This is a review of clinically interesting items — posts on politics, speculation are excluded.

• “Individuals within the more severe cluster [of POTS] had significantly more brain fog at the beginning and end of the survey when compared to cluster two[less severe].” An assessment of fatigue in patients with postural orthostatic tachycardia syndrome[Oct 2015].

• “There was little evidence of differences in outcomes between the randomised treatment groups at long-term follow-up.” Rehabilitative treatments for chronic fatigue syndrome: long-term follow-up from the PACE trial [Oct 2015].
  • i.e. CBT, SMC, GET,APT have short term effects (i.e. possibly Placebo effects) but are not effective long term
• “IL-1β was significantly reduced in severe compared with moderate CFS/ME patients. IL-6 was significantly decreased in moderate CFS/ME patients compared with healthy controls and severe CFS/ME patients…Serum IL-7 and IL-8 were significantly higher in the severe CFS/ME group compared with healthy controls and moderate CFS/ME patients. IFN-γ was significantly increased in severe CFS/ME patients compared with moderately affected patients.” Serum Immune Proteins in Moderate and Severe Chronic Fatigue Syndrome/Myalgic Encephalomyelitis Patients[Oct 2015] [Full Text]
• “Severe CFS/ME patients differed from controls and moderate CFS/ME patients over time and expressed significant alterations in iNKT cell phenotypes, CD8(+)T cell markers, NK cell receptors and γδT cells at 6 months.” [Sep 2015]

• Chronic fatigue syndrome (CFS) or myalgic encephalomyelitis (ME) is different in children compared to in adults: a study of UK and Dutch clinical cohorts[Oct 2015].

• Increased risk of chronic fatigue syndrome in patients with migraine: A retrospective cohort study [Oct 2015].

  • This suggests that migraines may be an indicator of the start of a dysfunction leading to CFS in some patients, see “evidence linking the migraine brain to various GI disorders” [What the Gut Can Teach Us About Migraine Jul 2015]
• Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is associated with pandemic influenza infection, but not with an adjuvanted pandemic influenza vaccine [Oct 2016].
• • Getting CFS after a “flu-like” illness may actually have been the flu — with the CFS being the failure of the gut bacteria alterations caused by the flu returning to normal.
• “CFS patients with the 5-HTT SS or SLG genotype had worse 30 weeks outcome than CFS patients with the 5-HTT LALG, SLA or LALA genotype.” [Oct 2015]
• “The results suggest that patients with CFS/FM are more disabled, have more cognitive complaints, and improve more slowly over time than patients with CFS alone. Specific cognitive difficulties are related to worse functional status, which supports the addition of cognitive difficulties to the FM case criteria.” [Oct 2015]
• “Associations Between Cognitive Performance and Pain in Chronic Fatigue Syndrome: Comorbidity with Fibromyalgia Does Matter.[Sep 2015]”
• “Dysregulation of acetylcholine and adrenergic signalling could also explain various clinical symptoms of CFS.” [Sep 2015]
• “The results from this pilot study suggest that NK cells from CFS/ME and MS patients may have undergone increased differentiation in response to external stimuli which may affect different mechanisms in the NK cell cytotoxic activity pathway.’ [Sep 2015]

What was interesting..

• First item: migraine may be cause by a gut bacteria dysfunction and increases the odds of getting CFS.
• Second item: That flu was associated with CFS (but not the vaccine) which agrees with prediction from my model. The vaccine would produce much less gut bacteria alteration than having the flu.

A friend message me about salicylate sensitivity [SS] which he had in the passed assumed was part of his condition.  I had not heard that term for a while and it occurred to me that some salicylate sensitivity symptoms could actually be a shift of the microbiome. An interesting question which I hope to explore in this post.

• “Salicylates are derivatives of salicylic acid that occur naturally in plants and serve as a natural immune hormone and preservative, protecting the plants against diseases, insects, fungi, and harmful bacteria… There are no laboratory or skin testing methods for testing salicylate sensitivity.” [wikipedia]

Robert H. Loblay, The Role of Food Intolerance in Chronic Fatigue Syndrome, in Dr.Hydes “The Clinical and Scientific Basis of M.E. / CFS [1992]” raises the issue, and was likely the source of many CFSers opting on the SS cart. There have been no PubMed studies following this hypothesis up, in fact, a salicylate is often used for treating Irritable bowel syndrome which is co-morbid with CFS.

• “Mesalazine (5-aminosalicylic acid) alters faecal bacterial profiles, but not mucosal proteolytic activity in diarrhoea-predominant irritable bowel syndrome.‘ [2011]

This suggests that reaction to salicylates is more likely due to alteration of the microbiome profile (with possible die-off/herx of some bacteria) than true salicylate sensitivity.

• “Four OTUs (Prevotella spp., Bacteroides spp, family Ruminococaceae, Barnesiella spp.) discriminated aspirin users from no medication (AUC=0.96; 95% CI 0.84, 1.00).” [2015]

So are you or are you not? The easiest way to test is to look at two lists of high histamine foods and see if you do not react to any items on the high list. List 1 and List 2. Salicylate sensitivity and histamine sensitivity are both easy “answers” to latch on to — often without anything solid to confirm it. It is good to be scientific and verify against detail, actually measured lists to see if there is actual consistency. Often the popular list miss some high items, which you may be eating with no side effects — no side effects calls the presumption of salicylate sensitivity into question.

A reader with Crohn’s who is trying to alter gut bacteria research on this site sent me a link about cannabidiol and Crohn’s disese, Since I view Crohn’s as one possible outcome of IBS that is associated with CFS, I thought that a review would be appropriate since cannabidiol is becoming more and more available legally in the US and Canada.

• “A pharmacological modulation of the endocannabinoid(eCB) system might be beneficial for widespread diseases such as gastrointestinal reflux disease, irritable bowel syndrome, inflammatory bowel disease, colon cancer, cystitis, and hyperactive bladder. Drugs that inhibit endocannabinoid degradation and raise the level of endocannabinoids, non-psychotropic cannabinoids (notably cannabidiol), and palmitoylethanolamide, an acylethanolamide co-released with the endocannabinoid anandamide, are promising candidates for gastrointestinal and urinary diseases.” [2015] Speculation
• “CBD is a very promising compound since it shares the typical cannabinoid beneficial effects on gut lacking any psychotropic effects. For years, its activity has been enigmatic for gastroenterologists and pharmacologists, but now it is evident that this compound may interact” [2013] Speculation

• “It is unclear if either CB (cannabinoid) receptor has a dominant role in modification of sensory signals or if differences exist at peripheral and central nervous sites.” [2014]

• “By interfering with the eCB system using CB(1) agonist and antagonist in lean and obese mouse models, we found that the eCB system controls gut permeability and adipogenesis…These data indicate that gut microbiota determine adipose tissue physiology through LPS-eCB system regulatory loops and may have critical functions in adipose tissue plasticity during obesity.“. [2010]

• “In this review we will discuss how the endocannabinoid system, intestinal microbiota and the brain-gut axis are involved in the regulation of energy balance and the development of obesity-associated systemic inflammation.” [2012]
• “cannabis produces significant clinical benefits in patients with Crohn’s disease.” [2014] “in agreement with the ancient use of Cannabis in intestinal disturbances and one decade of animal research, Cannabis was shown in a clinical trial to reduce symptoms in patients with CD.” [Full Text]
• “CBD reduced the expression of S100B and iNOS proteins in the human biopsies confirming its well documented effect” [2011]

• “Cannabinoids also reduce gastrointestinal motility in randomized clinical trials. Overall, modulation of the gut endogenous cannabinoid system may provide a useful therapeutic target for disorders of gastrointestinal motility.” [2008]

• “The extent to which the effects on gastrointestinal function of cannabinoid receptor agonists or antagonists/inverse agonists can be exploited therapeutically has yet to be investigated as has the extent to which these drugs can provoke unwanted effects in the gastrointestinal tract when used for other therapeutic purposes.” [2001]
• “Complete remission was achieved in 5 of 11 subjects in the cannabis group and 1 of 10 in the placebo group. Yet, in an additional study, low-dose cannabidiol did not have an effect on CD activity. In summary, evidence is gathering that manipulating the endocannabinoid system can have beneficial effects in IBD, but further research is required to declare cannabinoids a medicine…. We need to establish the specific cannabinoids, as well as appropriate medical conditions, optimal dose, and mode of administration, to maximize the beneficial effects while avoiding any potential harmful effects of cannabinoid use.” [2014] It was “tetrahydrocannabinol-rich cannabis with the placebo having littletetrahydrocannabinol”[2013]

So what is the bottom line?  This blog is striving for remission not symptom moderation. There is clear evidence that cannabinoids result in symptom moderation. This chart has cannabinoids with many desirable characteristics as does this report on clinical studies which include this report that 60% of Crohn’s patients improved. The not reproducible success above was not with cannabinoids but with cannabis high in tetrahydrocannabinol.  There is some evidence that it can help in remission, nor, how it impacts gut bacteria is unclear (a concern for this blogger). It does impact gut permeability.

In my last post I stumbled on a PubMed article that appears to identify two probiotics that should reduce histamines:

• “We found that mice that received GG and PJS[Propionibacterium freudenreichii] exhibited significantly lower numbers of intestinal mast cells compared with control mice.”[2013]

The implied logic is simple, less mast cells in the intestines, the less histamines to release. When I had visited this item before, I was searching directly for histamines and probiotics.  Changing the search to probiotics and mast cells I came up with 47+ articles.  “Accordingly, subsets of patients with IBS show higher numbers and an increased activation of mucosal immunocytes, particularly mast cells. “[2012]

“Although the effect of probiotics on allergic responses is different depending on the strains, doses, and experimental protocols, animal studies generally …reduction of degranulated mast cells,” [2009]

From these articles, I found the following interesting reports:

• Extracellular vesicle-derived protein from Bifidobacterium longum alleviates food allergy through mast cell suppression [2015].
• Effects of probiotic Lactobacillus rhamnosus GG and Propionibacterium freudenreichii ssp. shermanii JS supplementation on intestinal and systemic markers of inflammation in ApoE*3Leiden mice consuming a high-fat diet [2013].
• Probiotic Lactobacillus rhamnosus downregulates FCER1 and HRH4 expression in human mast cells [2011].
• “Oral treatment with both viable and heat-inactivated Lact. sakei probio 65 (isolated from Kimchi ) inhibits skin inflammation and AD-like skin lesions, as well as mast cell activation.”[2013]
• Systemic effects of ingested Lactobacillus rhamnosus: inhibition of mast cell membrane potassium (IKCa) current and degranulation.[2012] “the systemic effects of certain candidate probiotics may include mast cell stabilization and such actions could contribute to the beneficial effect of these organisms in allergic and other inflammatory disorders.”
• “numbers of total leukocytes and mast cells in BALF induced by OVA challenge were significantly suppressed by oral administration of LFK.[lysed Enterococcus faecalis FK-23 (LFK) orally for 28 days] [2012]
• “L. casei protected from anaphylaxis and arthritis, and inhibited mouse mast cell and human basophil activation.”[2011]
• “that high doses of non-pathogenic E. coli bacteria can function as a strong, direct inhibitor of MC [Mast Cell] degranulation.” [2008] – likely Mutaflor, i.e. E.Coli Nissle 1917

Following on to  the prior post,  we end up with the following being a group of mast cell inhibitors that appears to be fine to take together.

• Mutaflor (E. coli Nissle 1917) x Securil (Propionibacterium freudenreichii) x  Culturelle (Lactobacillus rhamnosus GG) x Yakult (Lactobacillus Casei)

A reader sent me a list of the probiotics that she took every day. The list is a nice collection, but she disclosed that she was taking ALL of them every day, with about 2 hours between each. She was legitimately concerned that one probiotic was reducing the effect of others. The size of the list shows that there are many PubMed studied probiotics available without prescriptions — but only a few available in your local health food store…

What we know

There is a lot of “common sense” out there — separate them by 2 hours from antibiotics, etc. As readers are aware, I tend to check common sense — because it is often wrong. The reality is that therapeutic probiotics such as the above produces antibiotics effective against other species. The bacteria in probiotics actually tries to build a consensus of like-minded bacteria – think of a political party – you may get some Mormons, Jews, Blacks, Spanish, Asians etc in the party. Many may actually be working against the “common or dominating behavior” of their ethic community. The same things happen with bacteria.

The ideal situation is when there have been studies of two probiotics taken together: Have there been an amplification or reduction of observed changes? For drugs, this happen, for example Heparin + Piractem has greater effect than adding the effect of Heparin and Piracetam taken separately.

With 9 bacteria, it means doing 9 x 8 = 72 PubMed searches to see if there have been ANY studies. I removed the stains to do a wider search. I did get some hits, of which the significant ones are below:

• Propionibacterium freudenreichii and Lactobacillus reuteri both impact Meticillin-resistant Staphylococcus aureus [2013]

• “Lactobacillus reuteri, Lc. lactis and P. freudenreichii reduced viability of adherent Staph. aureus by 27-36%, depending on the strain,“[2006]

• “Some trials showed a significant improvement of irritable bowel syndrome-related constipation via Lactobacillus casei Shirota and E. coli Nissle 1917.” [2005]

• “data suggests a favourable effect of treatment with Bifidobacterium lactis DN-173 010, Lactobacillus casei Shirota, and Escherichia coli Nissle 1917 on defecation frequency and stool consistency.” [2010]
• “heat treatment increased the adhesion of Propionibacterium freudenreichii and gamma-irradiation enhanced the adhesion of Lactobacillus ç.”[2000]
• “Bifidobacterium longum subsp. infantis M-63 and B. longum subsp. longum BB536..was significantly higher than that in the one-species group at weeks 1 and 6. [2013]
• “The antimicrobial activity of the intraurethrally administered probiotic Lactobacillus casei strain Shirota against Escherichia coli …L. casei Shirota exerted significant antimicrobial effects… L. reuteri JCM 1112(T), had no significant antimicrobial activity.” [2001]
• “Bifidobacterium infantis 35624 preferentially induced IL-10. Escherichia coli Nissle 1917 induced both IL-10 and IL-12p70.. When combining these microorganisms with the Th1-promoting cocktails, E. coli Nissle 1917 and B. infantis 35624 were potent suppressors of IL-12p70 secretion in an IL-10-independent manner, indicating a suppressive effect on Th1-inducing antigen-presenting cells.” [2011]

• The rat strain Lactobacillus reuteri R2LC, but not the human strain Lactobacillus rhamnosus GG, is of benefit in reducing the severity of acetic acid-induced colitis in rats. [2001]

• Two strains (Lactobacillus rhamnosus strain GG and L. reuteri) were found to exhibit disease-specific adhesion to intestinal tissue. All tested strains, with the exception of L. rhamnosus strain GG, displayed disease-specific adhesion to intestinal mucus. [2003]

• while both Lb. reuteri and Lb. rhamnosus GG reduced the acetaldehyde to ethanol [2004]

• We found that mice that received GG and PJS[Propionibacterium freudenreichii] exhibited significantly lower numbers of intestinal mast cells compared with control mice.[2013]

• Shirota and GG similar impact on bladder tumors [2010]
• “This is reflected in the solid evidence for the effect of E. coli Nissle 1917 (Mutaflor) in the maintenance of remission of ulcerative colitis, and of VSL#3(contains L. Bulgaricus, S.Thermophilus)  in preventing the recurrence of pouchitis.”[2006]
• “Four probiotic bacteria, Lactobacillus rhamnosus, Propionibacterium freudenreichii subsp. shermanii 56, P. freudenreichii subsp. shermanii 51, and P. freudenreichii subsp. freudenreichii 23, were evaluated individually or in coculture with traditional yogurt cultures (Lactobacillus delbrueckii subsp. bulgaricus and Streptococcus salivarius subsp. thermophilus)…Texture and flavor attributes of fermented milks produced with propionibacteria were significantly different than the fermented milks processed with yogurt cultures.. in coculture with yogurt cultures demonstrated similar acidity, texture, and flavor as the fermented milk produced with yogurt cultures.”[2005] i.e. evidence that the yogurt cultures may have eliminated the others…

From the above, I concluded that the following groups are more likely to be friendly to each other than fight each other (based on similarity of action in many cases – same action implies similar chemicals being produced):

• Propionibacterium freudenreichii x Lactobacillus reuteri x Lactobacillus casei Shirota x Lactobacillus rhamnosus GG
• E. coli Nissle 1917 x Lactobacillus casei Shirota x Lactobacillus reuteri x B. infantis 35624 x Lactobacillus rhamnosus GG
• Bifidobacterium longum infantis M-63 and B. longum subsp. longum BB536

Suggested schedule

The goal is to get healthy bacteria established. Many PubMed studies used a 14 day study to detect impacts of probiotics [2014][2014] suggesting that clinical study experience has been that this duration is essential.

Do each for 1-2 weeks:

• Mutaflor with Yakult and Femdophilus and Culturelle and Microbiome Plus and DanActive
• Securil with Yakult and Femdophilus and Culturelle and Microbiome Plus but NOT DanActive or any yogurts
• Bifidobacterium Longum BB536 and Align
• Probiotic 3 AOR and Miyarisan
• Prescript Assist

Why are strains important?

“Only six probiotic Lactobacillus strains isolated from human intestinal microbiota, i.e., L. rhamnosus GG, L. casei Shirota YIT9029, L. casei DN-114 001, L. johnsonii NCC 533, L. acidophilus LB, and L. reuteri DSM 17938, have been well characterized with regard to their potential antimicrobial effects against the major gastric and enteric bacterial pathogens and rotavirus.” [2014]

Taking a different strain may have zero effect (except for reduced bank account). Also, as a FYI “Lactinex(®), Align(®), Bio-K+(®), and Culturelle(®) had viable colony counts that were similar to those stated on the package.” [2014]