You may have a small heart

• “Cardiovascular symptoms are common in CFS patients. Cardiac dysfunction with low cardiac output due to small left ventricular chamber may contribute to the development of chronic fatigue as a constitutional factor in a considerable number of CFS patients.” [2009]
• “A considerable number of CFS patients have a small heart. Small heart syndrome may contribute to the development of CFS as a constitutional factor predisposing to fatigue, and may be included in the genesis of CFS.” [2008]
• Small heart syndrome in patients with chronic fatigue syndrome[2008]. “A considerable number of CFS patients have a small heart. Small heart syndrome may contribute to the development of CFS as a constitutional factor predisposing to fatigue, and may be included in the genesis of CFS.”
• “A small size of LV with low cardiac output was noted in OI, and its degree was more pronounced in CFS with Orthostatic intolerance  CFSOI(+). A small heart appears to be related to the genesis of OI and CFS via both cerebral and systemic hypoperfusion. CFSOI(+) seems to constitute a well-defined and predominant subgroup of CFS.”[2011]
• “”Small heart” on the chest X-ray photograph was prevalently noted in CFS patients. Echocardiographic examination revealed that CFS patients with “small heart” had an actually small LV chamber and poor cardiac performance.” [2009]
• From “Small Heart as a Constitutive Factor Predisposing to Chronic Fatigue Syndrome [2012]”(Full Text)

Rapid Heart Beat (Tachycardia) and POTS

A consequence of a small heart may be a tendency to increase blood flow to the body by beating faster. The small heart may also be connected to the DNA SNPs associated with CFS.

• “The heart rate dynamic response during the head-up tilt test differs between patients with CFS and healthy controls, supporting the increased prevalence of postural orthostatic tachycardia syndrome.” [2014]
• Painful temporomandibular disorders are common in patients with postural orthostatic tachycardia syndrome and impact significantly upon quality of life[2015].
• Postural tachycardia syndrome is associated with significant symptoms and functional impairment predominantly affecting young women: a UK perspective [2014]. “Patients with PoTS are predominantly women, young, well educated and have significant and debilitating symptoms that impact significantly on quality of life.”
• Postural neurocognitive and neuronal activated cerebral blood flow deficits in young chronic fatigue syndrome patients with postural tachycardia syndrome [2012].
  • ncreasing orthostatic stress impairs neurocognitive functioning in chronic fatigue syndrome with postural tachycardia syndrome [2012].
  • “A substantial number of CFS patients have orthostatic intolerance in the form of orthostatic hypocapnia[a state of reduced carbon dioxide in the blood].”[2007]
    • Patterns of hypocapnia on tilt in patients with fibromyalgia, chronic fatigue syndrome, nonspecific dizziness, and neurally mediated syncope [2006]. “Hypocapnia was diagnosed on tilt test in 9% to 27% of patients with fibromyalgia, CFS, dizziness, and NMS versus 0% to 2% of control subjects.”
• “Postural orthostatic tachycardia syndrome (POTS) is a heterogeneous disorder of the autonomic nervous system in which a change from the supine position to an upright position causes an abnormally large increase in heart rate or tachycardia (30 bpm within 10 min of standing or head-up tilt). This response is accompanied by a decrease in blood flow to the brain and hence a spectrum of symptoms associated with cerebral hypoperfusion. Many of these POTS-related symptoms are also observed in chronic anxiety and panic disorders, and therefore POTS is frequently under- and misdiagnosed.” [2016]

Blood Characteristics

For a good discussion on blood differences seen in CFS, see Les Simpson article in the Journal of IiME, Vol. 2 Issue , p. 24ff.

• “Echocardiographic measures indic ated that the severe CFS participants had 10.2% lower cardiac volume (i.e. stroke index and end-diastolic volume) and 25.1% lower contractility (velocity of circumferential shortening corrected by heart rate) than the control groups.” [2009]
• ” In conclusion, individuals with CFS have a significantly lower peak oxygen consumption and an insignificant trend toward lower blood volume compared with controls. These variables were highly related in both subject groups, indicating that blood volume is a strong physiological correlate of peak oxygen consumption in patients with CFS.” [2002]
• “Circulating Blood Volume in Chronic Fatigue Syndrome [1998]” ” Of the 19 patients reported here, abnormalities in blood volume were very common. The most common, found in 16 of 19 patients, was a reduction in red blood cell mass. Eleven subjects had low plasma volumes, and total circulating blood volume was subnormal in 12 of 19 subjects. In some individuals this abnormality was strikingly severe… red Blood Cell mass …46% of the expected normal, and a total blood volume ..which represents 49.7% of the expected normal value”
• • Objectively measured abnormalities of blood pressure variability in CFS[2012]
  • Lower blood pressure in sleep[2011]
  • Lower blood pressure[2009]

• • Less and slower variability of blood pressure (2012) (2011)
  • Lower total blood volume(8%(2009) – 9% (2002) – 15%(2009) less), plasma volume (13% (2009)) and red blood cell volume (19%) (2009)(2000)(2007)(1998).
  • 35% lower peak oxygen consumption(2002)
  • Significant decrease in red cell distribution width (2007)
  • Higher percentages of misshaped red blood cells[13] [14] (2001) (other)
  • Impaired capillary blood flow.
  • Changed red cell shape populations
  • High values for flat blood-cells
  • Percentage of deformed cells reduced with B12 injections within 24 hrs in responders (P. 245 Englebienne, P. (2002). Chronic Fatigue Syndrome: A Biological Approach.)

And now add thick blood!

• Chronic fatigue syndrome and/or fibromyalgia as a variation of antiphospholipid antibody syndrome: an explanatory model and approach to laboratory diagnosis [ 1999]. “CFS and/or FM patients who have a hereditary deficiency for thrombophilia or hypofibrinolysis may be unable to control thrombin generation properly. We have found that three out of four CFS and/or FM patients have a genetic deficiency (unpublished data). Certain pathogens induce the immune system generation of APL antibodie s and can be a triggering mechanism for APS. Once antibodies are formed, protective proteins are dislodged from endothelial cells, exposing PS. Coagulation proteins bind on exposed PS surfaces, generating thrombin on the EC surface. Excess thrombin converts fibrinogen to SFM, which may be deposited on the EC surface and/or circulate in the plasma. Fibrin deposition leads to decreased oxygen, nutrient and cellular passage to tissues around the microcirculation. This hypercoagulable state may cause localized pathology in many tissues, yielding the systemic compromises and symptoms characteristic of the CFS-FM complex. Since this hypercoagulable state does not necessarily result in a thrombosis, but rather in fibrin deposition, we suggest that an alternative name for this Antiphospholipid antibody process would be immune system activation of coagulation (ISAC) instead of antibody-mediated thrombosis [18]. Once this hypercoagulable state is detected, appropriate anticoagulant therapies may be given to relieve patient symptoms
• “Most symptoms of Gulf War Illness (GWI) are similar to Chronic Fatigue Syndrome (CFS) and/or Fibromyalgia (FM). We investigated whether these symptoms are associated with an activated coagulation system as has been reported in some cases of CFS/FM. The coagulation assays include activation markers of the cascade, platelet activation and hereditary risk factors. Our findings show activation of the coagulation system in GWI. This evidence of a hypercoagulable state suggests that symptoms may be due to poor blood flow and, therefore, a basis for the potential utility of anticoagulant therapy.” [2000]

Bottom Line

Recipe for CFS: Start with a small heart, then decrease it’s efficiency by having thicker blood and less blood, add in alterations of metabolites (amino acids and other chemicals) due to microbiome shifts — adding more chaos. Filter thru your DNA Snps to produce your own special collection of symptoms!

In terms of treatment:

• Fix metabolites
• Reduce coagulation / thick blood

Heart Problems?

• Why myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may kill you: disorders in the inflammatory and oxidative and nitrosative stress (IO&NS) pathways may explain cardiovascular disorders in ME/CFS [2009].
• 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].
• Lower plasma Coenzyme Q10 in depression: a marker for treatment resistance and chronic fatigue in depression and a risk factor to cardiovascular disorder in that illness [2009].
• Causes of death among patients with chronic fatigue syndrome [2006]. “The three most prevalent causes of death were heart failure, suicide, and cancer, which accounted for 59.6% of all deaths.”

LOW Akkermansia is associated with a variety of conditions according to the Smart Gut test, including Crohn’s Disease and Obesity.

A reader asked explicitly how to increase akkermansia bacteria in the body, is there a probiotic available? Low levels of akkermansia is associated with obesity.

• Melatonin: “… melatonin supplementation reversed 14 operational taxonomic units OTUs [of 69]…in particular through its ability to decrease the Firmicutes-to-Bacteroidetes ratio and increase the abundance of mucin-degrading bacteria Akkermansia, which is associated with healthy mucosa.” [2017]
• Capsaicin (CAP) – found in cayenne peppers! “reduces body weight…showed a higher abundance of Akkermansia muciniphila, a mucin-degrading bacterium with beneficial effects on host metabolism.” [2017]
• Lingonberries [IKEA stocks often] “The relative abundance of Akkermansia and Faecalibacterium, genera associated with healthy gut mucosa and anti-inflammation, was found to increase in response to lingonberry intake.” [2016]
• “Increased gut microbiota diversity and abundance of Faecalibacterium prausnitzii and Akkermansia after fasting: a pilot study.“Akkermanisa and Bifidobacteria increased in abundance due to intervention. The inflammation-associated gut microbes Enterobacteria and Lactobacilli increased during the first week and then declined by the end of the intervention.” [Human study — full text]
• Table Grapes: Table grape consumption reduces adiposity and markers of hepatic lipogenesis and alters gut microbiota in butter fat-fed mice [2016]. ” tended to increase the abundance of the beneficial bacterium Akkermansia muciniphila compared to controls”

• “First day: breakfast: Pernegg muesli (prunes, dates, raisins, flaxseed, water); lunch: potatoes and vegetables; dinner: vegetable soup.
  Second day: breakfast: herbal tea, Glauber’s salt, lunch: fresh squeezed fruit and vegetable juice, dinner: fasting soup.
  All other fasting days: breakfast: herbal tea, lunch: fresh squeezed fruit and vegetable juice, dinner: fasting soup.”

  • The modulatory effect of infusions of green tea, oolong tea, and black tea on gut microbiota in high-fat-induced obese mice[2016]. “Tea consumption has been identified to have an anti-obesity effect…it was revealed that tea infusion consumption substantially increased diversity and altered the structure of gut microbiota.”
  • ” the fibre-rich macrobiotic Ma-Pi 2 diet… resulting in an increase of the ecosystem diversity and supporting the recovery of a balanced community of health-promoting SCFA producers, such as Faecalibacterium, Roseburia, Lachnospira, Bacteroides and Akkermansia.”[2016] [British Medical Journal description of this diet is here: bmjdrc-2014-000079supp]
• A probiotic for use with lab animals is cited [2017] [2016]
  • Akkermansia muciniphila: a novel functional microbe with probiotic properties[2016]. “Moreover, products containing A. muciniphila are not on the market and are thus controlled by the Novel Foods Regulation, which requires extensive safety assessment.”
• “We observed a low abundance of the mucin-degrading bacterium Akkermansia muciniphila in the mice that were fed Enterococcus faecium  NCIMB 10415 for 8 weeks.” [2012] — So Enterococcus faecium  probiotics (like symbioflor-1) should not be taken concurrent with above approaches to increase Akkermansia. 😦
• [in terms of infants] ” In Finland probiotics were given to mothers (n = 79) for 2 months prior to and 2 months after delivery. In Germany probiotics were started in infants (n = 81) at weaning, at the latest at 1 month of age, and continued for 4 months …n breast-fed infants a trend toward higher counts of bifidobacteria was detected in Finland (p = 0.097) as against Germany, where a more diverse microbiota was reflected in higher Akkermansia (p = 0.003),”[2012] Again, an interaction between probiotics(bifidobacteria) and Akkermansia
• ” High Fat feeding significantly reduced (P < 0.05) 1 operational taxonomic unit (OTU) of the genus Bifidobacteria (64-fold) and 5 OTUs of the genus Akkermansia (≥16-fold).”  [2016] Reduce the amount of fat in your diet!
• “pH 5.5–8.0, with optimum growth at 37 C and pH 6.5″ [2004] – thus an alkaline environment would inhibit it some what.

Bottom Line

A shift reduce fat content and increase fiber content, especially fiber from fruits which in  polyphenol, appears to be an effective pattern. Table grapes and lingonberries are known to benefit. Increased tea consumption (increased polyphenols) and trying a fasting diet or Ma-Pi 2 diet are additional approaches.

I suspect that an Akkermansia probiotic could first appear in the US — given the current push for deregulation —  as long as there are no claims of actual benefits from it on the label…

A reader asked me about my hypothesize about methylation and antibiotics. I will respond to the first item in this post. The hypothesis is that DNA impacts methylation and is thus connected to some symptoms.

I have done one post on methylation in the past, Methylation, CFS and the microbiome [2016].  Methylation was a hot research topic reaching a peak in 2015 when interest started to drop according to PubMed

Irritable Bowel Syndrome

• Genome-wide DNA methylation profiling of peripheral blood mononuclear cells in irritable bowel syndrome[2016].
  • “Genome-wide DNA methylation profiling of IBS patients compared with HCs identified 133 differentially methylated positions (DMPs) (mean difference ≥10%; p < 0.05).”
  • Epigenetic changes in differential methylation of subcommissural organ (SCO)-Spondin (SSPO) gene were positively correlated with hospital anxiety and depression scores in IBS patients (r > 0.4 and false discovery rate <0.05).
• Peptide Therapeutics and the Pharmaceutical Industry: Barriers Encountered Translating from the Laboratory to Patients [2016]. Severe difficulties in using simple solutions — they don’t work!

Fibromyalgia

• ” Epigenome-wide analysis of DNA methylation was conducted…three CPGs reached significant p-values in the replication sample, including malate dehydrogenase 2 (MDH2; p-value 0.017), tetranectin (CLEC3B; p-value 0.039), and heat shock protein beta-6 (HSPB6; p-value 0.016)…we found evidence for the involvement of epigenetic factors. ” [2016]
• “The majority of differentially methylated (DM) sites (91%) were attributable to increased values in the women with FM. The DM sites included significant biological clusters involved in neuron differentiation/nervous system development, skeletal/organ system development, and chromatin compaction. Genes associated with DM sites whose function has particular relevance to FM included BDNF, NAT15, HDAC4, PRKCA, RTN1, and PRKG1.” [2013]

Chronic Fatigue Syndrome

• Epigenetic modifications and glucocorticoid sensitivity in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) [2017].
  
  ” we report DNA methylation differences in PBMCs of ME/CFS patients, some of which were significantly associated with overall quality of life as well as glucocorticoid hypersensitivity in a subgroup of ME/CFS patients. … we found that genes such as GSTM1, MYO3B, GSTM5, and ATP6V0E2 showed significant epigenetic modifications in ME/CFS. “
• Epigenome-wide DNA methylation patterns associated with fatigue in primary Sjögren’ssyndrome [2016]. “Some genes involved in regulation of the immune system and in inflammation are differently methylated in pSS patients with high vs low fatigue…. the most pronounced hypomethylation in pSS high fatigue annotated to the SBF2-antisense RNA1 gene.”
• “Overall NR3C1-1F DNA methylation was lower in [female] patients with CFS than in controls.” [2015]
• ” We found an increased abundance of differentially methylated genes related to the immune response, cellular metabolism, and kinase activity. Genes associated with immune cell regulation, the largest coordinated enrichment of differentially methylated pathways, showed hypomethylation within promoters and other gene regulatory elements in CFS.” [2014]

Bacteria

While we are dealing with DNA – the changes are epigenetic (relating to or arising from nongenetic influences on gene expression — i.e. the environment, food, stress and most important, the microbiome). This page describes it better.

• The Helicobacter pylori Methylome: Roles in Gene Regulation and Virulence[2017].
• “High-fat diets (HFD)  has been reported to induce DNA methylation changes in white adipose tissue” [2017]
  • Mechanisms for the induction of gastric cancer by Helicobacter pylori infection: aberrant DNA methylation pathway [2017].
• Identification of a Pseudomonas aeruginosa PAO1 DNA Methyltransferase, Its Targets, and Physiological Roles [2017]. A bacteria which can undergo methylization changes (which impacts what gets delivers to the body)
• Pathogenic mechanisms of intracellular bacteria[2017]. “Epigenetic regulators produced by intracellular bacteria alter the epigenotype and gene expression pattern of host cells and play an important role in pathogenesis.”
  • Changes in methylation of genomic DNA from chicken immune organs in response to H5N1 influenza virus infection[2016].
• Wilson Disease: Epigenetic effects of choline supplementation on phenotype and clinical course in a mouse model [2016]. The impact on increase in one amino acid changed the epigenetic state.

In summary:

“The human microbiota and epigenetic processes have both been shown to play a crucial role in health and disease. However, there is extremely scarce information on epigenetic modulation of microbiota members except for a few pathogens. … It would thus appear likely that such mechanisms are widespread for most bacterial members of the microbiota.” [2016]

Bottom Line

Yes, methylation is a significant factor for a subset of CFS patients, likely more common among female patients than male patients.  The problem is epigentic: induced issues (environment). We know very little about what  influences these epigentic changes. We know that some amino acids have an impact.

My preferred hypothesis is that the epigenetic shift is caused by a shift of metabolites (chemicals, including amino acids) produced by the microbiome. This would explain why some people with CFS and the same genes do or do not have epigenetic changes influencing methylation. It is preferred also, because it is actionable to correct the root cause! What is the root cause — a microbiome (gut bacteria) shift.  Yes, methyl-b12  (1000 mcg/ 1 mg seems to be the effective ongoing dosage, see this post) may help a subset but this is treating the end result and not the root cause.

“Hi Ken,

• Reg’Activ Detox & Liver Health, 60 Capsules – 6 billion CFU

• Reg’Activ Immune & Vitality Capsules, 60 Count – 4 billion CFU

The answer is simple, start with the lower dosage one.  Some readers have reported major herx from this probiotic. If you have capsule making equipment, consider splitting the capsules into smaller dosages.

Back to the above issue. The herx/histamine causing bacteria consisted of:

First, remember that doing single species probiotics is the safest path when practical (ideally with the strain named — above lack any strain information 😦 )

Second, search pubmed, it is not hard, just enter the words!

https://www.ncbi.nlm.nih.gov/pubmed/?term=bifidobacterium+lactis+histamine

• “Human peripheral-blood-derived mast cells were stimulated with Lactobacillus rhamnosus (L. rhamnosus) GG (LGG(®)), L. rhamnosus Lc705 (Lc705), Propionibacterium freudenreichii ssp. shermanii JS (PJS) and Bifidobacterium animalis ssp. lactis Bb12 (Bb12)” [2011] mast cell stimulation releases histamine.
• “Bifidobacterium bifidum G9-1… whereas those in mast cell mediators, histamine and cysteinyl leukotrienes were not [suppressed].” [2015]
• “Bifidobacterium infantis and Bifidobacterium longum… Prolonged treatment …significantly suppressed both the allergy-like behaviors and all of the above mentioned factors involved in histamine signaling.” [2008]

In other related articles, bifidobacterium reduced allergies over 2-4 months.  It appears that this may be due to this bacteria displacing higher histamine producing  bacteria over time. It does not mean that these probiotics do not produce histamine.

Bottom Line

Go slow and gentle with probiotics.  Antibiotics, herbs and spices flow thru the body with a drop of 50% (half-life) in a few hours usually.  Probiotics are living creatures that may not drop, but increase!! When you have too severe a probiotic herx, it can become a challenge to moderate it. A high dosage of probiotics that you do well with, may help — you are trying to displace the herxing probiotics.

In some cases, there are other probiotics known to be hostile. For example, lactobacillus and Clostridium butyricum (Miyarisan) will moderate E.Coli probiotics.

Start with low dosages and slowly work up — if you slip into a herx, it may last a much longer time than expected.