similar levels than controls.” [2013]

” Significant negative correlations between CoQ(10) or catalase levels in blood mononuclear cells and headache parameters were observed [in FM]” [2012]

Levels are Low, Lab improves but most symptoms do not

It looks like the low CoQ10 is the result of other processes and not the cause of symptoms. Supplementation will improve lab results, but likely not bring noticeable relief to symptoms. Given the relative high cost of CoQ10 and NADH and no clear symptom relief, it is likely not a priority item for CFS and FM patients.

B-Vitamins

B-12:

“Good responders had used significantly more frequent injections (p<0.03) and higher doses of B12 (p<0.03) for a longer time (p<0.0005), higher daily amounts of oral folic acid (p<0.003) in good relation with the individual MTHFR genotype, more often thyroid hormones (p<0.02), and no strong analgesics at all, while 70% of Mild responders (p<0.0005) used analgesics such as opioids, duloxetine or pregabalin on a daily basis…Dose-response relationship and long-lasting effects of B12/folic acid support a true positive response in the studied group of patients with ME/fibromyalgia..” [2015]

B-1 Thiamine

• High-dose thiamine improves the symptoms of fibromyalgia. [2013] “The oral therapy with 600–1800 mg/day of thiamine led to an appreciable attenuation of CWP, fatigue and all other symptoms in all patients within a few days”
  “The lowest dose that we used is 600 mg/day (patient 1), and then a dose of 300 mg was increased every 3 days depending on the weight and the results obtained. Patient numbers 2 and 3 never reported any improvement until the dose was increased up to 1500 mg/day, orally. An abrupt improvement instead occurred at doses of 1800 mg/day.”
• “The absence of blood thiamine deficiency and the efficacy of high-dose thiamine in our patients suggest thatfatigue is the manifestation of a thiamine deficiency, likely due to a dysfunction of the active transport of thiamineinside the cells, or due to structural enzymatic abnormalities.” [2013] The last phase would include dysfunctional microbiome.

• See post on B1 and post on Benfotiamine.

Vitamin B bottom line

Despite CFS patients being low in B-Vitamins being well documented for decades, there has been a surprising absence of studies finding positive effects. There can be two reasons: no one bother to study, or people tried studies and found insignificant results :-(.

Vitamin B-1 appears the best of the B-vitamins (mainly because there was no reports of significant differences of responses). The dosage reported to cause a change within one week is 600-1800 mg/day. This is 18x the typical daily dose of B-1 supplements (100mg), and 3-4x the typical daily dose of high potency supplements (500mg). Monthly cost: $14/month for 1500-2000 mg based on Amazon US pricing.

If you have tried B-1 in the past, there is a good chance that the dosage was well below that of the above study — so no change in symptoms would almost be expected.

CoQ10 and the Gut

We know that B-12 is produced by Lactobacillus Reuteri — which is very low in the gut of CFS patients. What about CoQ10? The answer is that many bacteria produces it — a shift of the microbiome may easily result in a decrease. One of these bacterium appears to be E.Coli which is very low in CFS patients.

• “these processes have relied on microbes that produce high levels of UQ-10 naturally.” [2007]
• “We found Q₉ in five other species of Pseudomonas, Q₈ and Q₉ in Pseudomonas fluorescens, and evidence for the presence of some form of Q in 32 cultures, representing 20 species out of 107 cultures which were examined.”[1960]
• [Production of coenzyme Q10 by metabolically engineered Escherichia coli].[2015]

300 mg/day – Studies in this post.

For at least ten years, I have avoided commenting about this drug — the CFS community at onetime was very divided over it. Ampligen is also know as rintatolimod and poly(I).poly(C12U).

• Efficacy of rintatolimod in the treatment of chronic fatigue syndrome/ myalgic encephalomyelitis (cfs/me). [2016] “Rintatolimod has achieved statistically significant improvements in primary endpoints in Phase II and Phase III double-blind, randomized, placebo-controlled clinical trials with a generally well tolerated safety profile and supported by open-label trials in the United States and Europe.”
  • Comment: while this sounds nice, “statistically significant” could mean as little as 1% improvement, see next quote
• “the immune modulator rintatolimod improved some measures of exercise performance compared with placebo in 2 trials (low strength of evidence).” [2015]
• A double-blind, placebo-controlled, randomized, clinical trial of the TLR-3 agonist rintatolimod in severe cases of chronic fatigue syndrome. [2012] “The improvement observed represents approximately twice the minimum considered medically significant by regulatory agencies.” — so, barely any improvement!
• A controlled clinical trial with a specifically configured RNA drug, poly(I).poly(C12U), in chronic fatigue syndrome. [1994] “After 24 weeks, patients receiving poly(I).poly(C12U) had higher scores for both global performance and perceived cognition than did patients receiving placebo.”

Bottom Line

After 22 years, the best results has been “statistically significant” being just a little above the minimum needed to make a claim of improvement. No remissions reported.  For this one, a major thumbs down!!!