The patient is in the mid 20’s male and under treatment with a very well known CFS specialist. “although he is stable we aren’t seeing any further improvement….  He doesn’t meet the official CFS definition since he only has the PEM (Post-exertional malaise), general on-going fatigue, and maybe some sleep issues.”

This is the first of two parts, the second part is after the first Pfizer covid shot. This will be interesting to see the shifts.

“Also, after this sample was sent into Thryve he had his first Pfizer covid shot and then had a crash – so I got another sample at that time that I should get results for in a few weeks.”

KEGG Results

KEGG Probiotics

I am going to do a multiway compare in the hope of clustering a consensus from different algorithms. Using advance suggestions

I tend to favor KEGG because the data it is working from is significantly complete. Using Net Benefit and Advance suggestions — we got only weak results (usually against) or no results, except for Lactobacillus paracasei. This would be my first choice for trying a probiotic except it is a histamine producer.

Probiotic (available commercially)

Bacillus thuringiensis or Bacillus mesentericus

Clostridium butyricum

Lactobacillus paracasei (D-Lactic acid producer [2013] )

Bifidobacterium adolescentis 

Enterococcus faecalis

Lactobacillus kefiri

Probiotic Suggestions Analysis

Look at the Lactobacillus Genus, we see that this person is at the 87%ile (i.e. much higher than most people). Bifidobacterium is 29%ile, i.e. in the normal range. It is not surprising that these two are low as suggestions. On the other side, there was ZERO bacillus reported (not unusual, Thryve only reports Bacillus 45% of the time) which seems to be reflected in the top suggestions being Bacillus probiotics.

Having high lactobacillus can contribute to ME/CFS Symptoms. In general, lactobacillus probiotic should be avoided unless verified to not be d-lactic acid producers (if no information, assume they produce!!)

• Reminder of D-Lactic acidosis and ME/CFS [2019]
• D-lactic Acidosis -Sauerkraut is not good for you if you have CFS! [2015]
• Reducing Lactic Acid Producing Bacteria – LABO [2017] – contains suggestions

KEGG Supplements

As with probiotics, I tend to favor KEGG suggestions for similar reasons. The list below is where their generated values falls in the bottom 5%. All of them are available on Amazon, iHerb and other suppliers

• #1 beta-alanine (quick intro: it may reduce both histamine [2019] and lactic acid[2020] – both of which have cognitive impact.)
  • beta-Alanine and gamma-aminobutyric acid in chronic fatigue syndrome [2007]
  • Preliminary determination of the association between symptom expression and urinary metabolites in subjects with chronic fatigue syndrome [1996] “strong associations of CFSUM1 and beta-alanine with CFS symptom expression”
  • Preliminary determination of a molecular basis of chronic fatigue syndrome [1996] “beta-alanine were positively correlated with symptom incidence, symptom severity, core CFS symptoms”
• iron
  • Iron insufficiency and hypovitaminosis D in adolescents with chronic fatigue and orthostatic intolerance [2011]
  • Serum concentrations of some metals and steroids in patients with chronic fatigue syndrome with reference to neurological and cognitive abnormalities [2001] ” The results indicate that patients had significantly increased serum aluminum and decreased iron compared to controls”
• L-asparagine
  • Hematologic and urinary excretion anomalies in patients with chronic fatigue syndrome [2007] “Significant decreases in the urinary excretion of asparagine”
• L-Lysine
  • Nothing explicit, implication that it may help from this study [2017]
• L-Proline
  • Comparison of differential metabolites in urine of the middle school students with chronic fatigue syndrome before and after exercise [2018] This is a good match for the PEM issue “The disorder of arginine-proline metabolic pathway is detected in CFS middle school students before exercise intervention.”
• Molybdenum – nothing found
• NADH
  • Common supplement suggested for ME/CFS, see this collection on PubMed.
• Phytase (Enzyme) – nothing found

As always consult with your medical professional. A pattern to discuss: start at 1/8 of the suggested dosage and increase every 4 days (usually doubling). Do one at a time, keeping those that have apparent benefit. If you stop giving one, wait 4 days before starting the next, on occasion, stopping may reveal that it helped — just slowly.

Most of the suggestions above appears to agree with studies as illustrated above. We have 3 suggestions that are novel (unstudied) for ME/CFS: Phytase, Molybdenum, L-Lysine.

This strong agreement to studies is reassuring for using the KEGG model. The model knows only the bacteria, no lab tests or diagnosis. Far more critical (for modelling), it appears to explain that the lab results can be reliability attributed to the ME/CFS microbiome population!

Core Supplements

While core supplements has largely been replaced by KEGG, it is still available. There was only one supplement computed that strongly suggests supplementation, DAO. There is no studies on PubMed for CFS and DAO, however DAO does reduce histamine levels — it is a possible experiment to try. I know several people with ME/CFS that have histamine issues, in some cases, severe hay fever. There is some literature in this direction:

• Chronic fatigue syndrome: influence of histamine, hormones and electrolytes [1993]
• “Because of anecdotal reports and uncontrolled trials showing antihistamine efficacy in CFS,”[1996]

The second lowest is Vitamin B6

• Vitamin B status in patients with chronic fatigue syndrome [1999] “data provide preliminary evidence of reduced functional B vitamin status, particularly of pyridoxine, in CFS patients.”

The third lowest is Vitamin D, a well establish lab result for CFS. Generally “low level” supplementation does not work because the ME/CFS microbiome does a poor job absorbing it. A collection of PubMed Studies, and my prior blog posts

• Vitamin 25D and 1,25D measure – one reduces symptoms and one indicates CFS state [2015]
• Vitamin D and the Microbiome [2017]
• Viral Reactivation and the Microbiome [2020]
• Anna Dorothea Hoeck, MD (ME-Pedia.org)

An important observation

All of the above suggestions came solely from the microbiome of the person (no diagnosis information at all!!!). The suggestions agree with significant subsets of ME/CFS patients. Using the microbiome, we appear to be able to be uber-specific to the person. We are not working off “general treatment suggestions” for ME/CFS. The suggestions in this post may not apply to a different ME/CFS patient — they have a different microbiome! Likely similar, but different!

Philosophy

The concept is to supplement what is not being produced by reduced bacteria creating a more normal environment. The hope is that a more normal environment will trigger feedback loops in the microbiome that will increase the reduced (or excessive) bacteria. The microbiome is a city – with a city, reducing the crime rate can often be the result of eliminating causes like: poverty, education, job opportunities, etc.

National Library of Medicine Comparison

In general, the bacteria identified for Chronic Fatigue Syndrome in Studies is not suitable for strong pattern matching. Chronic Fatigue Syndrome has a spectrum with many subsets. This variety is reflected in the studies.

I went to the Component Analysis / Medical Conditions page and then clicked under the Count Column, i.e. by the 📚 for Chronic Fatigue. I then Clicked on Direction to put all of the flagged items (💥) at the top. I then put checked the checkbox besides them (family, genus, species). On this page the 💥 is NOT outside of the Kaltoft-Moltrup Normal Range, but above 75%ile or below 25%ile. The Change Your Microbiome / Medical Condition (PubMed) Outliers applies the 💥 with the K-M ranges (in this sample, there were actually zero outliers!!!)

Why this change? The studies reported averages were above or below for Chronic Fatigue Sydrome compared to controls. The studies did not report extreme values (which is the K-M goal).

Above we have the Hand-Picked Suggestions (which uses only the above).

First, we see that two of my favorites (as a person who has dealt with ME/CFS personally) is at the top of the list: Slippery Elm and Triphala. All of the probiotics suggested are non-lactic acid producers: Bifidobacterium. We do have a disagreement with CORE suggestions on Vitamin B6 (CORE says levels may be low, above says avoid). Given that the avoid list is full of B-Vitamins, I would tend to avoid.

Other ways of Getting Suggestions

Since ME/CFS often have cognitive challenges, I have a canned computation ( Changing Your Microbiome / For Chronic Fatigue Syndrome./ Brain Fogged ). The suggestions are below.

Above I did the path that I felt was best focused a person for Chronic Fatigue Syndrome. The scopes here is less bacteria and also flags high Lactobacillus. We could add Lactobacillus to the hand picked bacteria (exercise for the reader), but I am inclined not too because lactobacillus will dominate suggestions because there are so many studies for it, the other bacteria will fade off the suggestions.

Bacteria Name	Analysis
Dorea longicatena	Too Low
Lactobacillus	Too High
Odoribacter splanchnicus	Too Low

There are some others options on the site:

Dr. Jason Hawrelak Guidance

His results are based on general health and not ME/CFS. With this sample, we see these bacteria being selected. There is nothing in common with our first analysis, and only lactobacillus with our one above.

Bacteria Name	Analysis
Akkermansia	Too Low
Bifidobacterium	Too Low
Blautia	Too Low
Faecalibacterium prausnitzii	Too High
Lactobacillus	Too High
Roseburia	Too Low

I would not run with these suggestions — they are simply not focused on ME/CFS.

Symptom Prediction – Citizen Science

The bacteria pattern found with some 1700 prior samples appears to match. This implies that many symptoms are microbiome bacteria caused — something that may be modified. Many of the prediction agrees with what we know. One item is new, Carbohydrate intolerance which is hinted at by our Phytase (Enzyme) recommendation from KEGG.

It also lines up with the iron recommendation and suggests the mechanism for iron being low:

• Potential of Phytase-Mediated Iron Release from Cereal-Based Foods: A Quantitative View [2013]
• ” In the absence of phytase, phytic acid can impede the absorption of other minerals like iron, zinc, magnesium and calcium by binding to them” [2021]

Antibiotics?

The physician being worked with is not dogmatically opposed to using antibiotics. So I did antibiotics only suggestions with the results shown below. Remember this is off label use of these antibiotics.

We have everyone agreeing!!! The Tetracycline family (which includes minocycline and doxycycline). My personal preference in minocycline. Not only do we have agreement between methods — we have agreement with protocols reporting success (to various extents) with ME/CFS. [Success or failure is likely connected to each patience’s microbiome]. This approach fell out of favor during the crackdown on “inappropriate use of antibiotics to prevent antibiotic resistance”, and appears to be considered again in 2021.

• Oral Minocycline Therapy Improves Symptoms of Myalgic Encephalomyelitis, Especially in the Initial Disease Stage [2021]
• Could Minocycline be a “Magic Bullet” for the Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome? [2021]
• Treatment of chronic fatigue syndrome with antibiotics: pilot study assessing the involvement of Coxiella burnetii infection [2005] “we administered tetracycline antibiotics to subjects with CFS …  In the QFS group …mean temperatures and headache scores were significantly decreased after treatment (p<0.001).  performance status scores were also improved.”
• Nicolson GL, Nasralla M, Franco AR, A. Robert F, Nancy LN, et al. (2000) Diagnosis and integrative treatment of intracellular bacterial infections in chronic fatigue and fibromyalgia syndrome, Gulf War illness, rheumatoid arthritis and other chronic illnesses. Clin Pract Alt Med 1: 92-102.
• Role of Rickettsiae and Chlamydiae in the Psychopathology of Chronic Fatigue Syndrome (CFS) Patients: A Diagnostic and Therapeutic Report [2000]
  

In this case, “prescribing antibiotics to address a microbiome dysfunction” (which is exactly what we are doing), would likely fly with most medical review boards 🙂

Bottom Line

We have come up with some very specific suggestions based on the person’s microbiome and ME/CFS as a condition. We have also looked at some less specific approaches. These approaches would often be the “stock-in-trade path” that many medical professional will walk. IMHO, they are “ok” but not as “good” or “awesome” as a really focused approach.

Remember, all suggestions should be discussed with a medical professional before doing. The Microbiome Prescription site goal is to model a variety of diseases and compute theoretical candidates for treatment. In some cases, like this post, we find that many candidates have been tested with positive results. Other candidates have not been and thus are potential ones (with logic and studies inferring their benefit).

A reader forwarded a new study from March, 2021. Unfortunately, ME/CFS seems to be in an infinite loop of similar hypotheses that keep repeating with a preliminary investigation and recommendations that are not followed up. I have seen this pattern over the decades that I have followed CFS/ME research.

Potential role of microbiome in Chronic Fatigue Syndrome/Myalgic Encephalomyelits (CFS/ME)

• Published in Nature : 29 March 2021

The present research explored the composition of the intestinal and oral microbiota in CFS/ME patients as compared to healthy controls. The fecal metabolomic profile of a subgroup of CFS/ME patients was also compared with the one of healthy controls. The fecal and salivary bacterial composition in CFS/ME patients was investigated by Illumina sequencing of 16S rRNA gene amplicons. The metabolomic analysis was performed by an UHPLC-MS. The fecal microbiota of CFS/ME patients showed a reduction of Lachnospiraceae, particularly Anaerostipes, and an increased abundance of genera Bacteroides and Phascolarctobacterium compared to the non-CFS/ME groups. The oral microbiota of CFS/ME patients showed an increase of Rothia dentocariosa. The fecal metabolomic profile of CFS/ME patients revealed high levels of glutamic acid and argininosuccinic acid, together with a decrease of alpha-tocopherol. Our results reveal microbial signatures of dysbiosis in the intestinal microbiota of CFS/ME patients. Further studies are needed to better understand if the microbial composition changes are cause or consequence of the onset of CFS/ME and if they are related to any of the several secondary symptoms.

Abstract

This is not a new finding. Similar have been reported — dating back to 1998. For prior studies see these links:

• PubMed Conditions Citations for Chronic Fatigue Syndrome
• PubMed Conditions Citations for ME/CFS with IBS
• PubMed Conditions Citations for ME/CFS without IBS

Going thru the article and the methodology, I was disappointed on the use of ancient data-analysis (Principal Component Analysis, Canonical correspondence analysis) instead of Random Forest. Moving over to the good news.

The Microbiome of the ME/CFS mouth is a factor!

The study illustrated a clear pattern between controls, patients and the patients’ relatives

This suggests that there is a pre-disposition via the salivary microbiome for ME/CFS. The salivary microbiome is formed by kisses, and just being in the same living space (this was demonstrated in a recent study where the microbiome of family pets were transferred to the children [2021] [2021])

It is nice to see this clearly demonstrated. This has been reported prior Chronic fatigue syndrome patients have alterations in their oral microbiome composition and function. [Sep 2018]

In prior posts, over the last 7 years, I have flagged this issue:

• A mouth full – for better or worst [2014]
• Your mouth can trigger flares [2017]
• Science based mouth wash for ME/CFS [2019]

What are the changes in the mouth bacteria (with links to what modifies these bacteria)

• Actinobacteria (High)
• Actinomycetales (High)
• Micrococcaceae (High)
• Rothia (High)

Bottom Line

The authors asked “if they are related to any of the several secondary symptoms“, the answer is yes. For several years we have demonstrated that on Microbiome Prescription with citizen science.

Similarly, “if the microbial composition changes are cause or consequence of the onset of CFS/ME” can be answered as: Some transitory event (i.e. infection, stress, vaccination) causes a change of the microbiome composition. This altered composition takes on a life of its own and cascade into ME/CFS.

My own experience, and some others, are that by altering the microbiome composition back towards normal, ME/CFS improves or disappears.

The unfortunate aspect is that it cannot be handled in ‘one drug solves it’ or a pro-forma cookbook by medical professionals. Every individual has a different microbiome shift with items suggested for one ME/CFS person being contraindicated for a different ME/CFS person based on their 16s determined microbiome and using the artificial intelligence used for suggestions on Microbiome Prescription.

My expectations are that they will be no traction towards treating ME/CFS by conventional researchers. The reason is simple — the ground rules for studies and processes will send them into cascading challenges which required “stepping outside” of establish processes to get traction. This has been described as the “Dogma of Conformity”.

A reader asked for my thoughts on “Pathophysiology of skeletal muscle disturbances in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)” 21 Apr 2021. With over 20 years of reading many many hypothesis of ME/CFS, I have learnt to look for earlier indicators that it will be unlikely.

First, “skeletal muscle disturbances” applies to a subset of ME/CFS only. The second item is simple – is this a new hypothesis or an old one-recycled? What I found was:

• Symptoms, signs and laboratory findings in patients with chronic fatigue syndrome [1992]
  “The characteristic abnormality in CFS patients is the low values of 17-Ketosteroid-Sulfates/creatinine in morning urine and the acylcarnitine deficiency. It seems likely that this deficiency of acylcarnitine induces an energy deficit in the skeletal muscle, “
  • Long-chain acylcarnitine deficiency in patients with chronic fatigue syndrome. Potential involvement of altered carnitine palmitoyltransferase-I activity [2011]
  • Low levels of serum acylcarnitine in chronic fatigue syndrome and chronic hepatitis type C, but not seen in other diseases [1998]
  • Acylcarnitine deficiency in chronic fatigue syndrome [1994]
  • Serum carnitine and disabling fatigue in multiple sclerosis [1996]
  • Normal carnitine levels in patients with chronic fatigue syndrome[2000] “ The previously reported decreased level of acylcarnitine in CFS patients was not confirmed.“
• Specific correlations between muscle oxidative stress and chronic fatigue syndrome: a working hypothesis [2008]

What is the new hypothesis?

The author’s earlier title was “A Unifying Hypothesis of the Pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Recognitions from the finding of autoantibodies against ß2-adrenergic receptors” [2020] There is no reference to acylcarnitine in the document – this is a red flag for an under-researched paper. You want to cite and discuss prior papers on the same topic.

“sympathetic overactivity in the presence of vascular dysregulation by ß2AdR dysfunction causes predominance of vasoconstrictor influences in brain and skeletal muscles,”

The conclusion is below and amounts (IMHO) to a bunch of hand-waving. The key factor is that the hypothesis is really not testable (hence authors get credit for a publication, suffers of ME/CFS gets nothing).

Considering all the potential predisposing factors we think that in the presence of a high sympathetic tone dysfunction of the ß2AdR could play an essential role (conditio sine qua non) in the etiology of ME/CFS although secondary and rather complex mechanisms have to get involved and to interact, particularly in the chronification of the disease (Figs. 4 and 5). Dysfunction of the ß2AdR by autoantibodies, mutations and desensitization by chronic stress would favor vascular dysfunction and cause insufficient stimulation of the Na⁺/K⁺-ATPase at least as a risk factor together with other precipitating factors. There may be numbers of different, still unknown predispositions.

According to our hypothesis dysfunctions of the ß2AdR or post-receptor mechanisms, of the NHE1, the Na⁺/K⁺ATPase, the NCX, the RAAS and the KKS could be causally involved in ME/CFS and should therefore be further investigated. This concept offers potential novel strategies for the treatment of this debilitating disease.

The only use of the word “treatment” is in the last sentence.

Going to the earlier study by the same author, I read “Metabolic changes in ME/CFS are also in line with a concept of hypoxia and ischemia.” — that echoes the old hypercoagulation hypothesis from Dave Berg [1999, 2000]. The key difference is that Berg’s hypothesis was testable (via the ISAC Panel) and a variety of treatments (depending on the results). For myself, it worked and I went into full remission. This was confirmed in a trial but then a series of poorly done studies faded away. I recall one study that tested using baby-aspirin on ME/CFS patients and reported no results, thus dismissing the coagulation hypothesis.

A major factor in Berg’s hypothesis fading was the complexity of multiple treatment plans was more than most ME/CFS physicians wanted to deal with (give me one magic bullet please!) , patients referred to hematologists were tossed back because low grade chronic coagulation was not of interest to them.

How well studied is ß2-adrenergic receptors?

I checked PubMed and found there is only 16 results. Several deal with asthma, and thus I would expect an association to asthma to be in the ME/CFS literature – which I was unable to find

Bottom Line

I would drop this concept into the circular filing cabinet. It lacks any direct test results on ME/CFS patients to support it, offers no treatments. It is full of speculation and “reasoning”, i.e. “Therefore, QTc shortening can be explained only by ß2AdR dysfunction in the presence of intact ß1-adrenergic receptors and a high sympathetic tone.” The use of the phrase “can be explained only” instead of ” could be explained” signals spin-doctoring and salesmanship to me, not careful science.

‘

This morning I dropped a note to my physician about immune system activation symptoms from getting my 2nd covid shot. One item cited was suspected activation of coagulation resulting in brain fog. I mention that it disappears for half of the day with 300 mg of Piracetam. I expect an email back asking what is Piracetam?

From Wikipedia, you can get general background. It is NOT to be confused with paracetamol (acetaminophen). It’s sits in a murky space in the US, so while legal, without prescription, it can be hard to find.

It improves brain function for many conditions

• [2020] After treatment, the quality of life scores was significantly higher than the control group, and the difference was statistically significant (P<0.05). For patients with vascular dementia after cerebral infarction, piracetam combined with nimodipine can improve the cognitive function, improve the quality of life, and have a significant clinical effect.
• [2021] Although Piracetam is officially recognized as a nootropic, its enhancing effects in the healthy individual’s brain are moderate [104,54]. The racetam molecules are being used across a range of brain disorders, including Alzheimer’s disease, narcolepsy, ADHD, Parkinson’s disease and brain aging [105,106].
• [2020] Piracetam shifted the balance of mitochondrial fission or fusion toward fusion, which is more favorable for ATP production, which would indirectly benefit synaptic function because of the energy requirements of synapses. ⁴³ A review indicated favorable effects on neurotransmission and neuroplasticity. ⁴⁴ Another report showed that the increased neurite length after piracetam treatment was accompanied by increased expression of the synaptic marker GAP43, thus improving neural plasticity. ⁴⁵

In days long ago when I often fly between Seattle and India for work, I used a heparin-piracetam cocktail to reduce risk of DVT. As a side effect, I never experienced jet-lag.

• [1998] ” The heparin-piracetam complex had a more pronounced anticoagulant and fibrinolytic activities than the individual components.”
• [1993] “The particular efficacy of 8 g piracetam daily in 3 divided doses at 8-hourly intervals can be attributed to its unique dual mode of action; inhibition of platelet function by inhibition of thromboxane A2 synthetase or antagonism of thromboxane A2 and increased formation of prostaglandin I2, together with a rheological effect involving reduction in blood and plasma viscosity through an increase in cell membrane deformability and a reduction of 30-40% in the plasma concentrations of fibrinogen and von Willebrand’s factor”

This last study is why it is my go to when brain fog occurs. I have a mutation that results in higher levels of fibrinogen.

Coagulation in various forms in ME/CFS was demonstrated in the late 1990’s by David Berg. [Other Berg Links: [A,B, *] .

COVID Coagulation

Doing a search on PubMed for “covid coagulopathy“, we find over 1100 citations. For long haul covid to include persistent coagulation is very probable. It may be due to microbiome alterations or other mechanisms.

Bottom Line

Trying piracetam for brain fog is something to discuss with your MD. You may need to educate him about the contents of this article. The [1993] study was on humans and thus showed safety and also dosage (8 grams/day in 3 dosages).