I have done prior posts on POTS (POTS Revisited) and been requested to check the latest research. Checking PUBMED statistics, we see there have been many papers in the last few years

• “The physiology underlying “brain fog” in the absence of orthostatic stress in postural tachycardia syndrome (POTS) remains poorly understood. … greater slowing in psychomotor speed and a greater increase in symptom scores at study completion in the patients with POTS, including increased difficulty with concentration. All other physiologic responses (blood pressure and end-tidal carbon dioxide) did not differ between groups after PCST ” [2020]
• Restless legs syndrome is increased in postural orthostatic tachycardia syndrome [2020]
• Dry Eye Syndrome and Sicca Complex are Commonly Found in Patients with Postural Orthostatic Tachycardia Syndrome [2020]
• Mechanisms and management of gastrointestinal symptoms in postural orthostatic tachycardia syndrome [2020]
• Treatment of Postural Orthostatic Tachycardia Syndrome With Medication: A Systematic Review [2020] “Postural orthostatic tachycardia syndrome has been recognized for decades, but treatment is largely based on anecdotal experience and expert opinion. Pharmacologic treatment is inconsistent and unstandardized. …There is a paucity [very few] of high-quality data about effectiveness of medication in the treatment of postural orthostatic tachycardia syndrome. “

Trying Citizen Science

We have 55 samples annotated with POTS and we recently added enzymes to the system. Time to go on a statistical fishing expedition… and we found some fish, all of them small one (i.e. too low production)

EnzymeName	POTS Average	No POTS Average	Test Statistic	Obs
crotonobetainyl-CoA reductase	174	1500	-5.31511	28
L-carnitine CoA-transferase	177	1381	-5.04204	31
D-apionate oxidoisomerase	573	1541	-4.57861	29
nitrite reductase (NO-forming)	5311	17941	-4.46254	51
5-aminopentanamidase	5900	16862	-4.31631	51
phosphatidyl-myo-inositol alpha-mannosyltransferase	5523	17379	-4.16094	50
cysteinylglycine-S-conjugate dipeptidase	5611	17868	-4.15823	48
polyphosphate—glucose phosphotransferase	5621	17638	-4.09764	48
8-oxo-dGDP phosphatase	5725	17788	-4.05173	47
8-oxo-(d)GTP phosphatase	5930	17351	-3.93432	48
lactocepin	1411	8104	-3.90514	50
formyl-CoA transferase	5998	17156	-3.84911	46
oxalyl-CoA decarboxylase	6234	18799	-3.80263	39
galactofuranosylgalactofuranosylrhamnosyl-N-acetylglucosaminyl-diphospho-decaprenol beta-1,5/1,6-galactofuranosyltransferase	5714	14910	-3.60734	50
lipid II isoglutaminyl synthase (glutamine-hydrolysing)	8292	22101	-3.5937	54
galactan exo-1,6-beta-galactobiohydrolase (non-reducing end)	6876	19457	-3.53129	35
N-acetylhexosamine 1-kinase	6876	19434	-3.52637	35
dehydrogluconokinase	6710	18931	-3.52007	36
Pup amidohydrolase	5718	15393	-3.51166	47
prokaryotic ubiquitin-like protein ligase	5718	15393	-3.51166	47
all-trans-retinol dehydrogenase (NAD+)	6484	17326	-3.47966	41
gamma-glutamyl hercynylcysteine S-oxide hydrolase	6876	19217	-3.47867	35
glucosyl-3-phosphoglycerate phosphatase	7804	18811	-3.474	50
isopenicillin-N epimerase	6367	17710	-3.44546	38
2-acetylphloroglucinol acetyltransferase	6295	15991	-3.43971	45
phosphatidylinositol dimannoside acyltransferase	8899	20502	-3.38033	50
dolichyl-phosphate-mannose—protein mannosyltransferase	8156	17812	-3.34246	54
sorbose reductase	6144	15938	-3.29349	41
tRNA (adenine57-N1/adenine58-N1)-methyltransferase	8093	18743	-3.26853	48
tRNA (adenine58-N1)-methyltransferase	8093	18743	-3.26853	48

This is actually a happy path because for too low, we can identify probiotics that produces these missing enzymes. Three bifidobacterium are at the top of the list. Custom Probiotics daily recommended dosage for these are 350-400 BCFU /day.

bacillus pumilus	8
bacillus simplex	2
bacillus velezensis	8
bifidobacterium adolescentis	26
bifidobacterium animalis subsp. lactis bb-12	26
bifidobacterium longum	26
clostridium beijerinckii	5
clostridium butyricum	5
enterococcus durans	1
enterococcus faecalis	1
lactobacillus acidophilus	4
lactobacillus helveticus	4
lactobacillus kefiri	2
lactobacillus paracasei	2
lactobacillus plantarum	1
lactobacillus rhamnosus (strain atcc 53103 / gg)	2
lactobacillus salivarius	2
lactococcus lactis	3
leuconostoc lactis	2
streptococcus thermophilus	3

Bottom Line

We have deduced which probiotics should help POTS (if taken in sufficient dosage) by using citizen science on the annotated-with-symptoms uploads, the KEGG Enzyme data and statistics. We may not know the why’s of these enzymes missing causing POTS, but we have some ideas of where to start looking for explanations. Until then, we at least know what to try.

There have been NO STUDIES using Bifidobacterium probiotics with POTS published.

Again consult with your medical professional first.

This person has an interesting set of symptoms for ME/CFS. 40 yo male. I am following the same pattern as the two previous analysis. Every ME/CFS person share some factors and are different in other factors. There is nothing that works for all ME/CFS people.

• Symptoms
  • Depression
  • Irritability
  • Brain fog
  • Post exercise malaise
  • Tinnitus
  • Post nasal drip
  • Stuffy nose
  • Cold extremities & insensitivity to cold
  • Fragmented sleep
  • Low libido
  • Low appetite
  • Frequent bowel movements
• I’ve had different tests and bloodwork done over the years and these were the common outliers:
  • Low DHEA-s
  • Very high B12
  • High Vitamin D despite not supplementing
  • Low Estradiol (E2)
  • Mild blood coagulation
  • High(ish) eosinophils% (~5%)

Looking at Naive Predicted Symptoms From Bacteria table, we have:

Enzyme Analysis

The awesome results in a past post on an autism child, where the enzymes were identified as coming from bacteria species constantly reported as high with Autism, is causing me to look at enzymes shifts as a good strategy to identify the key bacteria to look at.

So the next step is to look for probiotics that can also produce these enzymes.

The easiest combination to obtain retail from the above are clostridium butyricum (Miyarisan ) which produces all 5 enzymes! or any of bifidobacterium adolescentis, bifidobacterium animalis subsp. lactis bb-12, and bifidobacterium longum. The latter ones (without additives) are available at Custom Probiotics (with a recommended daily dosage of 320-400 BCFU/daily) at the lowest cost per BCFU that I have seen.

KEGG Module Analysis

This is another way to evaluate the functions of the bacteria in a microbiome sample. There are less items then with Enzymes and, to be honest, I have not examined the results much after adding the code and data to compute them. There was nothing there.

End Product Outliers

Nothing was found outside of the ranges, and looking at Core Supplements there was one item of concern, high d-lactate production. High D-lactate is associated with neurological issues. (See these posts: Killing Lactobacillus to improve Brain Fog, Approaches to D-Lactic Acidosis). We also see that the microbiome suggests high B-12 (at 76%ile) which the labs report.

Unlike my last post on an autism child, there were no high enzymes to indicate the troublesome bacteria.

We turn to the Advance Suggestion engine and apply some filters.

Pass 1 for suggestions

First from Citizen Science we look at filtering for neurological decision making and drive a blank until we widen the search as shown below

Looking at the suggestions, we only find one item in common with the prior ME/CFS person: inulin (prebiotic).

Top probiotics suggestions all contain  saccharomyces boulardii. Flavonoids are a short list

• Barley, hulled – Weight: 0.98
• Barley, whole grain flour – Weight: 0.98
• Walnut – Weight: 0.98

This is close to my usual breakfast for many months: Barley porridge with walnuts!

Pass 2 for suggestions

We change the filtering to CFS/ME and drop back to the most extreme 3% – where we get results

We have a conflict on triphala. One subset of bacteria says to use it, a different subset says not to use it. Given that it’s the highest value in both cases we need to do an experiment. I would advocate doing triphala for 4-6 weeks to see if it improves neurological issues, then stop it and re-evaluate.

We have a long list of probiotics, all with appropriately the same value

Bottom Line

Remember this is strictly on the basis of the microbiome and our current state of knowledge in interpreting and being able to act on it. It is important not to view microbiome analysis as a magic silver bullet. A summary of suggestions to discuss with your medical professional.

• Probiotics
  • lactobacillus plantarum (probiotics)
  • At least one of bifidobacterium adolescentis, bifidobacterium animalis subsp. lactis bb-12, and bifidobacterium longum.
  • saccharomyces boulardii.
• Foods
  • Trial on triphala
  • Barley (and oats?) – note this would be deemed low or no gluten by some people
  • Walnuts
  • Inulin
• For brain fog issues (see earlier links)
  • berberine
  • neem
  • enterococcus faecium (probiotic)
  • miyarisan (clostridium-butyricum)
  • 100 mg every 12 hours of Thiamine (Vitamin B1) 
  • Acetylcysteine (NAC),
• For low-grade coagulation, See
  • Coagulation: Thick Blood Supplements for CFS )

In summary, clinical studies have tested some substances on various conditions which have been reported on PubMed. Microbiome analysis is based on microbiome shifts reported on PubMed by consuming some substances (ignoring medical conditions usually). If you construct a full list of both sets of substances, you will likely have only 10-20% of the substances in common. What has been studied in one context, has not been studied in the other context. Microbiome analysis is complimentary, not a replacement.

As always, to be reviewed with your medical professional before starting. There are algorithm/artificial intelligence generated suggestion based on data that has been entered (usually from gold standard sources).

Postscript on High Vitamin D

See these posts:

• Vitamin 25D and 1,25D measure – one reduces symptoms and one indicates CFS state
• Vitamin D and the Microbiome
• Autoimmune and Vitamin 1,25D

Feed back from person

” Indeed very insightful! Strangely enough, walnuts, tea and inulin both made me feel better despite not knowing why and your analysis make a lot of sense.”

This person has an interesting set of symptoms for ME/CFS. 34 yo female

• Neurological
  • Visual agnosia (inability to interpret sensations and hence to recognize things, typically as a result of brain damage.)
  • Severe hyperphagia ( abnormally strong sensation of hunger or desire to eat often leading)
  • Severe sleep circadian rhythm disturbance (only thing it responded to shortly was methylated Bs)
  • social anxiety (was severe now mild)
  • brain fog 
  • intermittent prosopagnosia ( the inability to recognize the faces of familiar people)
  • sensory overload – can’t stand showers, need darker room often

• Many of the above responds in some way to antibiotics 
• Official Diagnosis: autonomic/small fiber neuropathy, POTS, Hashimoto and now Sjogrens sicca with swollen parotids.

The positive response to antibiotics suggests that the microbiome pays a significant factor.

Looking at Naive Predicted Symptoms From Bacteria table, we have:

For predicted medical conditions from PubMed studies, we had one good match, Hay Fever — and for that it was due to no Clostridium butyricum being found. Note that bacteria because it reoccurs as an issue using an entirely different analysis path.

Enzyme Analysis

The awesome results in my last post on an autism child, where the enzymes were identified as coming from bacteria species constantly reported as high with Autism, is causing me to look at enzymes shifts as a good strategy to identify the key bacteria to look at.

So the next step is to look for probiotics that can also produce these enzymes.

The easiest combination to obtain retail from the above are clostridium butyricum (Miyarisan ) which produces all 11 enzymes! and streptococcus thermophilus (which produces 10/11) and is available without other things at Custom Probiotics (with a recommended daily dosage of 320 BCFU). Miyarisan is cited in my 2017 post, What is the ideal probiotic for CFS / IBS / FM patients? As always, start with a low dosage and increase to a therapeutic dosage (typically 3x the normal dosage) after consulting with your medical professional.

Note that the prior analysis of a ME/CFS person’s microbiome also have these two probiotics being the first choice.

• Probiotic Streptococcus thermophilus FP4 and Bifidobacterium breve BR03 Supplementation Attenuates Performance and Range-of-Motion Decrements Following Muscle Damaging Exercise
• Other studies used streptococcus thermophilus with other bacteria and found neurological improvements.

KEGG Module Analysis

This is another way to evaluate the functions of the bacteria in a microbiome sample. There are less items then with Enzymes and, to be honest, I have not examined the results much after adding the code and data to compute them. So here goes….

The first item above is associated with Vitamin C (Ascorbate) and influences gene expression [2018]. Looking at the chart below, I notice that H2O2 (hydrogen peroxide) is associated with it. Hydrogen peroxide is a major player for controlling some bacteria. It also feeds the Pentose phosphate pathway which cites “The PPP is one of the three main ways the body creates molecules with reducing power, accounting for approximately 60% of NADPH production in human”

Unfortunately, none of the bacteria producing this exist as probiotics.

End Product Outliers

Nothing was found outside of the ranges, but looking at Core Supplements there are two suggestions (low values, i.e. between 3 and 10ile%) Vitamin D, DAO Producing (diamine oxidase) with Cobalamin (Vitamin B12) and Gamma-Amino butyric acid (GABA) sitting around 15%ile. These are commonly used with ME/CFS and helpful to many. Because this person has cognitive issues, I did a little research on possible dosages.

• Suggested Dosages (should be reviewed with your medical professional)
  • Vitamin D: See this post for calculation, I suspect 10-15,000 IU/day
  • Cobalamin (Vitamin B12): 2000 μg/day
    •  One trial used 2000 μg/day vitamin B₁₂ and demonstrated a mean difference of 680 pg/mL (95% confidence interval 392.7 to 967.3) in favour of oral vitamin B₁₂ [2018]
  • GABA: 300 mg /day (2018)
    • [Gamma-aminobutyric acid–metabolism and its disorders].“stiff-person syndrome, chronic fatigue syndrome, anxiety disorders and seizures”
    • Brain Fog association (sub-clinical hypercoagulation):
      • [The effect of various doses of gamma-aminobutyric acid, adrenaline and insulin on coagulation time, prothrombin time and the prothromboplastic activity of rat blood]
      • Effect of GABA derivatives on the rate of thrombus formation, platelet aggregation, and plasma coagulation capacity in rats with experimental gestosis
      • Effects of Oral Gamma-Aminobutyric Acid (GABA) Administration on Stress and Sleep in Humans: A Systematic Review [2020]
  • DAO: Nothing dosage specific, people that I know who uses it, does it on an in-need basis.
    • “Histamine intolerance, also referred to as enteral histaminosis or sensitivity to dietary histamine, can be defined as a disorder arising from reduced histamine degradation capacity in the intestine due to impaired DAO activity, leading to its accumulation in plasma and the appearance of adverse effects [11,41,55].”

The above are compensating items that should be taken daily (or broken in every 8-12 hrs) which attempts to create a more healthy/normal environment for the rest of the microbiome and body to be living in. They are symptom relief and likely not cause relief — which takes us to the next step: Clostridium butyricum:

Unlike my last post on an autism child, there were no high enzymes to indicate the troublesome bacteria.

We turn to the Advance Suggestion engine and apply some filters.

Pass 1 for suggestions

First from Citizen Science we look at filtering for neurological decision making and drive a blank until we widen the search as shown below

Flavonoid Foods (Most important first): Pomegranate, Apples, Nuts, almonds ,Coconut (and water), Bananas, Cinnamon, and Dates, deglet noor 

Pass 2 for suggestions

We change the filtering to CFS/ME and drop back to the most extreme 3% – where we get results

Flavonoid Foods was similar to above, but apples and banana were dropped off.

Bottom Line

Remember this is strictly on the basis of the microbiome and our current state of knowledge in interpreting and being able to act on it. It is important not to view this as a magic silver bullet. This person has some symptoms where the existing medical literature has suggestions (and which I have done posts summarizing and cited sources for ME/CFS) including the following:

• Bacopa monniera and Cognitive Function (we have no information on this supplement impact on the microbiome)
• Intrinsic Factor and low Vitamin B-12 levels Cognitive Impact
• The Neuroprotectors: Remember your super heroes for cognitive issues!
• Dry Eye Disease (Sjogren)/Syndrome – where suggestions include, Bioferim S (containing 2 of the probiotics suggested above)
• CFS: Insomnia and Sleep Disturbance
• Anxiety and the Microbiome
• POTS Revisited
• Microbiome Site Update – POTS and ALA
• and this older decision chart A decision chart for biohacking M.E. et al and What is comorbid with CFS/FM 

In summary, clinical studies have tested some substances on various conditions which have been reported on PubMed. Microbiome analysis is based on microbiome shifts reported on PubMed by consuming some substances (ignoring medical conditions usually). If you construct a full list of both sets of substances, you will likely have only 10-20% of the substances in common. What has been studies in one context, has not been studied in the other context. Microbiome analysis is complimentary, not a replacement.

From the Microbiome

We have two set of items from above

• Items that will compensate for existing issues with enzymes and end product production (symptom relief)
  • Miyarisan, Vitamin D, DAO Producing (diamine oxidase), Cobalamin (Vitamin B12), Gamma-Amino butyric acid (GABA), streptococcus thermophilus

• Items that will help shift the microbiome to a better state (fixing the root problem) – this is based on one of dozens of possible filtering of bacteria into subsets.
  • Number 1 item is Cocoa — as in 85% – 92% Chocolate daily (or more often)… a rough prescription
  • Several different probiotics (if you get a mixture — make sure that it is on the positive list. Some species of probiotics will make things worse for some people).

Oops — we forgot antibiotics

This user had improvement on antibiotics, so which ones are suggested? Back to the suggestion page and checking/unchecking items.

And more important, which ones to avoid!

As always, to be reviewed with your medical professional before starting. There are algorithm/artificial intelligence generated suggestion based on data that has been entered (usually from gold standard sources).

A reader has been kind and granted permissions to use their samples for another analysis. The samples were done by Thryve, and the FASTQ files processed thru Biome Sight. There was also a GI-MAP result available.

The medical diagnosis is Seizures Lennox-Gastaut syndrome to be exact. And severe low functioning autism. It is suspected/speculated that the cause was vaccine injury.

Enzyme Analysis

First I am going to look at the last sample and then do a comparison to the three prior ones. I am starting to feel that the Enzyme analysis is a good indicator of microbiome dysfunction. It measures thousands of enzymes using the genes found in the bacteria found.

• Thryve: Literally 139 Items, all HIGH VALUES
• BiomeSight: 131 items most high with 9 low and 12 low.

Probiotic suggests are only for LOW values (i.e. bacteria that produces the enzymes that you are low in). The list looks similar to prior analysis with lactobacillus paracasei being prominent.

Comparing latest to prior, we found

• Thryve: Literally 190 Items being outside of the earlier ranges. Some increasing and some decreasing, the general pattern is ones with high ranges are going higher, and those with low ranges are going lower 😦

• BiomeSight: 36 items all showing lower values than the 3 prior samples
  

In short, there appears to be a major dysfunction for the enzymes being produced, and it seems to be getting worst.

But…. For End Products, with both samples, there was no change from prior samples. Thryve alone reported possible outliers — all of them them high values (thus no sense in taking supplements for these)

For Bacteria Changes:

• Thryve showed an major increase in Clostridium intestinale, Bacteroides uniformis, Bacteroides cellulosilyticus, Alistipes shahii, Mycoplasmatales with the values being high compared to other uploaded samples.
• BiomeSight showed major increase in Bacteroides uniformis, Bacteroides cellulosilyticus, with the values being high compared to other uploaded samples.

GI MAP Report

The following abnormalities were reported.

• Escherichia spp. – 50% below low bound – Not reported by Thryve or Biomesighe
• Akkermansia muciniphila – 4700% above high bound (between 30-65%ile on samples)
• Firmicutes – slightly above high bound (between 20-70%ile)
• Bacillus spp. – 7800% above high bound (all between 50-75%ile, except for one at 15%ile)
• Enterococcus faecalis – 8230% above high bound (none reported)
• Pseudomonas spp. – 132% above (all between 50-70%ile)
• Streptococcus spp. -2920% above (all between 28%-60%ile)

In short, none of the samples are in agreement with the report from GI-MAP. Personally, I do not have GI-MAP on my reliable/useful lab reports — the above differences are just too troubling.

Approach: Backtrack from Enzymes to Bacteria

These samples are a problem for traditional analysis. Individual bacteria may well be in the normal range, but may be in the high end of these ranges, causing too much enzymes to be produced when a bunch occur at the same time.

The result was my creating a novel analysis process: Compute by backtracking from the enzymes to the genes that produces the enzymes, and then use these genes to backtrack to the species and strains that have those enzymes. From both labs reading of FASTQ files, we get the same dominant players as shown below. Faecalibacterium prausnitzii was interesting — because of the high count, many will assume it to be a major player… it’s not (remember the counts for this bacteria will be different from each lab).

I then wired this into the existing suggestion system using the hand-picked bacteria approach (all are pre-selected on this page). You will now see a new button on the sample pages.

You can then custom tune the suggestions you wish to receive. For example, restricting to drugs and herbs, we have:

Pass 2

Since we are entirely at the species level, we may wish to include items that modify the genus these species are in. This is a simple change.

Suggestions were very similar without significant changes. Including probiotics, nothing showed a reasonable confidence (i.e. lactobacillus paracasei (probiotics) was a 0.038, I usually stop at 0.5)

Bottom Line

There are many paths for getting suggestions. For this person, the usual paths had been tried before with little success from experts that I know. When I saw the Enzyme madness, I realized that the first goal, a measurable goal in subsequent samples, is reducing these high enzyme levels.

To do this, I had to add more algorithms to the site to allow a backtrace from enzymes to bacteria.

In checking the literature for Epilepsy, I found the following articles which may be worth reviewing

• Gut Microbiota, the Ketogenic Diet and Epilepsy [2018] – no symptom improvement cited with KD diet
• Current Perspectives On The Role Of The Ketogenic Diet In Epilepsy Management [2019] “Multiple trials have demonstrated that KD is an effective treatment modality in children with Dravet Syndrome” but not for this person’s condition

Of interest/concern is that with KD diets, “after KD therapy and revealed significantly decreased abundance of Firmicutes and increased levels of Bacteroidetes.” In this case HIGH Bacteroidetes appear to be the issue, at least specific species, changing the Bacteroidetes species may result in positive results — speculation.

Now going to the other aspect, Autism

• Gut Microbiota Features in Young Children With Autism Spectrum Disorders [2018]
  “22 Bacteroidetes OTUs owing to genus Bacteroides, mainly assigned to B. uniformis and B. vulgatus and P. distasonis species, were more abundant in ASD patients … an increase of Faecalibacterium prausnitzii,  “
• Fecal Microbiota and Metabolome of Children with Autism and Pervasive Developmental Disorder Not Otherwise Specified [2013] Table 2 list many of the species that we identified above.

My conclusion, for these samples, is that looking at the enzyme shifts lead us back to the same bacteria already identified for autism. What we’ve added is that a contributing factor for autism may be the overproduction of specific enzymes which may lead to alternative treatment approaches. Using this as an assumption, we also can rank order the most important ones to change (i.e. Bacteroides uniformis – links to a list of items that inhibits this specific bacteria)

Recipe book to discussion with Medical Professional

• Vitamins:
  • Vitamin C (ascorbic acid)
  • B Vitamins ( B1, B3, B6, B7, B-9, B12)
• Melatonin supplement
• Herbs and Spices: Cinnamon, Thyme, Anise, Fennel
• Supplements
  • N-Acetyl Cysteine (NAC)
• Probiotics:
  • CustomProbiotics.com / L. Casei Probiotic Powder :
  • schiff / digestive advantage (any that contains bacillus coagulans – I believe there are some gummies available with it)
• Foods
  • whole-grain barley (ideally as porridge every day)
  • walnuts
  • momordia charantia(bitter melon, karela, balsam pear, or bitter gourd) – may be an acquired taste

None of the following: Licorice, resistant starch , tannic acid (cranberries, strawberries, blueberries, apricots, barley, peaches, mint, basil, rosemary), stevia, saccharin

Toss up on apples — some of its ingredients may help or make worse. Do as an experiment when he is stable.

Remember this is not medical advice, before doing any changes make sure that you review them with your medical professional. This is what a data nerd logically deduced (showing their logic), and not a qualified medical professional.

For latest codes, see https://cfsremission.wordpress.com/top-microbiome-providers-with-discount-codes/