A reader email me  and stated that he believe that he has an overgrowth of (bad) Enterococcus. I had done an earlier post and thought that I should dig deeper, there are some hints that enterococcus is involved with Chronic Lyme [2007]

Background

“The first description of Enterococcus spp. as agents of infection causing infective endocarditis was reported in 1899 (Maccallum and Hastings 1899); however, enterococci emerged as major multidrug-resistant opportunistic pathogens in the 1990s (Uttley, Collins, Naidoo et al., 1988; Sood, Malhotra, Das et al., 2008). As recently reviewed by Arias and Van Tyne, ‘enterococci epidemiology’ has evolved with antibiotic use and evolution of medical practices (Arias and Murray 2012; Van Tyne and Gilmore 2014). Over the past 30 years, enterococci have become a leading cause of healthcare-associated infections (HCAIs) worldwide (Arias and Murray 2012). Enterococcus faecalis was the first species found to be responsible for infections, but clinical E. faecium strains have been increasingly reported since 2000. A correlation was established between the use of antibiotics in animal feed and human medicine and the emergence of resistant enterococci, in particular of vancomycin-resistant enterococci (VRE) and ampicillin-resistant enterococci (ARE) in fragilized populations (Agudelo Higuita and Huycke 2014).” [2015]

Option #1 Displace the bad Enterococcus

My initial take would be to displace them with good Enterococcus from probiotics:

1. * Symbioflor-1   Enterococcus faecalis (Germany)
2. * Bioflorin – Enterococcus faecium SF 68 (Germany)
3. * BENOIT Enterococcus AF2 (ITALY)

Option #2 Probiotics that reduce enterococcs

• Mutaflor (E.Coli Nissle 1917) [2011]
  • Potentially Symbioflor-2 may also be effective.
• “Lactobacillus fermentum VET 9A, L. rhamnosus VET 16A, and L. plantarum VET 14A … the concentrations of Clostridium perfringens and Enterococcus faecium, which typically increase during diarrhea episodes in dogs, were decreased in probiotic group feces” [2016]
• “six lactobacillus strains (L. gasseri, L. rhamnosus, L. acidophilus, L. plantarum, L. paracasei, L. acidophilus)… had similar moderate antimicrobial activities against…Enterococcus fecalis. [2016]
• “ingestion of the Butyricicoccus pullicaecorum strain 25-3^T  strain significantly lowered the abundance of Campylobacter spp. in the caecum and Enterococcus and Escherichia/Shigella spp. in the ileum at day 40.” [2016]
• Lactobacillus rhamnosus GG Outcompetes Enterococcus faecium via Mucus-Binding Pili: Evidence for a Novel and Heterospecific Probiotic Mechanism [2016].
  • Effect of Lactobacillus rhamnosus GG Administration on Vancomycin-Resistant Enterococcus Colonization in Adults with Comorbidities.[2015]
  • Potential use of probiotic and commensal bacteria as non-antibiotic strategies against vancomycin-resistant enterococci. [2015]
    • Lactobacillus rhamnosus GG but “In contrast, L. rhamnosus Lcr35, related to the strain GG, did not show a significant decrease in VRE” – the right strain is needed!
    • “a probiotic mix of 10 strains of Bifidobacterium bifidum, Bifidobacterium lactis, E. faecium, Lactobacillus acidophilus, Lactobacillus rhamnosus, Lactobacillus paracasei, Lactobacillus plantarum and Lactobacillus salivarius …At the end of the 4.5 month trial, …showing no preventive effect”
    • In lab animals: Bacillus coagulans, Pediococcus acidilactis MM33, Lactococcus lactis MM19, Bacteroides thetaiotaomicron

• “Brillantaisia lamium… Enterococcus faecalis… were the most sensitive to all the tested compounds.” [2011]
• “the annual herb Acanthospermum hispidum DC. (Asteraceae) …a selective antibacterial activity was observed against pathogenic strains of Staphylococcus aureus and Enterococcus faecalis ” [2012]
• “Rubus parvifolius L. (Rp) is a medicinal herb that possesses antibacterial activity…inhibited the growth of a wide range of Gram positive and negative bacteria, including … Enterococcus faecalis,[2012]
• “Conyza sumatrensis (Retz.) E.WALKER (Asteraceae) is a spontaneous annual herb.. the leaf oil exhibited significant in vitro antibacterial activity against Enterococcus faecalis” [2013]
• “among the most active EOs against MDR E. faecalis strains, O. glandulosum, T. capitata, L. multifida, and A. verticillata EOs are constituted principally by terpenoid phenols,…a good synergetic effect between compounds of Eucalyptus globulus EO against multidrug-resistant bacteria, Staphylococcus aureus and Enterococcus faecalis. [2014]
• From my earlier post on Enterococcus overgrowth,
  • Azadirachta indica
  • Ocimum tenuiflorum
  • Monolaurin: Some species of E. are resistant [2007],

There have been some recent articles and a nice summary from a presentation given (before the articles was published). One of the things that I have observed in some 15 years being involved with the CFS community is that hypothesis never die– despite many studies blowing holes in them. For example the view that CFS is a mitochondrial disease.

• Sara Myhill, Chronic fatigue syndrome and mitochondrial dysfunction [2009]
• Mitochondrial dysfunction in a family with psychosis and chronic fatigue syndrome[2016].
• Bottom-up proteomics suggests an association between differential expression of mitochondrial proteins and chronic fatigue syndrome [2016].
• Metabolic features of chronic fatigue syndrome [2016].

Recent research found was that the symptoms (but not the disease) are related to mitochondrial.

• Association of mitochondrial DNA variants with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) symptoms[Dec 2016].
• Mitochondrial DNA variants correlate with symptoms in myalgic encephalomyelitis/chronic fatigue syndrome [2016].

What Cornell found (and I agree!)

1. Do some patients with ME/CFS identified by expert M.D.s actually have a genetic mitochondrial disease? NO
2. Can mitochondrial genome variation be correlated with susceptibility to ME/CFS?  NO
3. Is mitochondrial genome variation correlated with particular ME/CFS symptoms or their severity? YES
4. Anti-inflammatory bacterial species are reduced in ME/CFS patients? YES

Presentations to Watch

What evidence is there of not being DNA etc.

Twin studies — Same DNA, same mitochondria. So what is the difference between having or not having CFS?

Bottom Line

My base hypothesis is that CFS/IBS/ etc is caused by a microbiome shift. This shift decreases TH1 associated bacteria and increases TH2 associated bacteria. The shift to TH2 results in increased histamine release and histamine sensitivity.

This shift results in alteration of the amino acids and the metabolites produces by the bacteria in the microbiome because different bacteria produce different amino acid and metabolites. For example, B12 is mainly produced by Lactobacilus Reuteri; if the quantity of L. Reuteri drops then a person ends up with low B12 levels.

A reader asked:

“I was wondering…have you done a blog post on probiotics that might help shift the Th1-Th2 balance?”

“T(H)2-cytokines increase the production of IgE and stimulate mast cells [aka histamine release] and eosinophils, whereas T(H)1-cytokines, such as IFN-gamma, may suppress IgE synthesis and stimulate the expression of the secretory piece of IgA.”[2008]

“Type 1 Th cells (Th1 cells) secrete IL-2, interferon-gamma (IFN-γ) and tumour necrosis factor (TNF), whereas type 2 Th cells (Th2 cells) produce IL-4, IL-5, IL-6 and IL-13. ” [1998]

• Evidence for T-helper 2 shift and association with illness parameters in chronic fatigue syndrome (CFS) [2008].
• Gulf War syndrome: is it due to a systemic shift in cytokine balance towards a Th2 profile[1997]?

IMHO, there will be limited literature.  Much of the literature is for specific strains that are not available commercially.

• Probiotic Escherichia coli Nissle 1917 suppresses allergen-induced Th2 responses in the airways [2009].
• “Soil-based organisms improve immune function: shift cytokine profile from TH2 to TH1.“[1998] – i.e. Prescript Assist, General Biotics Equilibrium
• “B. breve diet …increased percentages of activated Th1 cells were observed in the spleen.”[2016]”
• All bifidobacteria tested were able to induce full DC maturation but showed differences in the levels of cytokine production, especially IL-12, IL-10, TNFalpha and IL-1beta, suggesting that specific cytokine ratios could be used to predict the type of Th response that they may promote” [2010]
• ” Lactobacillus plantarum strain 06CC2 may be a versatile oral adjuvant to activate Th1 immune response.” [2016]
  • “oral administration of strain 06CC2 was effective in inducing Th1 cytokine production activating the Th1 immune response associated with intestinal immunity in normal mice.” [2013]
• “The relationship between modulation of gut microbiota and regulation of host immunity by different doses of probiotics is complex. LGG exerted divergent dose-dependent effects on the intestinal immune cell signaling pathway responses, with 9-doses Lactobacillus rhamnosus GG being more effective in activating the innate immunostimulating TLR9 signaling pathway than 14-doses” [2016]
• “VSL#3-treated NOD mice modulate gut immunity by… reducing differentiation/expansion of Th1 and Th17 cells” [2016]
• “Of ten LAB extracts, four (from L. acidophilus, L. bulgaricus, L. casei, and S. thermophiles) promoted both cell proliferating and TH1 cytokine production. [2015]
• Surface-Displayed IL-10 by Recombinant Lactobacillus plantarum Reduces Th1 Responses of RAW264.7 Cells Stimulated with Poly(I:C) or LPS [2016].
• “Analysis of the impact of these three strains on the T helper balance revealed different mechanisms of action. The Lactobacillus salivarius LA307 strain proved to block Th1 and Th2 responses, while the Bifidobacterium longum subsp. infantis LA308 strain induced a pro-Th1 profile and the Lactobacillus rhamnosus LA305 strain induced pro-Th1 and regulatory responses.” [2016]
• Th1 Cytokine Production Induced by Lactobacillus acidophilus in BALB/c Mice Bearing Transplanted Breast Tumor [2015].
• ” Lactobacillus paracasei V0151.. the T helper 1/T helper 2 (Th1/Th2) balance was also skewed toward Th1 dominance through the elevation of Th1 cytokine production.” [2015]
• “L. salivarius CICC 23174 was the more effective strain at maintaining the Th1/Th2 balance” [2015]
• “Enterococcus faecalis CECT7121 implants itself and persists in the murine gastrointestinal tract, and enhances and skews the profile of cytokines towards the Th1 phenotype in several biological models.” [2015]
• “Lactobacillus casei variety rhamnosus (LCR35) … possibly through the modulation of Th1/Th2 balance and gut microbiota.” [2015]
• ” B. infantis feeding reduced Th1-related cytokines” [2014]
• “Lactobacillus kefiranofaciens M1…  strongest response in terms of splenic Th1 cytokine IFN-γ and IL-12 production” [2013]
• “Lactobacillus brevis HY7401…showed a tendency to induce Th1 cytokines and inhibit Th2 cytokines.” [2013]
• Lactobacillus casei ssp.casei induced Th1 cytokine profile and natural killer cells activity in invasive ductal carcinoma bearing mice [2012].
• Heat-killed lactic acid bacteria enhance immunomodulatory potential by skewing the immune response toward Th1 polarization [2011].
• Lactobacillus plantarum strain YU from fermented foods activates Th1 and protective immune responses [2011].
• “0.5 × 10⁸ Bifidobacterium longum, 0.5 × 10⁷ Lactobacillus bulgaricus, and 0.5 × 10⁷ Streptococcus thermophilus…. could attenuate the deviated Th1/Th2 response induced by severe TBI.. Traumatic brain injury (TBI) is associated with a profound immunological dysfunction manifested by a severe shift from T-helper type 1 (Th1) to T-helper type 2 (Th2) response. ” [2011] i.e. the above increased Th1 and reduced Th2.
• Treatment with Bifidobacterium bifidum 17 partially protects mice from Th1-driven inflammation in a chemically induced model of colitis [2011].
• “in vitro studies on mouse spleen cells indicates that the VSL#3 preparation has the capacity to shift a polarized Th2 response to a Th1/T regulatory-type profile.” [2011]
• Probiotic Bio-Three induces Th1 and anti-inflammatory effects in PBMC and dendritic cells [2010].
• “L. crispatus KT-11 strain reduces allergic symptoms in NC/Nga mice via the adjustment of the type 1 helper T cell and type 2 helper T cell balance via TLR2, NOD1, and NOD2.” [2009]

Bottom Line

For most of the probiotics reported above, they induce TH1 and reduce TH2. Alternatively, the loss of these families of bacteria in CFS patients could explain the shift to TH2. The degree of shift each probiotic does varied greatly from strain to strain.  In other words, if you favor the TH2 – shift hypothesis for CFS, then you should definitely be taking probiotics. There are a few probiotics that decreases TH1.. so  “taking a probiotic” is not a magic formula.

The observed shift in CFS patients microbiome would explain the shift towards TH2 seen in CFS patients

Personally, I believe that the TH1/TH2 shift is a simplification that masks a lot of details on which cytokines are involved. For example, which one of the IL-4, IL-5, IL-6 and IL-1 are high? Only one may be — we should be treating the specifics and not doing a shotgun approach.

I came across this while examining environmental illness. There are two features that makes Lactobacillus fermentum ME-3 DSM-14241 of special interest:

• It is human sourced — thus there is a reasonable chance that it may take up residence
• It produces glutathione — very unusual

Last, it is available on Amazon.com (this specific strain)

Pub Med Literature Review

• ” L. fermentum ME-3 is a unique strain of Lactobacillus species, having at the same time the antimicrobial and physiologically effective antioxidative properties and expressing health-promoting characteristics if consumed. Tartu University has patented this strain in Estonia (priority June 2001, patent in 2006), Russia (patent in 2006) and the USA (patent in 2007).” [2009] [Full text– an interesting read]
  • ” the strains of the L. fermentum species were also found from some other Estonian children, yet not from Swedes!”
• “The consumption of Reg’Activ Cholesterol  (containing Lactobacillus fermentum ME-3) in clinically asymptomatic volunteers with borderline-high values of risk factors for cardiovascular disease (BMI, HbA1c%, LDL cholesterol) for 4 weeks had a positive effect on blood lipoprotein, oxidative stress and inflammatory profile.” [2016]
• ” this study show that probiotic L. fermentum ME-3 contains both glutathione peroxidase and glutathione reductase. We also present that L. fermentum ME-3 can transport GSH from environment and synthesize GSH. This means that it is characterized by a complete glutathione system: synthesis, uptake and redox turnover ability that makes L. fermentum ME-3 a perfect protector against oxidative stress. To our best knowledge studies on existence of the complete glutathione system in probiotic LAB strains are still absent and glutathione synthesis in them has not been demonstrated.” [2010]
• “only L. casei spp. (including L. casei 114001) and L. fermentum ME-3 revealed pronounced ability to suppress oxidation of luminol (by 43-65,8%) and microsomal lipid peroxidation (by 57,9-89,5%).” [2009]
• Available in some cheeses in Europe (Baltic area) [2004]

Histamines?

• “The gene encoding for the multi-copper oxidase was sequenced and detected also in other amine-degrading strains of Lb. fermentum, … was able to degrade all the BAs were singly used as adjunct starter for decreasing the concentration of histamine and tyramine in industrial Caciocavallo cheese.” [2016]
• “Lactobacillus fermentum (two strains) caused very low (4.2% – 8.8%) histamine release.” [2002]
• “Histamine release induced by … L. fermentum was lower (at a range of 2.4%-8.2%).” [2000]

Blood-Brain Barrier

• ” one of the  L. fermentum (LAC 42) showed activity also against Pseudomonas aeruginosa and Klebsiella pneumoniae… Our data on this antibacterial molecule suggest that it is a compound with low molecular weight and with highly hydrophilic component.” [2016] – low molecular weight is needed to cross the blood-brain barrier.
• “the current study demonstrated that probiotic consumption(Including L.F) for 12 weeks positively affects cognitive function and some metabolic statuses in the Alzheimer’s disease patients.” [2016]

From Patent Filing

• “has a high anti-microbial effect on Escherichia coli, Shigella sonnei, Staphylococcus aureus, Salmonella typhimurium, and moderate activity against Helicobacter pylori strains.”
• “Up to the present no strain of lactobacilli with an extensive anti-microbial effect against numerous pathogens and opportunistic pathogens has been described.” – this one does!!!!
• “The innate resistance of Lactobacillus fermentum ME-3 against antimicrobial preparations (TMP-SMX, ofloxacin, aztreonam, cefoxitin and metronidazole) allows to use it as a preparation accompanying antibiotic treatment in case of gastrointestinal and uroinfections”
• For making Yogurt: “Lactobacillus fermentum ME-3 pure culture in 0.15% MRS-agar is used for producing the yoghurt, additionally the pure cultures of Lactobacillus plantarum and Lactobacillus buchneri are seeded into fresh goat milk autoclaved for 20 min at 110° C. Three cultures of these strains of lactobacilli are mixed in equal proportions together with 2% of Streptococcus thermophilus and are added in 0.2% of content into autoclaved goat milk.”

Sources

• Press Release
• Reg’Activ – Amazon US – available first in 2015.

A reader forwarded me a copy of their results. As usual, I like to go thru it via a blog post. The report gives good information but in the context of CFS/IBS we may be approaching the edge of what we can do with it (i.e. no studies, etc). Here goes….

First item, I am in general very happy with their presentation of information, as shown below.

Organic Acids Test  – Nutritional and Metabolic Profile

The following were all in the normal range:

• Glycolytic Cycle Metabolities
• Mitochondrial Markers – Krebs Cycle Metabolites
• Mitochondrial Markers – Amino Acid Metabolities
• Pyrimidine Metabolites – Folate Metabolism
• Ketone and Fatty Acid Oxidation
• Indicators of Detoxification
• Mineral Metabolism

Mitochondrial markers being normal excludes one set of hypothesis about CFS for this patient. See these PubMed articles where CFS patients were found to have mitochondrial issues.

Yeast and Fungal Markers

The following were high:

• Citramalic (~ 96%ile)
• Tartaric Acid – very high (3x high normal range)
• Arabinose – high (2x high normal range)

My read would be to take prescription  Metronidazole/Flagyl  (people responded well to it according to the surveys) or other anti-fungal medications. For herbs  Cistus Incancus is one of many choices.

• Increased number of Candida albicans in the faecal microflora of chronic fatigue syndrome patients during the acute phase of illness[2007].
• Yeast metabolic products, yeast antigens and yeasts as possible triggers for irritable bowel syndrome [2005]. ” But more research is needed before antifungal treatment can be recommended as a first line treatment for IBS.”
• Chronic intestinal candidiasis as a possible etiological factor in the chronic fatigue syndrome [1995].

In short — evidence that a subset have issues here — but a lack of followup studies.

Bacterial Markers

• Hippuric – very high 4x high normal range
  • “Hippuric acid is a normal component of urine and is typically increased with increased consumption of phenolic compounds (tea, wine, fruit juices).” [source] – other sources are exposure to high levels of toluene.
    • Mulder TP, Rietveld AG, van Amelsvoort JM.
      Consumption of both black tea and green tea results in an increase in the excretion of hippuric acid into urine. Am J Clin Nutr 2005;81:256S-260S.
    • Clifford MN, Copeland EL, Bloxsidge JP, Mitchell 10.
      LA. Hippuric acid as a major excretion product associated with black tea consumption. Xenobiotica 2000;30:317-326. Li C, Lee MJ, Sheng
• 4-Hydroxybenzoin ~ 98%ile

What I could find:

• Probiotics Blunt the Anti-Hypertensive Effect of Blueberry Feeding in Hypertensive Rats without Altering Hippuric Acid Production[2015].

Lab’s Recommendation: “High hippuric acid (Marker 10) may derive from food, GI bacterial activity, or exposure to the solvent toluene. …. Bacterial overgrowth can be treated with natural anti-bacterial agents and/or probiotics (30-50 billion cfu’s) that include Lactobacillus rhamnosus.”

Actions: None beyond the above

Clostridia Bacterial Markers

Three markers were in the normal range, only one was outside

• HPHPA – 96%ile
  • “(HPHPA) was found in higher concentrations in urine samples of children with autism compared to age and sex appropriate controls and in an adult with recurrent diarrhea due to Clostridium difficile infections… a value 300 times the median normal adult value,”[2010]  – reader value is no where need this
  • “After oral vancomycin treatment, urinary excretion of HPHPA … decreased markedly, which indicated that these compounds may also be from gut Clostridium species.”[2016]
    • If the reader was taking any Clostridium probiotics, this could account for the slightly high reading.

Lab’s Recommendations: “Treatment with Metronidazole or Vancomycin is almost 100% effective in killing parent Clostridia organisms but not their spores. At least three months of probiotic therapy is recommended after antimicrobial treatment due to spore formation by Clostridia species. Clostridia overgrowth can sometimes be controlled by supplementation with Lactobacillus rhamnosus GG (Culturelle) or Saccharomyces boulardii. Phenalalanine or tyrosine supplements should be avoided because of the possibility of conversion to HPHPA or other toxic byproducts.”

Actions: Not sufficiently high to warrant 3 months of antibiotics (which will cause other side effects)

Oxalate Metabolites

• Oxalic – 98%ile

Lab’s Recommendations: “…. are also byproducts of molds such as Aspergillus and Penicillium and probably Candida.  ….Elevated oxalate values with a concomitant increase in glycolic acid may indicate genetic hyperoxaluria (type I), whereas increased glyceric acid may indicate a genetic hyperoxaluria (type II). Elevated oxalic acid with normal levels of glyceric or glycolic metabolites rules out a genetic cause for high oxalate. However, elevated oxalates may be due to a new genetic disorder, hyperoxaluria type III.
Organic ”

Actions: Resolve the Candida/Fungal/Yeast and then get retested.

Neurotransmitter Metabolites

• Quinolinic / 5-HIAA Ratio — very high ( 5-HIAA was near bottom of range — hence the high ratio). 5-HIAA is a metabolite of serotonin which is typically low in CFS [2015] [2004]

Lab’s Recommendations: ” Supplementation with the precursor 5-HTP (5-hydroxytryptophan) at 50-300 mg/day may be beneficial. Supplementation with tryptophan itself may form the neurotoxic metabolite quinolinic acid, however, 5-HTP is not metabolized to quinolinic acid. Excessive tryptophan supplementation has been associated with eosinophilia myalgia syndrome. ”

Actions: Consider d-ribose — if does result in improvement of symptoms. Taking tryptophan has no improvement for CFS [2010] [2014]

Nutritional Markers

• Pantothenic (Vitamin B5) – High

Lab’s Recommendations: “High pantothenic acid (B5) (Marker 52) indicates high recent intake of pantothenic acid. Pantothenic acid is an essential B vitamin. Since some individuals may require very high doses of pantothenic acid, high values do not necessarily indicate the need to reduce pantothenic acid intake.”

Actions: None suggested

• Ascorbic (Vitamin C) – Low

Lab’s Recommendations: “Ascorbic acid (vitamin C) levels below the mean (Marker 54) may indicate a less than optimum level of the antioxidant vitamin C. Suggested supplementation is 1000 mg/day of buffered vitamin C, divided into 2-3 doses.”

Actions: Follow the labs — nothing specific for CFS is reported. However, do not get from orange juice as it may increase Hippuric levels further [2014]

Amino Acid Metabolites

Many(5) values were zero at bottom of normal range.

Lab’s Recommendations: “Low values for amino acid metabolites (Markers 62-74) indicate the absence of genetic disorders of amino acid metabolism. These markers are deamination (ammonia removed) byproducts that are very elevated only when a key enzyme has low activity; slight elevations may indicate a genetic variation or heterozygous condition which may be mitigated with diet or supplementation. Low values are not associated with inadequate protein intake and have not been proven to indicate specific amino acid deficiencies.

Actions: Consider supplementation with those listed in this post. Alternatively visit http://www.hmdb.ca/ and see what they suggest for each. For example for having zero 3-Hydroxyisovaleric acid  “Levels may also be increased from prolonged consumption of raw egg-whites (PMID: 16895887 , 9523856 , 15447901 , 9176832 )(OMIM: 210210 , 253270 , 600529 , 253260 , 246450 , 210200 , 238331 ).”

Bottom Line

Apart from address Fungal/Yeast issues – there does not seem to be any actionable items beyond the existing lab recommendations.

For other CFS patients — the results will likely vary greatly because of the variation in the microbiome shifts.