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!!!

In this post I look at another antiviral that has been used.

• Response to valganciclovir in chronic fatigue syndrome patients with human herpesvirus 6 and Epstein-Barr virus IgG antibody titers.[2012] “61 CFS patients treated with 900 mg valganciclovir daily (55 of whom took an induction dose of 1,800 mg daily for the first 3 weeks). Antibody titers were considered high if HHV-6 IgG ≥ 1:320, EBV viral capsid antigen (VCA) IgG ≥ 1:640, and EBV early antigen (EA) IgG ≥ 1:160 …Thirty-two patients (52%) were categorized as responders. Among these, 19 patients (59%) responded physically and 26 patients (81%) responded cognitively.
• Randomized clinical trial to evaluate the efficacy and safety of valganciclovir in a subset of patients with chronic fatigue syndrome. [2013] “Thirty CFS patients with elevated IgG antibody titers against HHV-6 and EBV were randomized 2:1 to receive valganciclovir (VGCV) or placebo for 6 months in a double-blind, placebo-controlled trial… MFI-20 mental fatigue subscore (P = 0.039), FSS score (P = 0.006), and cognitive function (P = 0.025).. experienced these improvements within the first 3 months and maintained that benefit over the remaining 9 months….monocyte counts decreased (P < 0.001), neutrophil counts increased (P = 0.037) and cytokines were more likely to evolve towards a Th1-profile (P < 0.001)….Viral IgG antibody titers did not differ “
• Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Systematic Review for a National Institutes of Health Pathways to Prevention Workshop. [2015] ” Trials of galantamine, hydrocortisone, IgG, valganciclovir, isoprinosine, fluoxetine, and various complementary medicines were inconclusive (insufficient evidence).”

Bottom Line

About 21% had improvement in both physical and cognitive issues, 48% had no benefits. There was no remissions reported (unlike  Valacyclovir which reported some patients with complete resolution of symptoms). Not recommended while higher probability of improvement approaches have been tried (like getting Vitamin D in to the top 10% of the normal range)

Readers sometime share the list of prescription from their MDs and ask for my comment. My usual comment are notes like this page, citing what we know from PubMed.

Valacyclovir and CFS

Studies have been done only on a subset of CFS that were EBV positive. One for FM and none for IBS.

• Valacyclovir treatment of chronic fatigue in adolescents. (2014)
  “. All patients were treated subsequently with valacyclovir, with 93% having a positive response. At the end of treatment, scores on fatigue self-assessment scales improved significantly (P < .001). Vigor subscale scores also improved significantly (P < .001). Some patients experienced complete resolution of symptoms. Although not every patient was tested, available laboratory testing revealed increased counts of natural killer (NK) cells and decreased human herpesvirus 6 (HHV-6) antibody titers in all patients who responded to valacyclovir. This article discusses the significance of infectious agents in the pathogenesis of psychiatric symptoms. The study’s data support an intriguing hypothesis that a portion of treatment-resistant depression in fact may be undiagnosed CFS or other chronic viral infection.”
• Antibody to Epstein-Barr virus deoxyuridine triphosphate nucleotidohydrolase and deoxyribonucleotide polymerase in a chronic fatigue syndrome subset. (2012)
  “There is prolonged elevated antibody level against the encoded proteins EBV dUTPase and EBV DNA polymerase in a subset of CFS patients, suggesting that this antibody panel could be used to identify these patients,”
• Valacyclovir treatment in Epstein-Barr virus subset chronic fatigue syndrome: thirty-six months follow-up. (2007)
  “Patients were given valacyclovir at 14.3 mg/kg every 6 hours… Sinus tachycardias decreased and abnormal cardiac wall motion improved. Serum antibody titers to EBV VCA IgM decreased. Patients resumed normal activities.”
• A six-month trial of valacyclovir in the Epstein-Barr virus subset of chronic fatigue syndrome: improvement in left ventricular function. (2002)
  ” We concluded that the 16 CFS patients (included in both phases of this study) with EBV-persistent infection (EBV single-virus subset) are improved after 6 months of continuous pharmacokinetic dosing with valacyclovir. Nine CFS patients with EBV/human cytomegalovirus co-infection did not benefit from 6 months of similar treatment. Valacyclovir is not an effective anti-human cytomegalovirus antiviral drug.”
• “No effect of antiviral (valacyclovir) treatment in fibromyalgia: a double blind, randomized study.” [2004]

Diagnostic Line:

EBV testing must be positive, CMV testing must be negative if you expect any benefit. Testing for EBV can result in some tests being negative (see below), so do not rely on a single negative test as being reliable.

EBV and Brain Inflammation

Note: Encephalitis is inflammation of the brain and that the traditional name for CFS is Myalgic Encephalomyelitis.

• [Encephalitis due to the Epstein-Barr virus: a description of a clinical case and review of the literature]. [2013]
  “oral valaciclovir with clinical resolution and improvement of the liquoral parameters. Polymerase chain reaction in the cerebrospinal fluid was positive for EBV and negative for the other neurotropic viruses. In blood, the serology test for EBV with IgG was positive, while IgM and heterophile antibody tests [for EBV] were negative… EBV infection can give rise to acute disseminated encephalomyelitis or affect several locations in the central nervous system, especially the cerebellum.”
• Ataxia and Encephalitis in a Young Adult with EBV Mononucleosis: A Case Report.[2013]
  “The patient was clinically diagnosed with EBV-associated cerebellitis and encephalitis, displaying neurological and psychiatric impairment commonly seen in postconcussion syndrome. MRI showed no acute changes. She was started on valacyclovir and a prednisone taper, recovering by the end of twelve weeks.”
• [Effect of the Epstein-Barr virus on the nervous system]. [2001]
  “it has been shown that this infection can be accompanied by acute and chronic affections of the central and peripheral nervous system. The pathogenesis of chronic EBV-infection involves autoimmune disorders, neurosensitization, a hazard of an injury to the muscular tissue”

Alternative EBV treatment

• Bosewellia “showed potent inhibitory effects on EBV-EA induction” [2006]
• Turmeric
  • The effect of curcumin on human B-cell immortalization by Epstein-Barr virus. [1998] “A strongly promote in vitro B-cell immortalization with EBV … and curcumin, an extract of a common spice is an effective inhibitor of this process;”
  • “Seven rhizomes were found to possess inhibitory activity towards EBV activation, induced by TPA; they are:Curcuma domestica, C. xanthorrhiza, Kaempferia galanga, Zingiber cassumunar, Z. officinale, Z. officinale (red variety), and Z. zerumbet.” [1999]
• White Mugwort (Artemisia lactiflora) ” In addition, AL-1 strongly inhibited tumor promoter-induced Epstein-Barr virus (EBV) activation” [1999]

Bottom Line

This is effective for a subset of CFS patients that are positive for only one Herpes virus, EBV. Multiple virus or no virus are unlikely to benefit according to the studies.