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

• Personalized Gut Mucosal Colonization Resistance to Empiric Probiotics Is Associated with Unique Host and Microbiome Features in the journal Cell
• Post-Antibiotic Gut Mucosal Microbiome Reconstitution Is Impaired by Probiotics and Improved by Autologous FMT in the journal Cell

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

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.

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

• • Using Antibiotics and Antivirals Drugs
  • Using Prescription Drugs
  • Using Supplements
  • Using Probiotics and Prebiotics
  • Using Diet, Herbs and Spices
  • Other Substances
  • Complete List

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 B. thetaiotamicron, B. acidifaciens, B. fragilis, B.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

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.

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.

• Endocannabinoids in the treatment of gastrointestinal inflammation and symptoms[2018].
  • ” Results from clinical trials have to be carefully interpreted owing to possible reporting-biases related to cannabinoids psychotropic effects. Moreover, discriminating between symptomatic improvement and the real gain on the underlying inflammatory process is often challenging.”
• Cellular localization and regulation of receptors and enzymes of the endocannabinoid system in intestinal and systemic inflammation[2018].
  • ” In summary, our study reveals changes in gene expression of members of the endocannabinoid system in situ attesting particularly GPR55 and MGL a distinct cellular role in the regulation of the immune response to intestinal and systemic inflammation.”
• The Use of Cannabinoids in Colitis: A Systematic Review and Meta-Analysis.[2018]
  • “There is abundant preclinical literature demonstrating the anti-inflammatory effects of cannabinoid drugs in inflammation of the gut. Larger randomised controlled-trials are warranted.”
• Endocannabinoid-related compounds in gastrointestinal diseases [2018].
  • “the identification of several EC-like compounds able to modulate ECS function without the typical central side effects of cannabino-mimetics has paved the way for emerging peripherally acting drugs. This review summarizes the possible mechanisms linking the ECS to GI disorders and describes the most recent advances in the manipulation of the ECS in the treatment of GI diseases.”
  • Chart below is from this 2018 article

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.

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

• The Cortene Way: New Drug to Be Trialed in Chronic Fatigue Syndrome (ME/CFS) Soon – Pt. I
• Cortene II: A New Drug & A New Hypothesis For Chronic Fatigue Syndrome (ME/CFS)
• Cortene III – A New Drug for Chronic Fatigue Syndrome (ME/CFS): The Clinical Trial
• Cortene IV – The Co rtene Chronic Fatigue Syndrome (ME/CFS) Drug Trial Begins

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

• Microbiota affects the expression of genes involved in HPA axis regulation and local metabolism of glucocorticoids in chronic psychosocial stress.[2018]
  • ” we studied the effects of the chronic stress-microbiota interaction on HPA axis activity and on the expression of colonic corticotropin-releasing hormone (CRH) system, cytokines and 11β-hydroxysteroid dehydrogenase type 1 (11HSD1), an enzyme that determines locally produced glucocorticoids…  In the colon, the microbiota attenuated the expression of 11HSD1, CRH, urocortin UCN2 and its receptor, CRHR2, but potentiated the expression of cytokines TNFα, IFNγ, IL-4, IL-5, IL-6, IL-10, IL-13 and IL-17, with the exception of IL-1β….The data suggest that the presence of microbiota/intestinal commensals plays an important role in shaping the response of peripheral tissues to stress and indicates possible pathways by which the environment can interact with glucocorticoid signaling.”
  • Microbiota Modulate Anxiety-Like Behavior and Endocrine Abnormalities in Hypothalamic-Pituitary-Adrenal Axis. [2017]
• Involvement of Corticotropin-Releasing Factor and Receptors in Immune Cells in Irritable Bowel Syndrome [2018].
  • “Corticotropin-releasing factor (CRF), a major mediator in the stress response, is involved in altered function in GI, including inflammatory processes, colonic transit time, contractile activity, defecation pattern, pain threshold, mucosal secretory function, and barrier functions. This mini review focuses on the recently establish local GI-CRF system, its involvement in modulating the immune response in IBS, and summarizes current IBS animal models and mapping of CRF, CRFR1, and CRFR2 expression in colon tissues. CRF and receptors might be a key molecule involving the immune and movement function via brain-gut axis in IBS.”
  • Impaired emotional learning and involvement of the corticotropin-releasing factor signaling system in patients with irritable bowel syndrome. [2013]
    • “CRF-R1 ….appears to be up-regulated in patients with IBS. This up-regulation might contribute to the previously reported abnormal brain responses to expected abdominal pain.”
• Inhibition of corticotropin-releasing hormone receptor 1 and activation of receptor 2 protect against colonic injury and promote epithelium repair.[2017]
  • “Our results show that in response to MS, CRHR1 mediates gut injury by promoting intestinal inflammation, increasing gut permeability, altering intestinal morphology, and modulating the intestinal microbiota. In contrast, CRHR2 activates intestinal stem cells and is important for gut repair. “

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.