Overview of this Blog and the Microbiome

My ideas on this blog have evolved, as more and more information becomes available. This post is an attempt to bring readers up to date with my current thinking. I am striving to be transparent in my logic — showing the evidence I am working from, and my thought processes.


Notes to Treating Physicians     Quick Self Start on treating CFS


Analysis of Microbiome/stool with recommendations

Site: has moved to http://microbiomeprescription.azurewebsites.net

The data is available in an online collaborative python workbook for analysis. See this post.


Microbiome Definition of CFS/FM/IBS

A coarse condition that results from:

  • Low or no Lactobacillus, AND/OR
  • Low or no Bifidobacteria , AND/OR
  • Low or no E.Coli , AND/OR
  • A marked increase in number of bacteria genus (as measured by uBiome) to the top range
    • Most of these genus are hostile to/suppress Lactobacillus, Bifidobacteria, E.Coli
    • Several are two or more times higher than normally seen
    • The number of bacteria genus goes very high (using uBiome results), but most of them are low amounts.
      (“Death by a thousand microbiome cuts” and not “Death by a single bacteria blow”)
  • The appearance of rarely seen bacteria genus in uBiome Samples.

A finer definition would be a condition with a significant number of abnormalities in the ‘Autoimmune profiles see this page for the current criteria (i.e. over 25%).

The specific genus and their interactions determine the symptoms seen — likely due to the over- or under-production of metabolites (chemicals). Other autoimmune conditions may share these core shifts. The specific high and low bacteria determine the symptoms if the person was the DNA/SNP associated with the symptoms.

Replace the metabolites produced by the missing bacteria

Replacing the metabolites should result in the reduction of symptoms associated with a deficiency of these metabolites.

See this post for the study references. These items should/could be done continuously.

Other Supplements Reported to Help

Bootstrapping Bifidobacterium and Lactobacillus

The items below were found in studies to increase bifidobacterium and lactobacillus:

Unless the bifidobacterium and lactobacillus (B&L) are human sourcedthere is almost zero chance of taking up residency. Taking probiotics will not allow B&L to get established. In fact, there are grounds to believe that most commercial probiotics actually reduce your  native B&L. You want to encourage your native B&L. See this post for citations.

Bootstrapping E.Coli

The E.Coli probiotics below are human sourced and known to take up residency in the human gut.

  • Core: D-Ribose a preferred food that it uses
  • Mutaflor probiotics — E.Coli Nissle 1917
  • Symbioflor 2 — multiple strains

Dealing with the other microbiome shifts

The other microbiome shifts appear to be in different clusters of microbiome shifts. This 2017 paper by Peterson, Klimas, Komaroff, Lipkin (and a stack of other CFS researchers) makes that clear in its title: “Fecal metagenomic profiles in subgroups of patients with myalgic encephalomyelitis/chronic fatigue syndrome”.

The best way at present to proceed is to order an analysis from uBiome. (Disclosure: I have no financial interest in this company.) When your get your results back, log in, click on the “Compare” tab, then go to “Genus,” and click on “ratio” twice, so the results are in descending order.

This is the “hit list” of what you are trying to reduce. DataPunk provides a nice summary of what we know about these. See, for example, Alistipes:

At this point, we run into a logistical challenge.  You want to avoid items that are “Enhanced By” (which is in common across all of the high items) and take the items that are “Inhibited By” (which are not on any of the “Enhanced By” lists).  You may also wish to reduce foods that are high in items listed in “Nutrients/Substrates.”  It becomes a jig-saw puzzle! I have done this exercise for many readers’ uBiome results:

I have discovered that DataPunk is not absolutely current, and have started creating posts based on its data, and then added studies from 2016 and 2017 to the page. Past pages are below, for current list MicrobiomePrescription site.

nihms-731256-f0001

Src: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4754147/

General Suggestions (no uBiome results)

Some of these items are contraindicated with a few uBiomes that I have reviewed. This likely is why person B reports no results while person A reports improvement. Example: Magnesium is usually very helpful — but there are a few cases where it encourages overgrowth of undesired  bacteria.

Probiotics

Most probiotics do not take up residency. They are “here today, gone tomorrow”. Their primary role in my model is producing natural antibiotics against other bacteria. For example:

Probiotics should be rotated: 2 weeks on a specific one, then several weeks off. As a general rule, you want about  6-12 B CFU taken three times a day (or 2-3 times the recommended dosage) — but work up slowly because you may get be a major herx! In general, do not take Lactobacillus with Bifidobacteria or with E.Coli etc. Keep to one family per cycle. You do not want them to kill off one another!

Why 3x per day? Because almost none of them are detected after 12-24 hrs. So to keep them — and the production of natural antibiotics — going, you need to keep taking them during the day. See this post for citations.

The following probiotics commonly seem to help people with CFS/Lyme/Fibro:

Some probiotics, however, may make your symptoms worse! And, unfortunately, most commercial probiotics contains some of these. At the moment Bifidobacterium animalis, Saccharomyces boulardii and Lactobacillus acidophilus are on my best to totally avoid list.

  • “. The findings show that the six species of Bifidobacterium differed in their ability to relieve constipation. B. longum, B. infantis and B. bifidum were the most effective in relieving constipation, B. adolescentis and B. breve were partially effective and B. animalis was not effective. Furthermore, edible Bifidobacterium treated constipation by increasing the abundance of Lactobacillus and decreasing the abundance of Alistipes, Odoribacter and Clostridium. .” [2017]

On my neutral list (no clear benefit) is Lactobacillus Plantarum.

Teas

Some teas can also be antibiotics (among other roles). There are two teas that seem to produce significant results quickly:

Again, rotate and, if practical, change brands too. Their antibiotic compounds are different from different sources.

Herbs and Spices

The best choice needs examination of your microbiome (i.e. uBiome results) and doing the work cited above.  Survey results found:

  1. Neem and Oregano with 80% improving
  2. Olive Leaf and Licorice with 56% improving
  3. Thyme with 50% improving
  4. Wormwood and Tulsi with 33% improving

Other things

If you do not know your microbiome, then see https://cfsremission.com/reader-surveys-of-probiotics-herbs-etc/  for suggestions. Your results will vary because your microbiome vary.

Thick blood is an issue also — but here things gets more complicated and not suitable for this recap.

Antibiotics can have a role — but getting prescriptions for the right ones can be a major challenge.

Metabolism Shifts

From volunteered data, we can identify some distinctive shifts, see Metabolism Explorer Summary

Bottom Line

Working with the microbiome and autoimmune is like working with fragments of the dead sea scrolls. For many bacteria we can identify it — what inhibits or encourages it is not known to modern medical science.  We have extremely thin slices of knowledge –Almonds enhances Bifidobacterium, Lactobacillus (B&L)  as do sesame seeds. What about sunflower seeds? Peanuts? Cashews? We find that Walnuts help the bacteria that inhibits B&L — so we cannot safely generalize to “all seeds/nuts are helpful”.

In many cases, we find that healthy diet or supplements demonstrated to work for normal people have the opposite effect on CFS and other altered microbiome conditions. This is made even worst because most of the studies were done on males and most people with CFS are females. We end up having to swim up-stream thru good and valid suggestions — that are just wrong for us.

My model is simple to understand and allows us to filter many suggestions and candidates. With the availability of uBiome testing (without needing a prescription!) we have entered the age of explicit treatment based on your unique microbiome. We do not know the role of many bacteria involved. We do not know what will inhibit or enhanced all of these bacteria. Frustrating little knowledge!

On the flip side, many readers have reported significant improvement, reduction of prescription medication, etc. so the model and suggestions have potential and thus hope of remission! Microbiome studies are exploding on PubMed, a lot of research is being done and we can often borrow their results.

This is an education post to facilitate discussing this approach with your medical professionals. It is not medical advice for the treatment of any medical condition. Always consult with your medical professional before doing any  changes of diet, supplements or activity. Some items cites may interfere with prescription medicines.

Review of Antrantil

A reader asked me to review Antrantil which is often sold for digestive issues.

“Atrantíl is a nutraceutical made up of three botanical extracts that work by calming the gut with Peppermint Leaf (M. balsamea Willd extract), then soaking up hydrogen with Quebracho extract(flavonoid) and stops methane production with Horse Chestnut (Conker Tree extract).” [Product Site]

atrantil-bottle-ingredients2

Unfortunately, there is nothing on PubMed (so no recognized published studies). It’s name is also very close to the name of some very different chemicals!

This is nice to have the three components listed because it allows us to determine a probable profile of it’s action.

Quebracho extract

Unfortunately, most of the literature deal with cattle and chicken

Horse Chestnut

There are some risks with this:
Acute Effusive Pericarditis due to Horse Chestnut Consumption. [2016]

“Properly processing horse chestnut seed extract removes esculin. The processed extract is considered generally safe when used for short periods of time. However, the extract can cause some side effects, including itching, nausea, gastrointestinal upset, muscle spasm, or headache.”  [NIH]

Bottom Line

There are no human studies on PubMed for two of the ingredients. These items fall under the general classification of gallic acid and tannins , which we know the general impact of on microbiomeprescription.

The marketing site claims “clinical testing with real patients was used to truly identify what combination of a multiple array of natural botanicals could have a positive impact with finding real and meaningful relief.” It appears to be based on unpublished studies of unknown quality.

Economics

45 x 550mg = 24 grams or 0.8 Ounce for $40.00

Versus:

It is more economic to buy the components by far. It also allows you to see what the impact of each component is. I would avoid the horse chestnut (or do it under MD supervision).

For a digestive product to use a component know to cause “gastrointestinal upset” does raise my eyebrows. 

This is an education post to facilitate discussing this approach with your medical professionals. It is not medical advice for the treatment of any medical condition. Always consult with your medical professional before doing any  changes of diet, supplements or activity. Some items cites may interfere with prescription medicines.

 

 

 

Probiotic Resistance

Last night, I caught a podcast from CBC on Quirks & Quarks. The 15 minute podcast is on the page linked. There are two papers linked

There are several highlights:

  • The murine (mouse) & human gut mucosal microbiome only partially correlates with stool
  • Mice feature an indigenous-microbiome driven colonization resistance to probiotics
  • Humans feature a person-specific gut mucosal colonization resistance to probiotics
  • Probiotic colonization is predictable by pre-treatment microbiome & host features
  • Murine gut mucosal probiotic colonization is only mildly enhanced by antibiotics
  • Human gut mucosal probiotic colonization is significantly enhanced by antibiotics
  • Post antibiotics, probiotics delay gut microbiome and transcriptome reconstitution
  • In contrast, aFMT restores mucosal microbiome and gut transcriptome reconstitution

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Some quotes from reviews:

“”Although all of our probiotic-consuming volunteers showed probiotics in their stool, only some of them showed them in their gut, which is where they need to be,” says Segal.

They also found that stool only partially correlates with the microbiome functioning inside the body, so relying on stool as was done in previous studies for many years could be misleading.

“Contrary to the current dogma that probiotics are harmless and benefit everyone, these results reveal a new potential adverse side effect of probiotic use with antibiotics that might even bring long-term consequences,” Elinav says. ” [src]

“While probiotics are viewed as safe for healthy individuals, potential harms may be underreported: a recent systematic review of randomized controlled trials of probiotics, prebiotics or synbiotics showed that only nine of 384 trials (2 percent) appropriately reported harms according to guidelines outlined in the CONSORT (Consolidated Standards of Reporting Trials) Statement. Further, the long-term impact of taking probiotics has not been systematically investigated.

In the participants where probiotic strains could be detected, yes, there was a detectable change in their gut microbiome. However, there was no predictability or consistency in the change to the microbiome.” [src]

“Elinav’s group found that six of the treated subjects had higher levels of colonization with the probiotic microbes, whereas the other four remained the same as their baseline….Just by looking at stool samples, the researchers could not differentiate between the two groups—the responders and the nonresponders—corroborating their earlier findings that stool samples may not always reflect what is happening inside the gut. ” [src]

Bottom Line

These papers help clarify that trying probiotics is around a coin-toss in terms of probability. In my humble opinion, non-antibiotic and non-probiotic intervention is looking more and more a better path. It may also be slower, but the changes are more likely to persist.

This recent study, also in Cell, help illustrates the point of diet impacting the microbiome.

gutbacteriaus

My analysis site has the current evidence base interactions between a vast number of substances and the microbiome.

Exercise and the microbiome

While doing my periodic review of articles on PubMed dealing with the microbiome, I came across Gut dysbiosis is associated with the reduced exercise capacity of elderly patients with hypertension [2018].

  • “The abundance of Betaproteobacteria, Burkholderiales, Alcaligenaceae, Faecalibacterium and Ruminococcaceae was diminished in subjects with a reduced exercise capacity”
  • “Escherichia coli are a primary producer of trimethylamine and inflammation in the human gut, and the abundance of this bacteria was increased in patients with a reduced exercise capacity”

A related article Intestinal Metagenomes and Metabolomes in Healthy Young Males: Inactivity and Hypoxia Generated Negative Physiological Symptoms Precede Microbial Dysbiosis [2018] found that after inactivity (HBR):

  • Eubacterium ventriosum(p = 0.028), Bacteroides sp. (p = 0.045) and Proteobacteria [Escherichia coli (p = 0.026), Shigella sp. (p = 0.029), Veillonella sp. (p = 0.042)] were significantly enriched “
  • “members of the genus Bacteroides were significantly enriched at the end of HBR variant [B. xylanisolvens (p = 0.012), B. finegoldii (p = 0.015), B. ovatus (p = 0.015), B. sp. D22 (p = 0.018); B. sp. D1 (p = 0.021), B. thetaiotaomicron (p = 0.021), B. fragilis (p = 0.033), B. caccae(p = 0.036), B. cellulosilyticus (p = 0.04), B. capillosus (p = 0.045), B. dorei (p = 0.048)]. In addition, B. eggerthii (p = 0.02) and B. pectinophilus (p = 0.049) were decreased at the end”
  • “a significant increase in the presence of the members of the genus Bacteroides in HBR participants that belonged to species, previously linked to various dysbioses in humans (e.g., intestinal tract inflammation, obesity, insulin resistance, hyperglycemia, metabolic syndrome, T2D “

Hypoxia and inactivity related physiological changes precede or take place in absence of significant rearrangements in bacterial community structure: The PlanHab randomized trial pilot study [2017]

  • “The first significantly enriched taxa were probably inflammagenic and mucin degrading species BthetaiotamicronBacidifaciensBfragilisB.dorei and other members of the genus Bacteroides in HBR variant characterized with the most severe inflammation symptoms, indicating a shift towards host mucin degradation and harmful immune crosstalk. “
  • “The inactivity-generated negative physiological and psychological symptoms diminished after reintroduction of exercise …over 14 days”

Bottom Line

A change of microbiome is seen in as little as 5 days of inactivity. Once changed, it may take up to 2 weeks after activity is resumed for the microbiome to return to normal. A secondary aspect, from looking at the microbiome of the elderly, is that some microbiome shift may diminish exercise capacity on an ongoing basis.

For those dealing with microbiome dysbiosis associated with an autoimmune condition, it re-emphasis the importance of getting regular daily exercise — but expectations should be not to see any real changes until 2 weeks into this life style changes

Changes in microbiome due to fever and virus

While doing my monthly review of recent articles on PubMed dealing with the microbiome, I came across

  • Alterations of Gut Microbiome in the Patients With Severe Fever With Thrombocytopenia Syndrome[2018].
    • “Reduced gut microbiota diversity and dramatic shifts of fecal microbial composition in SFTS patients were observed compared with health controls. “
    • Lachnospiraceae and Ruminococcaceae which could produce short-chain fatty acids were clearly dropped. Sutterella which have anti-inflammation properties were reduced too. On the contrary, some common opportunistic pathogens like Enterococcus and Streptococcus and endotoxin-producing bacteria Escherichia which could rise the risk of infections were increased in SFTS patients than healthy people, in addition lactate-producing bacteria Lactobacillaceae also significantly increased in SFTS patients.
    • “the changes of gut microbiota of SFTS patients were closely associated with clinical symptoms”

This is in general what I expected to see with my model, especially due to the Bergen experience with a giardiasis outbreak. The increase of lactate producing bacteria is significant because with ME/CFS, a condition that often occurs post viral infection, is often associated with lactic acidosis.

“These results demonstrate that some patients have a disrupted microbiota following Norovirus infection, and therefore may be at elevated risk for long-term health complications.” [2012]

A third article, Antiviral effect of vitamin A on norovirus infection via modulation of the gut microbiome [2016]

  • “We demonstrated the inhibitory effect of vitamin A against MNV replication both in vitro and in vivo. Interestingly, these inhibitory effects occurred directly or indirectly via microbiome changes, particularly on Lactobacillus strains in the gut…In previous studies, Lactobacillus spp. exhibited antiviral effects and alleviated the symptoms caused by rotavirus and influenza viral infections..In this study, we demonstrated that Lactobacillus spp. was enriched by vitamin A intake and significantly inhibited MNV replication. “
  • “the abundance of Proteobacteria was increased by MNV inoculation, consistent with observations in patients whose gut microbiota was perturbed by human norovirus infection”

Bottom Line

A viral or bacterial infection may have significant impact on the microbiome. If the microbiome does not return to a healthy state, a wide variety of other conditions may arise in the days, months and years following.

For Canadian readers: Endocannabinoids

I have usually avoid looking at items that are advocated on ideological wishfulness. A reader forwarded me a link to “The Endocannabinoid System’s Intriguing Role in Gut Health” in the Townsend Letter, October 2018, so it’s time to check current reality.

canna

Microbiome Aspect

The few available studies on mice found no impact on lean mice but significant impact on overweight mice [2015]

  •  increased Akkermansia muciniphila
  • decreased Roseburia
  • decreased Bacteroides/Prevotella
  • decreased Clostridium coccoides
  • decreased Clostridium leptum

And from [2017]

  • increased relative abundance of Akkermansia muciniphila
  • decreased Lanchnospiraceae and Erysipelotrichaceae

Bottom Line

The use of Endocannabinoids is not a simple use or do not use question. There can be negative effects reported with some studies for some conditions as shown in the table above.

It probable vector of benefit is Akkermansia muciniphila. There is active work in both Europe and the US on creating a Akkermansia muciniphila probiotic. Alternative ways of increasing Akkermansia muciniphila are covered in this earlier post.

Initial reflections on Cortene (CT38) drug.

My long time friend Cort Johnson has done four posts on this promising new drug for CFS/ME (and possibly other autoimmune conditions).

My own focus is the microbiome – keeping to a merging of concepts from Occam’s razor and Osler’s Principles. For a new drug that is just starting clinical trials, this presents a challenge.

The model behind this application is the HPA axis, hypothalamic-pituitary-adrenal axis. And specifically three items are cites:

  • Corticotropin-releasing factor
    • CRF1 – low stress,
    • CRF2 – high stress
  • Urocortin 1 (UCN1) – a 40 amino acid peptide that normalizes the above

What related information is on PubMed

Short Version

It appears to be established that CRF shifts are associated with issues associated with intestinal inflammation, gut permeability, and changes in the intestinal microbiota. There is a chicken-and-the-egg question. Did the microbiota change first and the others are consequences OR did things like gut permeability altered the microbiota. My working hypothesis is that the microbiota shift occurred first.

This may also explain why I seem to be able to recover from CFS/ME multiple times. My personality type has been evaluated as a Pollyanna, thus significantly less inclined to be stressed mentally, nor dwelling on the past and with a strong positive future perspective.

Bacteria links:

  • “Both CRF and UCN1 were significantly augmented by Bacteroides vulgatus and Fusobacterium varium at both the mRNA and protein levels. In particular, B. vulgatus stimulated human MoDCs, resulting in extremely high levels of CRF and UCN1. Conclusion: Stimulation of MoDCs by B. vulgatus and F. varium may be associated with CRF/UCN1-related intestinal disorders, such as irritable bowel syndrome and inflammatory bowel disease.” [2014]
  • “. In conclusion, Lactobacillus rhamnosus GG (LGG)  stimulates IL-4, IL-10 and Ucn expression ”  [2010]

How does Cortene work is the question!

My first prediction is simple: it will alter the microbiome. If it’s main mechanism of action is the microbiome, then my second prediction is that will be effective for only a percentage of patients — why? Every patient have a unique, and frequently very different, microbiome.

“Cortene’s drug, CT38, is a CRF2 agonist, i.e., it stimulates CRF2. It is comprised only of amino acids that occur naturally in the human body.” [post]

Bottom Line

This drug is still in early stages and my gut feeling is that it will have limited success for a small number of people.  The CRF/UCN imbalance is very likely real — but my bet is on a microbiome shift being the maintainer and likely cause of this imbalance.

Estrobolome: Microbiome, estrogen and cancer

A reader asked me to do a research dive and post on Estrobolome. This is likely a new word for most of my readers as it was for myself.

” estrobolome, the gut bacterial genes capable of metabolizing estrogens in both healthy individuals and in women diagnosed with estrogen-driven breast cancer ” [2016]

or a more technical definition

 “the aggregate of enteric bacterial genes whose products are capable of metabolizing estrogens”  [2011]

This visual may put things is a clearer perspective: [2016 src]

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“Recent research suggests that the microbiota of women with breast cancer differs from that of healthy women, indicating that certain bacteria may be associated with cancer development and with different responses to therapy.”[2018]

 

The differences of genes determine what happens with estrogens.

  • “In the human GI tract, the BG gene is well represented in the bacterial phyla Bacteroidetes and Firmicutes whereas gus is more common in Firmicutes” [2012]

The technical details are  ß-glucuronidase and/or ß-galactosidase +, on which we have some basic taxonomy information [2012]

Genus ß-glucuronidase ß-galactosidase
Collinsella +
Edwardsiella +
Alistipes + +
Bacteroides + +
Bifidobacterium + +
Citrobacter + +
Clostridium + +
Dermabacter + +
Escherichia + +
Faecalibacterium + +
Lactobacillus + +
Marvinbryantia + +
Propionibacterium + +
Roseburia + +
Tannerella + +
Actinomyces +
Alistipes +
Anaerostipes +
Bacteroides +
Barnesiella +
Bifidobacterium +
Blautia +
Butyricicoccus +
Butyrivibrio +
Catenibacterium +
Cedecea +
Cetobacterium +
Citrobacter +
Clostridium +
Collinsella +
Coprobacillus +
Coprococcus +
Dorea +
Dysgonomonas +
Enterobacter +
Enterococcus +
Eubacterium +
Fusobacterium +
Hafnia +
Holdemania +
Klebsiella +
Lactobacillus +
Megamonas +
Mitsuokella +
Odoribacter +
Paenibacillus +
Parabacteroides +
Paraprevotella +
Pediococcus +
Porphyromonas +
Prevotella +
Pseudoflavonifractor +
Roseburia +
Ruminococcus +
Staphylococcus +
Streptococcus +
Subdoligranulum +
Turicibacter +
Weissella +
Yokenella +

I will be adding this information to http://microbiomeprescription.azurewebsites.net analysis underexp

Example:
exa

Additional Literature

  • “Relative abundances of the order Clostridiales and the genus Bacteroideswere directly and inversely related with the ratio estrogen metabolites to estrogen parents, respectively.” [2014]
  • ” However, Methylobacterium radiotolerans was the most significantly enriched and the most prevalent (100% of samples) in tumor tissues, and Sphingomonas yanoikuyae(95% of samples) in paired normal tissues. ” [2014]
  • ” Authors only found higher abundance of Escherichia coli in [cancer] cases compared with healthy controls. [2014]
  • “Absolute numbers of Bifidobacterium and Blautia, and proportion of F Prausnitzii and Blautia were significantly different according to clinical stages [of cancer]. Women with grade III had increased absolute numbers of Blautia sp. compared to women with grade I.
    Significant differences were also found in the absolute numbers of total bacteria and some bacterial groups (F prausnitziiFirmicutesBlautia and Egerthella), according to BMI.” [2015]
  • “Relative abundance of several taxa differed between cases and control: case patients had higher levels of ClostridiaceaeFaecalibacterium, and Ruminococcaceae; and lower levels of Dorea and Lachnospiraceae. ” [2015]

We are still in hypothesis land

” In conclusion, links between the microbiome and estrogen-driven breast cancer are growing, and we hope that research will identify specific characteristics of the gut microbiome that can be used to develop novel approaches for breast cancer risk assessment, prevention, and treatment.” [2016]

Bottom Line

The concept of microbiome influencing estrogen and possibly many cancers seems to be growing in popularity with researchers.  The microbiome shifts for different cancers are likely to be different and is a topic that is likely worth returning to in a year when the body of research would be  far greater.