Recently I revisited finding association between bacteria. We know bacteria both produce and consume metabolites and chemicals, as well as bacteriocins that will inhibit other bacteria. “Bacteriocins are potential alternatives to traditional antibiotics. These peptides, which are produced by many bacteria, can have a high potency and a low toxicity” {Nature 2012]. Finding the relationships has been a challenge because of the nature of the distribution (not a bell curve — see this post on the solution that I use for identifying abnormal values) Post #1 Post #2.

This is a technical note (WARNING: Geek Speak) on the 262,603 relationship with correlation coefficient R² of 0.10 or higher that is available on the site.

Example of Classic Association

For our example, we will compare two families: Brucellaceae and Caulobacteraceae. Their ancestry is shown below

• Proteobacteria; Alphaproteobacteria; Hyphomicrobiales Brucellaceae
• Proteobacteria; Alphaproteobacteria; Caulobacterales Caulobacteraceae

Because they have some shared ancestry, you would usually expect them to be friendly and suppurative of each other. The standard analysis is shown below, charting the counts from samples that have both bacteria.

Classic Approach

After an intro course to statistics, most people would do a regression. It is unlikely they would look at the chart because there are 2,669,956 charts that would be produced with the dataset that I am working with.

The regression and the chart is shown below, logical conclusion – no relationship.

Alternative Approach

The alternative is to use what is called monotonic increasing functions on the counts. We scale the function so that it’s range is 0 to 100. This preserves the nature of the data and discard the naïve assumption of linearity. The result is shown below. With this approach, we get the following chart. same data!!!

We could for each pair of bacteria derive the absolute optimal monotonic functions. This approach I find problematic because your appear to be fiddling with the data too much. I have put the additional constraint that you are allowed only one monotonic function per bacteria. I believe this will inhibit over-fitting the data to the model.

How many relationships over 0.1?

We have 1621 bacteria with at least one, and the top ones are shown below

taxonomy rank	taxonomy name	Count
family	Halanaerobiaceae	546
class	Fibrobacteria	526
class	Dehalococcoidia	506
family	Fibrobacteraceae	505
order	Fibrobacterales	501
genus	Fibrobacter	483
family	Nitrosomonadaceae	474
genus	Dehalogenimonas	474
order	Acidobacteriales	467
family	Micromonosporaceae	461
genus	Nitrosomonas	460
genus	Acinetobacter	459
family	Colwelliaceae	455
family	Acidobacteriaceae	453

What benefit does this give?

The impact of one bacteria on the other may be computed as slope * r² . So R² of .5 and a slope of .4 = .5 * .4 = .20 or 20%, thus for every 10 steps of one, the other will increase by 2.

We can use this when some bacteria X is high or low and we have no information on modifying it. We can look at the related bacteria with highest impact and its modifiers. We are trying to cascade by changing the associated bacteria to change our target bacteria! We are attempting to model the modifiers secondary changes into our suggestions.

Where is this on the site?

On the bacteria details pages. if there are associations, there will appear a link to it

Clicking this will take you to the impact page. In the example below you see that Lactobacillus accounts for 63% of it’s parent class. Lactobacillaceae(family) which includes  Lactobacillus , Pediococcus  , and    Sharpea. So it is the greatest contributor the three.

Orphan Detail Pages

I call these orphan because there is not literature on them or little studies. For example Pectinatus where there was just one know citation, ginko. We now have 10 more marked with the association icon as shown below.

Available to include for Suggestions

There is a new checkbox on the custom suggestion page. If you wish these to be factored into suggestions just check the box.

A reader asked for a review. The reader had a prior sample taken 6 weeks before and specific treatments between

I took Ivermectin  for 4 days during this month – one per day 12mg. I am treating yeast with nystatin 5,000 units 2 times per day for one month. I hope the die-off may have made room for bacteria to grow. I still feel crappy. I stopped lactobacillus ( I tried Lactobaciullis grains from Keith during that time. too much bloating), and started Akkermansia muciniphila and very recently some Bifidobacterium. I had cut back on dairy earlier (using soy milk and oat milk instead). I also took Sporonax (Itraconazole) antifungal about 5 times and Valtrex 500 mg 8 times.

My starting point (before looking at the samples) is to look at what we know about the impact of these items.

• nystatine,(prescription) – of the 1286 bacteria listed, it decreases ALL of them
• ivermectin,(prescription) – of the 1286 bacteria listed, it decreases ALL of them
• itraconazole,(prescription)  – of the 1286 bacteria listed, it decreases ALL of them
• valacyclovir hydrochloride,(prescription) (Valaciclovir, Valtrex, Zelitrex)  – of the 1286 bacteria listed, it decreases ALL of them

So the expectation of making room for bacteria appears very reasonable. The unfortunate aspect is that among the causalities are: Lactococcus, Lactobacillus, Bifidobacterium and Akkermansia muciniphila. So the question arises, will the good or the bad grow back faster?

What changed?

I first checked the common bacteria that most people are usually concerned with (cited above) and then will look at what increased. One item is of definite concern 💥, (class) Fusobacteria

Bacteria	Before	Latest
(genus) Lactobacillus	1150	⇲140
(genus) Lactococcus	380	⇲180
(genus) Bifidobacterium	640	⇲340
(species) Akkermansia muciniphila	50	⇲30
(species) Hathewaya histolytica	220	⬆️869
(class) Negativicutes	10090	⬆️14820
(class) Gammaproteobacteria	790	⬆️1500
(class) Bacteroidia	267,859	⬆️322,050
(class) Chitinophagia	20	⬆️70
(class) Fusobacteria	55280	⬆️90210 💥
(class) Coriobacteriia	3160	⇲670
(class) Sphingobacteriia	1010	⇲270

Checking back with what is decreased by the drugs, at the family level

• (family) Oceanospirillaceae had the largest increase, and is not listed as one that decreases
• (family) Clostridiales Family XIII. Incertae Sedis, the same
• (family) Clostridiales incertae sedis the same
• (family) Acidaminococcaceae the same
• (family) Hungateiclostridiaceae the same
• (family) Alcaligenaceae the same
• (family) Fusobacteriaceae is listed as a should decrease, but it increased — it should be noted that this was very high in the prior one and more resistant and thus increased when the vacuum was created,
• (family) Bacteroidaceae the same

It was interesting to note the many of the bacteria that were abnormally high (95%ile) stayed the same or increased. The fact that they were high implies more aggressive strains (and possibly more bacteriocin and antibiotic resistant).

Looking at species that are outside of the KM range, we have the following being excessively high

• (species) [Ruminococcus] gnavus
• (species) Bacteroides denticanum
• (species) Blautia glucerasea
• (species) Blautia producta
• (Species) Propionigenium modestum

Note that other Blautia species were abnormally low. These are already accounted for in the suggestions.

Looking further back

“I believe vancomycin started the problem to flare when I took in a couple of years ago. I also had my first covid shot of June 26, 2021 with immediate bad reactions and probably made worse since.

• vancomycin (antibiotic) Increases some and decreases other

The very high Fusobacteria identified above is one bacteria that would be decreased by this antibiotic (so this is unlikely that this the cause of this being high).

The following are items that have been reported to increase this bacteria:

• berberine
• Vitamin B
• Vitamin E
• Vitamin C (ascorbic acid)

Suggestions

I expect the suggestions to be very similar because the items high before stayed high (i.e. no change)

There was one additional probiotic suggested from the latest sample and it had a far stronger impact then the older ones.

The KEGG suggested probiotics are the same ones, just a higher value because of an increased deficiency in enzymes being produced by the microbiome.

Bottom Line

The data base correctly predicted the likely decrease of the common bacteria assumed important for health. Those that did no reduce were either not effected, more resistant strains (inferred from being high numbers prior)

What I found interesting was the absence of most probiotics (lactobacillus and bifidobacterium) in the safe suggestions, except for bifidobacterium breve. Securil (Propionibacterium freudenreichii) probiotic came in very strong.

• Giloteaux⁶⁵ found that supplementation with the bifidogenic substance Propionibacterium freudenreichii improved butyrate levels, which induces an anti-inflammatory cascade [2017]
• One of particular interest is found in the product Securil and is called – Propionibacterium freudenreichii, which produce propionic acid, a natural biological acid that benefits the bifidus flora. [2010]
• More studies here

Note that this is specific for this person. Suggestions will be different for other peoples taking the same items.

Reader’s Desire

“I was also trying to get my methylation working better and taking b vitamins again. Could it be the b vitamins?”

The B-vitamins are suspect for the high levels of Fusobacteria. We should also note that are the to avoid list we see many of the B vitamins which suggests that much of the dysbiosis may be vitamin B related.

Concerning methylation, I usually see what enzymes are involved by checking with the Kyoto Encyclopedia of Genes and Genomes, And then check the KEGG Enzyme Outliers report. This report had a very high 470 items listed!!

Drilling down into a few, we see some of the causes

This value is beyond the K-M range and thus suggestions to correct this is automatically captured in the above suggestions.

After a recent hospital visit for cellulitis (with many different antibiotics, both orally and by IV), my blood pressure was significantly elevated that the substitute MD (my usual was on vacation), that I was put on Lisinopril. Within a week I developed a dry cough that has for 35 years has been a “tell” for a relapse into Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Checking the literature, I found that about 30% of people develop this cough. To me it is an important tell, if it shows up — I need to do quick re-examination of what is going on. For a prescription drug to do so, really made me uncomfortable.

I then check Lisinopril against the bacteria shifts reported for ME/CFS, and it made them worst. In short, staying on it may well increase the risk of relapsing into ME/CFS. That is not acceptable.

I did a little more research and found a variety of different opinions on COVID and the use of ACE2, one example is Long-term ACE Inhibitor/ARB Use Is Associated With Severe Renal Dysfunction and Acute Kidney Injury in Patients With Severe COVID-19: Results From a Referral Center Cohort in the Northeast of France, 2020

In 2019, I had done a posting on hypertension citing Nutrients and Nutraceuticals for the Management of High Normal Blood Pressure: An Evidence-Based Consensus Document. [2019].

I stopped the lisinopril and proceeded to take the nutrients etc cited above, at or above the specified dosages. I know that it will take a little time for the microbiome to respond, but it did.

Bifidobacterium Correlation

Reviewing the literature, there is the appearance of blood pressure being strongly associated with the amount of bifidobacterium as we age. Children are very high in Bifidobacterium and low in BP. As the typical amount of bifidobacterium decreases with age, blood pressure increases.

I found this recent study,

• The effect of dietary fiber (oat bran) supplement on blood pressure in patients with essential hypertension: A randomized controlled trial [2021] “Increased DF (oat bran) supplement improved BP, reduced the amount of antihypertensive drugs, and modulated the gut microbiota.  The use of antihypertensive drugs in the DF group was significantly reduced. The changes[increase] of Bifidobacterium and Spirillum in the DF group were significant.”

As a result, I add 2 tablespoons of bran to the typical 4 table spoons of oats porridge that was doing. I also added a package of Holigos (Human Milk Oligosaccharides)  which I know is a super feeder of bifidobacterium.

This corresponded to the severe drop shown above.

Possible Probiotic Impact

I was taking the following based on modelling of the bacteria shifts seen in hypertension:

• Lactobacillus plantarum Lp-115 📚
• Lactococcus lactis JCM5805 (L. lactis plasma) 📚
• Bacillus subtilis DE111 📚

Samples are coming…

Just got notification from the lab that last weeks was received.

One addendum, when I was in hospital for cellulitis, my potassium was very low and I required a (painful) IV of potassium. I examined the amount of potassium that my usual diet provided… It was very low, so I started to supplement with potassium citrate also.

• Oral potassium supplementation for management of essential hypertension: A meta-analysis of randomized controlled trials [2017]

Bottom Line

I was able to normalize (for an almost 70 year old) blood pressure by using existing research and having patience. I believe the key items was encouraging bifidobacterium growth (sorry, bifidobacterium probiotics do not persist usually and have little impact), correcting mineral content (potassium, magnesium, calcium).

One more addendum, I usually did 10,000 steps a day with weekend hikes often being as high as 20,000 steps.

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.