In an earlier post I cited supplements demonstrated in human clinical trials to lower blood pressure. A still earlier post looked at gut bacteria associated with hypertension and hypotension. I have collected the bacteria shifts reported from studies published on PubMed here

Literature of the microbiome bacteria

The following are the sources for the bacteria information

Administration with Quinoa Protein Reduces the Blood Pressure in Spontaneously Hypertensive Rats and Modifies the Fecal Microbiota. Nutrients (Nutrients ) Vol: 13 Issue 7 Pages: Pub: 2021 Jul 17 Epub: 2021 Jul 17 Authors Guo H , Hao Y , Fan X , Richel A , Everaert N , Yang X , Ren G , Summary Html Article Publication

Changes of gut microbiome composition and metabolites associated with hypertensive heart failure rats. BMC microbiology (BMC Microbiol ) Vol: 21 Issue 1 Pages: 141 Pub: 2021 May 5 Epub: 2021 May 5 Authors Li L , Zhong SJ , Hu SY , Cheng B , Qiu H , Hu ZX , Summary Html Article Publication

Improvement of intestinal flora: accompany with the antihypertensive effect of electroacupuncture on stage 1 hypertension. Chinese medicine (Chin Med ) Vol: 16 Issue 1 Pages: 7 Pub: 2021 Jan 7 Epub: 2021 Jan 7 Authors Wang JM , Yang MX , Wu QF , Chen J , Deng SF , Chen L , Wei DN , Liang FR , Summary Html Article Publication

Associations between gut microbiota, faecal short-chain fatty acids, and blood pressure across ethnic groups: the HELIUS study. European heart journal (Eur Heart J ) Vol: 41 Issue 44 Pages: 4259-4267 Pub: 2020 Nov 21 Epub: Authors Verhaar BJH , Collard D , Prodan A , Levels JHM , Zwinderman AH , Bäckhed F , Vogt L , Peters MJL , Muller M , Nieuwdorp M , van den Born BH , Summary Html Article Publication

Changes in the Gut Microbiota are Associated with Hypertension, Hyperlipidemia, and Type 2 Diabetes Mellitus in Japanese Subjects. Nutrients (Nutrients ) Vol: 12 Issue 10 Pages: Pub: 2020 Sep 30 Epub: 2020 Sep 30 Authors Takagi T , Naito Y , Kashiwagi S , Uchiyama K , Mizushima K , Kamada K , Ishikawa T , Inoue R , Okuda K , Tsujimoto Y , Ohnogi H , Itoh Y , Summary Html Article Publication

Human genetic determinants of the gut microbiome and their associations with health and disease: a phenome-wide association study. Scientific reports (Sci Rep ) Vol: 10 Issue 1 Pages: 14771 Pub: 2020 Sep 8 Epub: 2020 Sep 8 Authors Groot HE , van de Vegte YJ , Verweij N , Lipsic E , Karper JC , van der Harst P , Summary Html Article Publication

Differential Analysis of Hypertension-Associated Intestinal Microbiota. International journal of medical sciences (Int J Med Sci ) Vol: 16 Issue 6 Pages: 872-881 Pub: 2019 Epub: 2019 Jun 2 Authors Dan X , Mushi Z , Baili W , Han L , Enqi W , Huanhu Z , Shuchun L , Summary Html Article Publication

Critical Role of the Interaction Gut Microbiota – Sympathetic Nervous System in the Regulation of Blood Pressure. Frontiers in physiology (Front Physiol ) Vol: 10 Issue Pages: 231 Pub: 2019 Epub: 2019 Mar 8 Authors Toral M , Robles-Vera I , de la Visitación N , Romero M , Yang T , Sánchez M , Gómez-Guzmán M , Jiménez R , Raizada MK , Duarte J , Summary Html Article Publication

DIFFERENCES IN MICROBIOME IN RAT MODELS OF CARDIOVASCULAR DISEASE. South African journal of surgery. Suid-Afrikaanse tydskrif vir chirurgie (S Afr J Surg ) Vol: 55 Issue 2 Pages: 71 Pub: 2017 Jun Epub: Authors Thiba A , Umar CA , Myende S , Nweke E , Rumbold K , Candy G , Summary

Altered Gut Microbiome Profile in Patients With Pulmonary Arterial Hypertension. Hypertension (Dallas, Tex. : 1979) (Hypertension ) Vol: Issue Pages: HYPERTENSIONAHA11914294 Pub: 2020 Feb 24 Epub: 2020 Feb 24 Authors Kim S , Rigatto K , Gazzana MB , Knorst MM , Richards EM , Pepine CJ , Raizada MK , Summary Publication Publication

Intestinal Flora Modulates Blood Pressure by Regulating the Synthesis of Intestinal-Derived Corticosterone in High Salt-Induced Hypertension. Circulation research (Circ Res ) Vol: Issue Pages: Pub: 2020 Feb 13 Epub: 2020 Feb 13 Authors Yan X , Jin J , Su X , Yin X , Gao J , Wang X , Zhang S , Bu P , Wang M , Zhang Y , Wang Z , Zhang Q , Summary Publication Publication

Exercise and food supplement of vitamin C ameliorate hypertension through improvement of gut microflora in the spontaneously hypertensive rats. Life sciences (Life Sci ) Vol: 269 Issue Pages: 119097 Pub: 2021 Mar 15 Epub: 2021 Jan 19 Authors Li Y , Zafar S , Salih Ibrahim RM , Chi HL , Xiao T , Xia WJ , Li HB , Kang YM , Summary Publication

Enterococcus faecalis contributes to hypertension and renal injury in Sprague-Dawley rats by disturbing lipid metabolism. Journal of hypertension (J Hypertens ) Vol: 39 Issue 6 Pages: 1112-1124 Pub: 2021 Jun 1 Epub: Authors Zhu Y , Liu Y , Wu C , Li H , Du H , Yu H , Huang C , Chen Y , Wang W , Zhu Q , Wang L , Summary Publication

Bifidobacterium reduction is associated with high blood pressure in children with type 1 diabetes mellitus. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie (Biomed Pharmacother ) Vol: 140 Issue Pages: 111736 Pub: 2021 Aug Epub: 2021 May 23 Authors Lakshmanan AP , Shatat IF , Zaidan S , Jacob S , Bangarusamy DK , Al-Abduljabbar S , Al-Khalaf F , Petroviski G , Terranegra A , Summary Publication

Gut microbiome diversity and composition is associated with hypertension in women. Journal of hypertension (J Hypertens ) Vol: Issue Pages: Pub: 2021 May 10 Epub: 2021 May 10 Authors Louca P , Nogal A , Wells PM , Asnicar F , Wolf J , Steves CJ , Spector TD , Segata N , Berry SE , Valdes AM , Menni C , Summary Publication

Probitotics

From Theoretical Model

These are based on the bacteria reported above and an AI engine on the impact of various probiotics (in order of confidence). Links to dosages found to be sufficient to cause changes in clinical trails are after each. It is a common mistake to take ‘homeopathic” dosage, that is, if a product contains one of these, then that is sufficient. This thinking is akin to thinking that a squirt gun is sufficient to put out a wildfire!

1. bacillus subtilis (probiotics)   📏🍽️ Dosages — Confirmed in Animal Studies
2. lactobacillus rhamnosus (probiotics)   📏🍽️ Dosages – Animal studies
3. lactobacillus plantarum (probiotics)   📏🍽️ Dosages -slight impact sometimes
4. lactobacillus reuteri (probiotics)   📏🍽️ Dosages
5. lactobacillus acidophilus (probiotics)   📏🍽️ Dosages
6. saccharomyces boulardii (probiotics)   📏🍽️ Dosages
7. bifidobacterium bifidum (probiotics)   📏🍽️ Dosages
8. bifidobacterium longum (probiotics)   📏🍽️ Dosages
9. lactobacillus casei (probiotics)   📏🍽️ Dosages

From Animal Studies

Often animal studies do NOT replicate to humans, so care need to be taken. Where it available, the strain is give with a link to the study.

• Lactobacillus fermentum CECT5716 (LC40) [2021]
• Bifidobacterium breve CECT7263 (BFM) [2021]
• ” The fermentation of beans with Bacillus Subtilis B060 may therefore constitute a successful strategy for producing a functional food with antihypertensive activity.” [2014]
• “water extracts of Bacillus subtilis-fermented pigeon pea (100 mg/kg body weight) significantly improved systolic blood pressure (21 mmHg) and diastolic blood pressure (30 mmHg) in spontaneously hypertensive rats.” [2015]
• ” treatment of model rats with Lactobacillus rhamnosus GG prevented aggravation of hypertension by reducing blood TMAO levels, modulating Th1/Th2 cytokine imbalance and suppressing phosphorylation levels of ERK1/2, Akt and mTOR.”[2019]

From Human Studies

• NO EFFECT from  Lactobacillus plantarum PS128 [2031] -dosage was sufficient
  • “The clinical significance of blood pressure-lowering effect of Lactobacillus Plantarum supplementation is not considerable; ” [2020]
  • “Our meta-analysis showed a modest but a significant reduction in SBP and DBP in patients with hypertension, particularly in those with diabetes mellitus, following probiotic supplementation. This effect was associated with treatment duration, dosage, and the age of subject but was not associated with single or multiple strains usage. Additionally, probiotic supplement had a beneficial effect in reducing BMI and blood glucose.” [2020]
• “Lactobacillus consumption significantly reduced systolic blood pressure (SBP) by -2.74 mmHg and diastolic blood pressure (DBP) by -1.50 mmHg when comparing with the control group.” Dosage above 5 Billion CFU per day. [2020]
• “Probiotic consumption significantly changed systolic BP by -3.56 mm Hg and diastolic BP by -2.38 mm Hg compared with control groups.” After 8 weeks at 10+ Billion CFU/day [2014] No strains or species specified
• “Lactobacillus para casei LPC-37, Lactobacillus rhamnosus HN001, Lactobacillus acidophilus NCFM, and Bifidobacterium lactis HN019 (109 CFU of each strain) for 8 weeks….Probiotic supplementation lowered, although without statistical significance, systolic BP by about 5 mmHg and diastolic BP by about 2 mmHg in hypertensive women.” [2020]
• Saccharomyces boulardii  – no effect [2012]
• Bifidobacterium reduction is associated with high blood pressure in children with type 1 diabetes mellitus [2021] — this does not mean the probiotics will have significant effect because bifidobacterium rarely persist and are gone in hours. However, the consumption of oat bran, reduces BP and increases bifidobacterium [2021]

Bottom Line

Bacillus subtilis (especially the Natto strain) appears to be most effective, both from a theoretical and animal study point of view. The theoretical model appears to work reasonably. Probiotic consumption appears to do no harm from clinical studies — however, the theoretical model indicates some may increase the microbiome shifts in the wrong direction.

Using supplements and changing diet (i.e. having oat bran daily) will have a far greater impact.

This post is an update of an earlier post. It deals mainly with non-prescription items. Some prescription items can have adverse effects on the microbiome seen with other conditions. “No medical condition is an Island“

After reviewing reviewed tested supplements, we use the Three-Legged-Stool model to get additional candidates and then check if there are studies supporting their use.

Prescription Responder and Non-Responders

I came across this 2021 article that was investigating DNA/SNP and hypertension drugs.

“Drug effectiveness was defined as 10% decrease in systolic blood pressure at 1 week follow-up. “

Genomic markers associated with successful treatment of hypertension with lisinopril: A pilot study [2021]

---

If you do not see that type of response, there may be genetics involved.

Base List

This base list comes from my 2019 review, “Hypertension – What we know” with most items coming from Nutrients and Nutraceuticals for the Management of High Normal Blood Pressure: An Evidence-Based Consensus Document. [2019] All of these are based on actual human clinical studies and not on rodent studies. See above for amount of impact for each substance. Current studies suggests that impact is linearly cummative.

Pycnogenol	100–200 mg
Lycopene	15–50 mg
Melatonin	2–5 mg
Coenzyme Q10	100–300 mg
Resveratrol	>300 mg
Magnesium	500-1000mg
Cocoa flavonoids	200 mg
Calcium	1500–2000 mg
Potassium	4–5 gr
L-Arginine	10-20 gr
Taurine	1-2 gr
Quercetin	150 mg [2009]

Additional items are discussed in Role of natural herbs in the treatment of hypertension, 2011, but with less critical review.

Candidate Modelled Substances

For modelling substances for a condition, I often use a three legged tool as shown below

Items were ranked by number of bacteria favorability impacted. The top 3 suggested modifiers are below. The next step is to see if there is any literature. [Good Impact: Bad Impact]

• resistant starch [12:6]
  • Trial using it [2021]
  • 3.3 mm HG drop in DBP (no change in SBP) [2019]
• berberine [12:10]
  • Studies suggests lowering [2021]
• Slippery Elm ( Ulmus macrocarpa ) [11:4]
  • Lowers in Rodent studies [2008]

The next 4 items contains one surprise – licorice is usually associated with increase of BP

• lactobacillus plantarum (probiotics) [9:7]
  • Reduced mean arterial pressure [2021]
  • Effect of Lactobacillus plantarum containing probiotics on blood pressure: A systematic review and meta-analysis [2020]
  • “A statistically significant reduction in systolic blood pressure was also observed”[2017]
• glycyrrhizic acid (licorice) [9:8}
  • “Women taking licorice have experienced elevated blood pressure” [2021]
  • ” No electrolyte abnormality, significant changes in blood pressure or blood glucose levels were observed during the [Licorice] study.” [2019]
  • appear to cause hypertension in association with potassium chloride [2018]
• rosmarinus officinalis (rosemary) [9:1]
  • “Both blood pressure variables of SBP and DBP reflect the clinically significant antihypotensive effect of Rosemary essential oil that was maintained throughout the treatment period. ” [2014]
• fructo-oligosaccharides (prebiotic) [9:6]
  • Nothing

The next items

• zinc [8:3]
  • “Angiotensin-converting enzyme (ACE) is a zinc-dependent dicarboxypeptidase ” [2021] – impacts prescription hypertension medicines
  • “Zinc and copper might be not independently associated with hypertension in US adults.” [2018]
• saccharomyces boulardii (probiotics) [8:3]
  • nothing
• wheat [8:1] – complex, ancient varieties appear to have benefits
  • “Antihypertensive and antioxidant activities of enzymatic wheat bran protein hydrolysates” [2020]
  • Short-Term Hemodynamic Effects of Modern Wheat Products Substitution in Diet with Ancient Wheat Products: A Cross-Over, Randomized Clinical Trial [2018] SBP decreased
• arabinoxylan oligosaccharides (prebiotic) [8:1]
  • nothing
• inulin (prebiotic) [8:2]
  • Inulin Supplementation Reduces Systolic Blood Pressure in Women with Breast Cancer Undergoing Neoadjuvant Chemotherapy [2019] SBP: -4 mm Hg
• lactobacillus salivarius (probiotics) [7:1]
  • Nothing
• vitamin a [7:2]
  • Inverse association between dietary vitamin A intake and new-onset hypertension[2021] “Our results emphasized the importance of maintaining relatively higher vitamin A intake levels for the prevention of hypertension.”
• oregano (origanum vulgare, oil) |[7:2]
  • Nothing

We do see some items from our first list, with predictions tending to agree. Remember that we are doing a naïve count by bacteria and dealing with fuzzy data

• quercetin [6:2]
• resveratrol (grape seed/polyphenols/red wine) [6:5]
• melatonin supplement [5:8]
• magnesium [4:0]
• Cacao [3:1]

Bottom Line

This illustrates the use of the three legged stool approach for treating conditions. The use of microbiome appears to produce an extended list of candidates substances that appears to be in general agreement with studies. Each candidate substance should be researched because we have a complex mixture of bacteria.

These modelled suggestions have been added to MicrobiomePrescription

A reader emails as shown below. The deep vein thrombosis (DVT) aspect interest me because it is typically associated with inherited coagulation defects (an interest that I have), although actual DVT has not been an interest (when I flew regularly, I was prescribed heparin and took it with piracetam (good for my specific defect).

On 15 July 2021 I uploaded my first Thryve sample to your website.  Prior to that sample I had a few Ubiome samples from a few years ago.  Thryve seems to detect many more bacteria than Ubiome.  
My results seem particularly unusual with numerous rare bacteria unfortunately.  My main symptoms have always been constipation, food allergies and 2 episodes of DVT whereby I remain on anticoag therapy to avoid further recurrences.
Bacteroides Vulgatus seems to be significantly high in all of my test results, both Ubiome and Thryve.  I wonder whether this could be the ‘root cause’ given that the numbers of it are so much higher than any other bacteria. 

What is known about DVT and Microbiome?

After a while searching PubMed, I finally found a 2020 article. Of special interest is Staphylococcus aureus which appears to have a significant role with ME/CFS [2016 Post] and may account for the high percentage of hypercoagulation seen there.

” Many known bacteria, such as Helicobacter pylori, Chlamydia pneumoniae, Mycoplasma pneumoniae, Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus aureus, and Escherichia coli, causing infections may increase the risk of thrombotic complications through platelet activation or may lead to an inflammatory reaction involving the fibrinolytic system.” Microbial Modulation of Coagulation Disorders in Venous Thromboembolism [2020]

A fuller list from the full article (Citing 2019) is, below

• Staphylococcus aureus,
• Streptococcus pyogenes
• Pseudomonas aeruginosa,
• Escherichia coli,
• Klebsiella pneumoniae,
• Chlamydia pneumoniae,
• Helicobacter pylori,
• Haemophilus influenzae

Looking at samples over three year, we have a strong candidate for causing DVT, Haemophilus parainfluenzae. It is consistently very high. Blank indicated no reported value.

Bacteria	21-07-15	19-06-15	18-12-19	18-08-13
Staphylococcus aureus
Streptococcus pyogenes	71% for Streptococcus (most not classified)
Pseudomonas aeruginosa
Escherichia coli
Klebsiella pneumoniae
Chlamydia pneumoniae
Helicobacter pylori
Haemophilus influenzae/ Haemophilus parainfluenzae	94.6%ile	89%ile	91.2%ile	95.8%ile

Checking the microbiome prescription summary for this bacteria, we see a short list of herbs impacting it (there is bigger list of antibiotics)

Almost every probiotics encourages it. PPI, ku ding cha tea also increases t.

Other items reported to decrease it are:

• vitamin d

Personally, I would address this as #1 item.

Constipation

Using the Nat.Library of Medicine filter for constipation and relaxing to include high and low 12%, we came up with only a very short list of candidates. Using Kaltoft-Moldrup bounds, nothing was selected.

As for allergies, “Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis are often involved in respiratory infections associated with wheezing, but there is no evidence for their active role in asthma pathogenesis or exacerbation. ” [2009]

Running Advance Suggestions “as Is”

The key items selected reflects our analysis above:

KEGG Suggested Probiotics

The numbers are low, indicating no major issues. None of the suggestions are known to increase (or decrease) our focus. For supplements, it is similar

• beta-alanine
• NADH

Bottom Line

The primary question from the user appears to be answered. I would suggest fixing the Haemophilus parainfluenzae in isolation from the other two issues. Those two issues resolution will likely tend towards the use of probiotics — which are counter indicated with Haemophilus parainfluenzae. You have to prioritize issues and be careful not to send mix messages to the microbiome.

As always, review and consult with your medical professional before implementing

A reader sent me this email (actually another one did too). The issue was fixed but not in the obvious way:

This was actually a coding error, the checkbox should not be there. To do what the user intended:

Now to pick bacteria for KEGG Vectors

Below is the revised page fixing the problem. Notice the RED RECTANGLE

Clicking this will take you to the page listing the bacteria for this item, example below

On this page the checkboxes work. You see all of the bacteria associated that you have and thus can target the specific one (likely Brochothrix thermosphacta   that is running well above the top of the normal range) that is causing the KEGG Vector (Product, Enzyme, Module) to be of concern.

While working on the last long COVID post, another Long COVID person contacted me. He was definitely frustrated (in the same way that I have seen people with ME/CFS be frustrated over the last decades).

 I’ve literally consulted with over 7 doctors (internist, hematologist, endocrinologist, ENT, GI specialist, cardiologist, & neurologist) over 3 weeks period and still have 4 consultations to go! All those doctors did is to request for more bloodwork and scans and then tell me that it’s all in my head (using smooth words) and send me home! 

Long Haul Covid Patient

Recap on the Literature

The Microbiome and COVID have strong relationships. The microbiome prior to COVID impacts the severity. The severity of the symptoms correlates with the microbiome changes. This leads naturally to Long COVID being a continuation of this theme.

 One study suggests that a core microbiota could predict COVID-19 severity in healthy subjects.²⁷ Another study shows that the composition of the intestinal microbiota in the Chinese cohort is different between COVID-19 infected and un-infected controls, with symptom severity correlating with specific bacterial taxa.²The gut microbiome of COVID-19 recovered patients returns to uninfected status in a minority-dominated United States cohort [2021]

A new study used fecal samples were collected at least 38 days following diagnosis. By common belief, the patients are fully recovered — except their microbiome are not!  What is the difference? It depends on where COVID presentation.

• positive detection of SARS-COV-2 RNA from the respiratory tract, defined as respiratory positive (RP) 
• failure to detect in the respiratory tract, but had covid, is negative

They found changes in “13 phyla, 18 classes, 44 orders, 88 families, 234 genera, 1 phylum, 1 class, and 1 order were significant”. To put it simply, look at the changes below — they are NOT minor but major shifts!

Our Long COVID Patient

My ongoing long haul symptoms:
– Vertigo/lightheadedness. Can’t maintain proper balance and head feels heavy 🙁 I was walking into furniture in my home! It’s difficult to drive a car or even fast walk or go down the stairs. I feel as if my head is heavy and will fall.
– Mood swings/anhedonia. No more feeling of happiness or pleasure. Low serotonin? Low dopamine?
– Brain fog/memory loss/loss of concentration. I’m back to work and it has been extremely difficult to get tasks done.
– Occasional blood in stool. Ulcers? Never had GI bleeding in my life!
– Early evening fatigue. Feel extremely tired past 8pm. I also wake up super early (5-6am) and can’t go back to sleep.
– Blurry vision during night.
– Slight shakiness/tremors in hands and legs. Low iron? Low dopamine?
– Low libido/sex drive despite getting morning erections.

In his own words

Pro Forma Analysis

I am going to do the same process as with the other Long COVID person. First, we have two lists of bacteria available, the number of studies are few but slowly increasing.

• Active COVID
• Post Covid

Bacteria Out of Range

The earlier sample had just 7 out of range, the latest sample increased to 16, implying the microbiome is drifting further away from normal. Comparing samples, we found the following concerningly high on both samples:

• (species) Prevotella multisaccharivorax
• (species) Prevotella maculosa
• (species) Bacteroides coprophilus
• (species) Bacteroides barnesiae

The following high level taxonomy items went out of range in the latest sample:

• (family) Leuconostocaceae
• (genus) Anaerocolumna
• (genus) Anaerostipes
• (genus) Pseudopedobacter

End Product Out of Range

Three items were out of range, one in common with the other Long COVID but in the opposite direction a-Galactosidase was high, and the other was low.

KEGG Bacteria Products Out of Range

The earlier sample had 9 out of range, the latest sample has 145!! Another indication of shifting further away from normal 🙁

KEGG Modules Out of Range

Just one in each sample, nothing in common.

KEGG Enzymes Out of Range

The earlier sample had 8 out of range, the latest sample has 139!! Another indication of shifting further away from normal 🙁

Kegg Suggestions

Where there are so many items with issues, I usually do not bother looking at them individually. Instead, I look at what can be computed to address them. Because every item is low, we do not need to look at trying to reduce anything — just add,

KEGG Suggested Probiotics

This is done by seeking out probiotic bacteria producing enzymes etc that are not being produced enough by existing bacteria. These can be viewed as a biological supplement producing items not available as regular supplements. The retail probiotics Sun Wave Pharma/Bio Sun Instant and Prescription Assist appear to be good choices (if available).

These are the same ones as with the other Long COVID person. What surprised me was that the earlier sample had a higher value list than the latest sample. This implies that the new overgrowth are providing the material to stablize the microbiome (unfortunately, in the current state of dysfunction)

A common mistake is to slip into a homeopathic thinking, “oh, I am taking some — that is enough”. In general I recommend starting low and increasing to the maximum dosages used in clinical studies. See this page for amounts used and links to the study or clinical trial.

KEGG Suggested Supplements

I tossed in the prior review for reference, two supplements are in common with all three samples.

Earlier Sample	Latest Sample	Other Person
beta-alanine iron L-Cysteine L-glutamine L-Lysine L-Proline Molybdenum NADH Vitamin B-12	beta-alanine Glycine L-asparagine L-Cysteine L-Lysine L-Proline L-Threonine L-Tyrosine Phytase (Enzyme)	beta-alanine D-Ribose iron L-Histidine L-Lysine L-Phenylalanine L-Tryptophan magnesium

We similarly identify supplements that are available retail (defined as being available on Amazon.com)

Suggestions

Using the last Long COVID post as a model, I jump directly to suggestions using the latest results. EXCEPT – I selected everything — including antibiotics and antivirals. No antibiotic made it high on either list.

12%ile and COVID-19

Remember, we are restricting to only those reported for active COVID and with the same direction of shift

12%ile and Long COVID

We have a much longer list of bacteria selected — which likely reflect that it is long COVID.

Quick Kaltoft-Moldrup suggestions

A very short list – this happen because we do not have studies reporting what modifies many of these bacteria.

Reminder – The WHY for suggestions

On the suggestion line, you may see a 📚. Clicking it will show the source of the recommendation and why. Remember the more positive impact (by number of studies reporting the same), the greater the confidence shown. It is the confidence that it will shift in the desired direction. It is not which works better.

Putting Suggestions Together

With much bigger lists of bacteria, we also run the risk of more complexity and contrary suggestions [for example, bifidobacterium longum bb536 (probiotics) was a take, but  bifidobacterium longum (probiotics) was an avoid]. I find myself giving the 12%ile and Long COVID Suggestions the greatest credence. It has some interesting

What seems to be reoccurring – make sure you look up dosages where available. Start low and work up to the maximum dosages used in clinical trials (after consulting with your medical professional)

• Human milk oligosaccharides (prebiotic, Holigos, Stachyose)
• iron (a component of rare meat and  high-protein diet)
• glycyrrhizic acid (licorice)

I also expanded the list to 50 pro and con and notice the following items of interest

• On Pro (take) List
  • Ayurveda and similar Herbs
    • Neem
    • Ajwain (trachyspermum ammi)
    •  olea europaea (olive leaf)
  • The Antibiotics used by Jadin for treating ME/CFS
    • minocycline (antibiotic)s
    • fluoroquinolone (antibiotic)s
    • piperacillin-tazobactam (antibiotic)s
• On Con (Avoid List)
  • Probiotics
    • lactobacillus plantarum (probiotics)
    • lactobacillus casei (probiotics)
    • lactobacillus rhamnosus gg (probiotics)
    • Lactobacillus Johnsonii (probiotic)
    • lactobacillus reuteri (probiotics)
    • lactobacillus gasseri (probiotics)
    • bifidobacterium (probiotics)
    • bifidobacterium pseudocatenulatum,(probiotics)
    •  bifidobacterium longum (probiotics)
  • Antibiotics
    • rifaximin (antibiotic)s

Probiotic Advice

My read of the data is to avoid all Lactobacillus and Bifidobacterium probiotics. You have above the median amounts of both of them 85%ile and 66%ile respectively – you do not need more, in fact, they likely contribute to the dysfunction! Miyarisan, Prescript Assist (or Equilibrium), aor / probiotic-3 and Sun Wave Pharma/Bio Sun Instant appears to be the best retail candidates for probiotics.

This is a MODEL not a PROTOCOL

This is directed to people reading this post and saying “I will do what is described”. What is the difference? A Protocol comes from clinical experience and is a defined set of actions that are repeated for each patient. A model is a theoretical way to generate candidate actions that may help. This is not a model for Long COVID patients, it is a model for one person’s microbiome. Every Long COVID patient will have a different microbiome and thus different candidate actions. You can see this by looking at the next post on Long COVID microbiome.

An analogy, Long COVID can be compared to a headache. There are at least 17 types of headaches. You may need to see a dentist (tooth issues), or take a antihistamine (allergy) or take oxygen or …. Details drives the treatment.

For information on suitable 16s Microbiome Providers.

To help illustrate this, I have put the bacteria targeted from each of them below. You will note a lot is in common.

Female Prior Long COVID	Male This Post

Logical Treatment Options based on test results

Above you read about this user’s frustrations with the medical professionals. The root problem is that profession runs on encyclopedic knowledge (often photographic memory) that looks for a match and retrieves it as treatment. I term this as cook-book medicine. If there are no matches, then we typically see “deer in the headlights“, a deer with a MD.

Microbiome Prescription builds predictive modelling with a wide variety of suggestion options. Most of the options do not require a prescription, the user is in primary control. There is a full chain-of-evidence to the basis of the suggestions for people to review (yes, some people may need to upgrade their reading skills). The core facts are your microbiome.

Improvements can be objectively measured (instead of a vague “do you feel better”). Feeling better is important, but it should not be the sole criteria.

Questions and Answers

For many of these questions I went to the “See Impact..” with the specific sample.

Q: I’m currently on bovine Colostrum, is it ok to keep taking it?

A: Bovine Colostrum is not the database, the closest match is whey. It has no known impact – so you can assume it is safe.

Q:  I’m eating boiled and cooled down potato every day as source of resistant starch. Is it ok?

A: Cooking an item with resistant starch can breakdown that starch.  see  Resistant Starch Content in Foods Commonly Consumed in the United States: A Narrative Review [2020]).
As above – potatoes– no known impact — so you can assume it is safe.
But : raw potato starch is a negative
Resistant starch is a NEGATIVE

Q: Is Mutaflor ok? Since my E coli appears low? I’m sorry if I’m not following I’m going through brain fog.

A: As above – no known impact — so you can assume it is safe.

Q: I see the suggestions recommend against inulin. However, I’ve recently included garlic, onion and ginger in my diet. Are they ok? 

• Garlic – mild negative
• Onion – no known impact — so you can assume it is safe.
• Ginger – no known impact — so you can assume it is safe.

Q: ThryveInside also says I have zero bacteria for absorbing Vitamin K2 and refers to Bacillus. Is it ok to take Bacillus Subtilis from Natto?

A: You may wish to contact ThryveInside to find out exactly how they computed this. I show that you are at the 56%ile for vitamin K production.

• You may wish to be explicitly tested for Vitamin K by your medical professional
• Vitamin K2 0 As above – no known impact — so you can assume it is safe.
• Bacillus Subtilis – it is a definite avoid, Use Vitamin K2 supplements

Q: Which product do you recommend for HMOs? I found this on Amazon:https://www.amazon.com/Holigos%C2%AE-Restore-Functional-Disorders-Medical/dp/B0859DHVK2Is this the one you are referring to?

A: Yes, That is actually the product that was used in most of the studies cited.

Q: Which nuts is best for my case (pistachio, hazelnut, cashew, brazillian nut, etc.)? I’ve been eating walnuts and almonds for several months.

A: I checked the types that we have data for:

• Peanuts – no known impact — so you can assume it is safe.
• Walnuts – positive impact
• Generic nuts – no known impact — so you can assume it is safe.

Q: My vitamin D turned out high-normal. My 25-hydroxy vitamin D reading is 29.1 ng/ml & reference range (20 – 40). The suggestions included Vitamin D.

A: Vitamin D supplement are estimated to be a net negative benefit (same numbers as above). I looked at the citations used to make that decision and see a mixed impact on different items according to different studies. The results illustrates why suggestions may change from month to month. If new studies are added (which happens monthly) then the impact estimates change. My goal is deliver the best estimate from current studies – a moving target,

 Whatever happens, I just want you to know that you have helped me a lot even before getting Covid-19… One word, thank you Ken  💐

REMINDER: These are suggestions generated by an artificial intelligence program. Before implementing, they should be reviewed by your medical professional.

The Microbiome and COVID have strong relationships. The microbiome prior to COVID impacts the severity. The severity of the symptoms correlates with the microbiome changes. This leads naturally to Long COVID being a continuation of this theme.

 One study suggests that a core microbiota could predict COVID-19 severity in healthy subjects.²⁷ Another study shows that the composition of the intestinal microbiota in the Chinese cohort is different between COVID-19 infected and un-infected controls, with symptom severity correlating with specific bacterial taxa.²

The gut microbiome of COVID-19 recovered patients returns to uninfected status in a minority-dominated United States cohort [2021]

A new study used fecal samples were collected at least 38 days following diagnosis. By common belief, the patients are fully recovered — except their microbiome are not!  What is the difference? It depends on how COVID presented.

• positive detection of SARS-COV-2 RNA from the respiratory tract, defined as respiratory positive (RP) 
• failure to detect in the respiratory tract, but had covid, is negative

They found changes in “13 phyla, 18 classes, 44 orders, 88 families, 234 genera, 1 phylum, 1 class, and 1 order were significant”. To put it simply, look at the changes below — they are NOT minor but major shifts!

Our Long COVID Patient

Their summary:

• End of March 2020: covid
• Tachycardia until July 2020.
• MRI showed pericarditis.Tachycardia stopped once I resumed H1 blockers
  • I had stopped out of paranoia when acutely ill, and B started antacid prescribed by cardiologist.
• Severe constipation started at around April 2020. So we’re talking about over a year ago.
• I had a break from constipation issue for about 6 months – november 2020 to may 2021.
• Other ongoing symptoms are pain on the left side under the ribcage and internal vibrations, numbing of sensation “down there” (don’t feel much the need to go to the toilet,
• Sex life is hampered too, nerve damage very likely according to myself and also gynecologist who thinks it’s postviral).
• The entire first half of 2021 i adopted a diet based on green smoothies.
  • Other than 80% veg based smoothies and flaxseed i ate some veg stir fries and fresh salmon and some crisps (in small quantities!!! but every day a little pack).
  • Before covid i ate only crap, all sort of crap, so that this diet was for me a huge sacrifice.
  • But since covid junk food made me feel bad anyway, so slowly i accepted to change my diet. 
  • I’m also taking a very long list of supplements. I had high cholesterol before covid, had it at 18 already despite being slim, but after covid it remained high and my sugar level got very high (not yet in the red). [This may no longer be true — the measurements were from a year ago]

Pro Forma Analysis

First, we have two lists of bacteria available, the number of studies are few but slowly increasing.

• Active COVID
• Post Covid

Bacteria Out of Range

I see 34 Outliers using the Kaltoft-Moldrup ranges (which are usually bigger ranges than most testing labs use). This person mentions 50+ out of range from their lab. Well, that huge number is precisely what the study above reported. This is not a typical microbiome disruption.

End Product Out of Range

Three items were LOW out of range, Vitamin D, Phosphoamidase, and a-Galactosidase. For Vitamin D we have the following literature:

• Relevance of vitamin D ₃ in COVID-19 infection [2021] in which we find:
  • “About 30% of COVID-19 patients also presented with cardiomyopathy (^{Arentz et al., 2020}). 1α,25(OH)₂D₃ plays a crucial role in the prevention of cholesterol build-up in the arteries by preventing the conversion of macrophages to foam cells (^{Oh et al., 2009}) and enhancing the cholesterol efflux from blood vessels (^{Yin et al., 2015})”
  • She has cholesterol build up and a form of cardiomyopathy (See What About Tachycardia-induced Cardiomyopathy?) So low Vitamin D, the literature and her lab results are in agreement. This suggest serious Vitamin D3 supplementation (see Clinical Therapeutic Dosages here, I would suggest at least 10,000 IU/day — to be discussed with her physician)

KEGG Bacteria Products Out of Range

Every single one of a list of 47 was low. Not enough being produced

KEGG Modules Out of Range

Nothing reported

KEGG Enzymes Out of Range

As above, a list of 48 items with every item being low

Kegg Suggestions

Where there are so many items with issues, I usually do not bother looking at them individually. Instead, I look at what can be computed to address them. Because every item is low, we do not need to look at trying to reduce anything — just add,

KEGG Suggested Probiotics

This is done by seeking out probiotic bacteria producing enzymes etc that are not being produced enough by existing bacteria. These can be viewed as a biological supplement producing items not available as regular supplements. The retail probiotics Sun Wave Pharma/Bio Sun Instant and Prescript Assist appear to be good choices (if available). The fall back by species are:

• Clostridium butyricum (Dosage Information)
• One of Bifidobacterium adolescentis(dosage), or Bifidobacterium longum (dosage), or Bifidobacterium animalis subsp. lactis BB-12 (dosage)

A common mistake is to slip into a homeopathic thinking, “oh, I am taking some — that is enough”. In general I recommend starting low and increasing to the maximum dosages used in clinical studies.

KEGG Suggested Supplements

We similarly identify supplements that are available retail (defined as being available on Amazon.com)

• beta-alanine
• D-Ribose
• iron
• L-Histidine
• L-Lysine
• L-Phenylalanine
• L-Tryptophan
• magnesium

Suggestions

One unique feature of Microbiome Prescription is that it not only identifies candidate issue areas, it also makes suggestions based solely on studies from the US National Library of Medicine. These suggests factor in side-effects on other bacteria. Every other site, has a blinkered thinking with their suggestions and do not consider side effects. Of course, there is one layer of side effects that only your MD can help — medical conditions you have. A suggestion may suggest peanut butter and you have an allergy to peanuts!

Checking against COVID and LONG COVID Profiles

The studies report on the US National Library of Medicine and are coded for averages being statistically high higher or lower than controls. This does not mean that the values are extremes. Statistically, this presents some challenges. I decided to explore how many matches happened with different definitions (Kaltoft-Moldrup ranges, top/bottom 3,6,9,12,15 %ile) for COVID and LONG COVID

Process

For those who wish to do it themselves, go to advance suggestions and do settings like below.

Then click the suggestions at the bottom. On the suggestion page, click Bacteria Details to see the bacteria that are picked

The results are below by bacteria. As we reduce how extreme values that are needed to be deemed “high” or “low”, we have more and more matches. C – active COVID; L – Long Haul COVID / Post COVID

Suggestions – 3 approaches

After viewing the table above, I decided to do 3 approaches:

• 12%ile and COVID-19
• 12%ile and Long COVID
• Quick Kaltoft-Moldrup suggestions

I expect all to be similar but with some differences. I will cut off suggestions around .425 to prevent information overload (which happens easily with the microbiome)

12%ile and COVID-19

The lack of a fine graduation of Confidence implies that we do not have that many applicable studies for the bacteria identified as important. Also this is what they had, not currently have.

12%ile and Long COVID

This has the graduation of Confidence values that I like to see.

Quick Kaltoft-Moldrup suggestions

Reminder – The WHY for suggestions

On the suggestion line, you may see a 📚. Clicking it will show the source of the recommendation and why. Remember the more positive impact (by number of studies reporting the same), the greater the confidence shown. It is the confidence that it will shift in the desired direction. It is not which works better. Microbiome Prescription strives to be open on the basis of it’s logic and allow easy verification by people who are interested.

Putting Suggestions together

Remember that the purpose of the site is to create prescriptions — suggestions to correct microbiome shifts. The suggestions attempt to be adjusted for side-effects on other bacteria. Labs suggestions are based on blinkered analysis, “You are too high in X, Z reduces X so we recommend it” – which often ignores the fact that X also increases Y which is also too high.

Suggestions are computed in two different ways with no overlap of source data (KEGG based on genes, and studies where substances were tested). Items that are on both sets of recommendations are definitely things to consider. There are items that may be only on KEGG suggestions because no one has done studies on them.

So our very top suggestions are:

• Probiotics
  • clostridium butyricum (probiotics) see 📏 for dosages
  • bifidobacterium longum (probiotics) see  📏 for dosages
• Supplements
  •  vitamin d see 📏 for dosages

Go to https://microbiomeprescription.com/Library/Dosages , then search for the probiotic of interest. then click on 📏 Studies and Trials beside it to see the dosages

A second criteria is to eliminate any items where there are contradictions (“playing it safe), the following are my top suggestions

• beta-alanine
• iron
• L-Histidine
• L-Lysine
• L-Phenylalanine
• L-Tryptophan
• magnesium
• inulin (prebiotic)
• fructo-oligosaccharides (prebiotic)
• arabinoxylan oligosaccharides (prebiotic)
• soy

At this point I should mention that a lot of items often used for microbiome issues appear contraindicated (i.e. AVOID). For example: neem,  quercetin,resveratrol,  triphala, resveratrol (grape seed/polyphenols/red wine),  glycyrrhizic acid (licorice),  melatonin supplement.

Remember, you can get opinions on over 3000 items in our database by going to the bottom of this list:

Iron was suggested by KEGG. I wanted to check it’s impact using the data from studies and was pleased with the result.

I also confirmed magnesium was also a positive (and magnesium deficient, a negative)

This is a MODEL not a PROTOCOL

This is directed to people reading this post and saying “I will do what is described”. What is the difference? A Protocol comes from clinical experience and is a defined set of actions that are repeated for each patient. A model is a theoretical way to generate candidate actions that may help. This is not a model for Long COVID patients, it is a model for one person’s microbiome. Every Long COVID patient will have a different microbiome and thus different candidate actions. You can see this by looking at the next post on Long COVID microbiome.

An analogy, Long COVID can be compared to a headache. There are at least 17 types of headaches. You may need to see a dentist (tooth issues), or take a antihistamine (allergy) or take oxygen or …. Details drives the treatment.

For information on suitable 16s Microbiome Providers.

Bottom Line

Another post COVID person just contacted me, with their samples, so a second COVID post is also available Both this person’s sample, and the recent study confirmed my suspicion that Long COVID is a Post-Infection Syndrome. Post-Infection Syndromes are, IMHO, infection altered microbiomes that failed to return to normal.

Dialog Notes with User

Q: “I’ve got a huge issue/reservation with a part of the concept: the norm in the distribution of the data base might be far from normal. And even further, what is normal might not be optimal at all. What is normal reflects an average diet, but maybe an optimal diet would lead to an outlier sample, how do you address that issue….”

A: I do not use a bell curve, See this post for where I have evolved to. It’s based on Percentile and shape of distributions

Q:  As a laywoman looking at the data my immediate focus went to methane-sibo. This matches my current issues and I’m surprised you didn’t mention it. 

A: SIBO does not have a microbiome signature that is reliable. See this 2017 post reviewing the literature on SIBO

REMINDER: These are suggestions generated by an artificial intelligence program. Before implementing, they should be reviewed by your medical professional.

A reader had initial success from modifying the microbiome but it did not persist.

The reason I ended up at your website doing research into the connection microbiome and ME/CFS was that firstly I tried Miyarisan and it turned out to be one of the best things I ever tried, MY headaches and brain fog were early completely gone and I had a lot more energy. Unfortunately this wonder only lasted about 6 weeks till I overdid it and crashed and with that crash Miyarisan lost it’s effect on me.

The other thing was Nystatin, which I was given for the candida found in my gut last year and right on from the first pills I took, it gave me more energy ( so I doubt it had anything to to with the candida, but rather must have changed something else in my gut for the better). This lasted about 10 weeks and then pooped out and was not reproducible. 

But these two times that I felt I got energy because of some changes in my gut, were very rare in the way the they just generally provided a relief in all symptoms, as I was just overall feeling better and had more energy, but without crashing. Most of the times I have trouble, because I am easily overstimulated and most things that give me energy give me instant fatigue rebound, so Miyarisan and Nystatin really were different and made me try to work on my gut. 

She attached her tests and summarized them as “As to my tests, I guess the most notable things are my low TH1(Interferon Gamma), my low glutathione, high TGF beta, my decreased SOD activity.”

Reminder that recovery is a journey

In an earlier youtube review of another ME/CFS patient, I used the graphic below

I used this model for my last flare and can be seen by the list of posts below on CFS Remission. Each report was associated with a new microbiome test and a change of supplements etc to address the changes that the prior changes caused.

• Report #1
• Report #2
• Report #3
• Report #4
• Report #5
• Report #6
• Report #7
• Report #8

I have been busy adding features that exposes more information about the microbiome. We shall see if these feature helps with the analysis.

Pro Formula Analysis

My usual starting point is to pick the low hanging fruit — identify outliers.

Bacteria Outliers

I quickly saw some massively high ones. I will focused on those. Note that  Firmicutes is massively overrepresented.

• HIGH Values (some are the highest seen in 2000 samples)
  • Species
    • Paraprevotella xylaniphila
    • Bacteroides oleiciplenus
  • Genus
    • Acetobacterium
    • Caloramator
    • Candidatus Phytoplasma
  • Family
    • Clostridiaceae

End Products

Only two items were suggested, none available as a supplement (a-Galactosidase , Phosphoamidase)

KEGG Bacteria Products Out of Range

A short list, as above none available as a supplement

KEGG Modules out of Range

Only one item (M00570) Isoleucine biosynthesis, threonine => 2-oxobutanoate => isoleucine

KEGG Enzymes Out of Range

A longer list — all being low. We hope over to KEGG Computed Probiotics and get the following list

Because this person is in Europe, they may be able to get lactobacillus kefiri which is described more in my post of 2017 and sold by online Italian sites. This is a researched probiotic. Also 🛒AOR, Probiotic 3 is a sweet one — all of the researched probiotic species in it, are on the above list. For the bifidobacterium, see Researched Probiotics list for recommended choices.

Predicted Symptoms – Citizen Science

At this point we get some very interesting results. First, the bacteria by themselves do not match any symptoms.

But when we go over to the KEGG components that the bacteria produces, we see the type of predictions that we would expect

Conclusion: She does not have the typical ME/CFS bacteria shifts but she has the typical jacked metabolites imbalance seen in people with ME/CFS. Same crime — different crime family!

Action Plan

At this point, we have identify major items of concern.

Hand Picked Suggestions

I am going to run it two ways — first with the extreme outliers shown above, then including Firmicutes (which I rarely do)

Remember we need to set Precision to the kitchen sink to have Firmicutes included in the calculations for the suggestions

What about the two strange strains?

These bacteria do not ring any bells with me, so over to pubmed.

• Paraprevotella xylaniphila Only items known to explicitly reduce are:
  • atorvastatin (prescription)
  • proton-pump inhibitors (prescription)
• Bacteroides oleiciplenus the following are known to reduce
  • glycyrrhizic acid (licorice)
  •  triphala

Proposed Plan for next cycle

• Rotate every 1-2 weeks the following probiotics
  • AOR, Probiotic 3 (Clostridium butyricum TO-A, Bacillus mesentericus TO-A, Enterococcus faecalis T-110)
    • Note that Bacillus mesentericus was once classified as Bacillus subtilis. This is a specific strain of it.
  • 🛒Kefibios (Lactobacillus Kefiri LKF01)
  • Bifidobacterium listed above (many options – you may wish to read the research first)
  • 🛒Miyarisan (Clostridium Butyricum MIYAIRI )

Rotate every 2-3 weeks:

• Triphala (we usually buy organic and make our own capsules) – 2000+ mg/day (source)
  

• Licorice (I prefer the Italian products — not teas or powders) . Dosage used in clinical studies are 24-32 grams/day
  

If your physician is willing to prescribe “off-label” also do alternating every two weeks between a PPI and atorvastatin (prescription). PPI is over the counter in some places and includes:

• omeprazole (Prilosec, Prilosec OTC, Zegerid)
• lansoprazole (Prevacid)
• pantoprazole (Protonix)
• rabeprazole (Aciphex)
• esomeprazole (Nexium)
• dexlansoprazole (Dexilant)

For items from the suggestions above, I would suggest going with handpicked suggestion list without firmicutes.

I would suggest an initial retest at 4 weeks or so, a full cycle of a PPI and atorvastatin, at the same time a cycle of alternating licorice and triphala. We want to see if this has caused a downward movement of the two species of concern.

I am a strong advocate on doing alternative pulses. It is what C. Jadin does for antibiotics (changing them every month) and I also have read several modelling studies that found rotation had better success than continuous. The english explanation is simple: for anything you may take — 90% of the bacteria may be killed and 10% survive (resistant). If you keep up with the same, then that 10% slowly regrows as resistant to whatever you are using. Changing between two things that are 90% effective (and different), then it becomes 99% killed and 1% survive.

As you have witnessed, 6 weeks with one item and then the resistors recovered your dysfunction, for another substance it lasted 10 weeks. We want to keep to 2 weeks on and then rotate.

I checked the parent taxa on these two, and I see  Carthamus tinctorius L (Safflower) inhibits one of them – so using safflower oil may help. There is no simple parent for the other.

As always, consult with your medical professional before implementing.

The data on Microbiome Prescription is based on studies and reports done using 16s methodology. At present, 16s studies greatly dominate reports on NIH National Library of Medicine. Similarly, ,major resources like KEGG: Kyoto Encyclopedia of Genes and Genomes and National Center for Biotechnology Information  use NCBI Taxon numbers to clearly identified the bacteria.

The key for creating an upload is identifying the taxon and the percentage of bacteria for a taxon.

Example

A reader wanted to upload his results and the lab would not provide a suitable CSV file. What they had was a page like shown below

The starting point is simple, hand copy the data to Excel or equivalent (in many cases you can just copy the page or report and paste into Excel

The next steps

• Delete any lines that do not have a measurement
• Copy the percentage (or compute it) into a new column.

For those familiar with excel I used these 3 formulas

• C: =FIND(” “,A3)
• D: =LEFT(A3,C3)
• E: =SUBSTITUTE(MID(A3,C3,10),”%”,””) * 1

The result is partial success with a few errors like below

For those caused by compound names, I need to count the characters to the last space and update Column C (I cheated by counting from the end and using =LEN(A25)-6. We ended up with

Also “Unclassified” should be deleted.

The Long Lookup

The next stage is time consuming… looking up the taxon numbers for each bacteria. There are two sources:

• Lookup on NCBI, i.e. https://www.ncbi.nlm.nih.gov/search/all/?term=lactobacillus
  

• Alternatively use https://microbiomeprescription.com/Library/Lookup
  

Add a new column before the percentage and put the taxon numbers there.

Next copy rows E and F to a new worksheet (remember to paste as values) and save as CSV file

The file should look like below.

Now Insert your email address as the first line. resulting in:

Next go to https://microbiomeprescription.com/Partners/transfer and paste the text there and click Test

You will be prompted for a download:

Which will contain the details about the bacteria:

You will also receive an email

Getting it saved

After verifying that everything is correct…

It is simple — enter “custom” for the API Key — That’s it. The information will show up on your next login.

• Data submitted as custom is excluded from percentile and other computation — it is assumed to be incomplete
• The number of taxon will usually increase, the system automatically add layers of the hierarchy when missing, our 22 lines became 57 automatically

Where as a supported lab shows more details.

The nature of data for the microbiome is not a straight line, nor a bell curve. Finding associations is challenging with often poor results I know from years working as a statistician that finding a “magical data transformation” is the key to finding associations. However, a ongoing issue is over-fitting the data when people try formula at random. I have tried a variety of methods from machine learning — with poor results in general.

I put my lateral thinking cap on. Instead of using a defined explicit formula — instead an intrinsic transformation: the percentile of the readings. To do this approach, you need a large sample size – fortunately I have such with over 1500 pairs of data points being common. A similar approach was discussed in Percentile Regression: A Parametric Approach 1978, Journal of the American Statistical Association, but never gained popularity.

This post gives a walk thru of the process being done on 14,374,869 possible associations that we have (excluding symptoms and conditions)

Example

I picked one of my initial good results and will walk thru charts showing how charts change according to the approach. First the raw numbers plotted

Then we chart of log of the raw numbers (log of the values worked well to determine the Kaltoft-Moldrup normal ranges – KM is based on different moments of the resulting curves)

The new way is shown below, using the intrinsic transformation to percentile

Bottom Line

Finding associations as illustrated above, means we can tease information from our data. For example, for B12 levels, we have a strong association to Glycolysis (Embden-Meyerhof pathway), glucose => pyruvate. This means that the bacteria associated with that is likely associated with B12 production. For example, a few of some 2000+ strains associated with this module.

• Faecalibacterium prausnitzii
• Bacteroides vulgatus
• Bacteroides uniformis
• Parabacteroides distasonis
• Bacteroides caccae
• Bacteroides dorei
• Bacteroides thetaiotaomicron
• Bacteroides ovatus
• Roseburia intestinalis
• Flavonifractor plautii
• Bacteroides fragilis
• Odoribacter splanchnicus
• Alistipes finegoldii
• Eggerthella lenta

Additionally, it means that where there is a relationship between bacteria but we know nothing about how to modify one of the bacteria and something about the other; then we can propose suggestions by association. This will be coming soon to Microbiome Prescription – the citizen science site.

Hey do you think microbiota dysbiosis could cause circadian disturbance? Most articles go in an opposite direction and say its lifestyle causing circadian disturbance…But my disturbance is resistant to lifestyle… I just have primary circadian problem that might be even my worst symptom… Most resistant and almost lifelong. 

Asked by a Reader

In keeping to “gold standard” of information instead of bloggers’ urban myths and ideologies, I head over to the National Library of Medicine studies.

• “gut microbial metabolites influence central and hepatic clock gene expression and sleep duration in the host and regulate body composition through circadian transcription factors”[2020]
• “Findings have suggested that gut microbiota play a major role in regulating brain functions through the gut-brain axis. A unique bidirectional communication between gut microbiota and maintenance of brain health could play a pivotal role in regulating incidences of neurodegenerative diseases. ” [2021]

Sleep, circadian rhythm, and gut microbiota [2020]

First, a more precise definition of circadian rhythms from the above study.

A fundamental part of eukaryotic life, circadian rhythms are endogenous, entrainable biological processes that oscillate in a 24-hour period in concert with the circadian environment of the earth. Circadian rhythms can be found at an intracellular level and have the ability to impact all aspects of metabolism (11). The mammalian circadian rhythm is orchestrated by a master clock, located in the suprachiasmatic nucleus (SCN) of the hypothalamus (12). The master clock follows the 24-hour light-dark cycle (the diurnal cycle) and coordinates the release of neurotransmitters such as serotonin and norepinephrine. Serotonin and norepinephrine are present at higher levels during wakefulness, while melatonin peaks during the night, regardless of the diurnal or nocturnal sleep cycles across species… The peripheral circadian clock is a system of organs within the 22 body which collect
environmental and internal signals in order to direct the expression of circadian clock genes

And then we read:

• “food intake can disassociate peripheral clock periodicity from the master clock; when this happens, greater immune system activation and metabolic dysfunction occur”
• “Dysbiosis and metabolic consequences resulting from circadian clock disruption may be due to increased permeability of the intestinal epithelial barrier “
• “gut microbial metabolites such as the short-chain fatty acids butyrate and acetate may influence clock gene expression“
• “Leone et al. found that a lack of gut microbiota, and consequently a deficit of microbial metabolites, resulted in markedly impaired central and hepatic circadian clock gene expression (40), suggesting the possibility that gut microbiota play a role in propagating circadian rhythm at the molecular level”
• “Serotonin deficiency elicits the loss of the circadian sleep-wake rhythm”
• “The microbes of the gastrointestinal tract exhibit circadian rhythm, and their composition oscillates in response to the daily feeding/fasting schedule.

The Role of Microbiome in Insomnia, Circadian Disturbance and Depression [2018]

The characteristics of the gastrointestinal microbiome and metabolism are related to the host’s sleep and circadian rhythm. Moreover, emotion and physiological stress can also affect the composition of the gut microorganisms. The gut microbiome and inflammation may be linked to sleep loss, circadian misalignment, affective disorders, and metabolic disease. 

Circadian misalignment and the gut microbiome. A bidirectional relationship triggering inflammation and metabolic disorders”- a literature review [2020]

On the other hand, peripheral clocks are found in the nucleus of almost every single cell (eg, enterocyte, hepatocyte, myocyte, adipocyte), and they show circadian rhythms and oscillations that are dependent and independent of the circadian rhythms from the master clock. While the master clock responds mainly to light/dark cycle, peripheral clocks respond to other zeitgebers (eg, temperature, diet, timing, and content of food intake), which indirectly regulate the central clock …
However, Parabacteroides, Lachnospira, and Bulleida were specific to the human GI tract. Lachnospira was unique in that it was the dominant species that were affected by time and behavior (energy consumption early during the day) [114]. However, it is not fully understood why some species increase with clock time throughout the day. One of the theories is that some species are bile resistant, so they increase during the day as the food is ingested, and bile is secreted (eg, Oscillospira and )

A day in the life of the meta-organism: diurnal rhythms of the intestinal microbiome and its host [2015]

“We found that up to 20% of all commensal species in mice and humans undergo diurnal fluctuations in their relative abundance, resulting in rhythmic changes of the entire bacterial community over the period of one day.  For instance, the common mouse and human commensal genus Lactobacillus increases in relative abundance during the resting phase (the light phase in a mouse) and declines during the active phase.”

Bottom Line

Time of day, time of year, eating time and diet impacts intra-day microbiome population and thus the metabolites being produced. Some of these metabolites have been shown to impact circadian cycle in recent studies. A few bacteria pulled from the studies cited above include:

• Fusobacterium
• Porphyromonas,
• Prevotella
• Bacteroides acidifaciens,
• Lactobacillus reuteri,
• Peptococcaceae
• Eggerthella,
• Anaerotruncus,
• Desulfovibrio,
• Roseburia,
• Ruminococcus

Time of year impacts (and may be a factor for Seasonal Affective Disorder – SAD)

• Helicobacter,
• Bacillus,
• Stenotrophomonas
• Proteobacteria,
• Lactobacillus
• Romboutsia

I was unable to find any 16s clinical studies on SAD

Advice for taking samples

Record the day of the week, time of day, and if female, where you are in your cycle for stool samples. For best consistency (i.e. seeing what actually changed between samples) — make sure all follow up control for these factors as much as possible.