Several people have commented about this probiotic available at http://www.gomegaspore.com/ and I am in correspondence with them to get more information.

My usual criteria is PubMed studies on the actual probiotic (by brand) or the strains in the probiotics. With reports of herx and the mixture of species (and some potential characteristics), I thought that should do a preliminary review simply because it is easily available in the US (and the last two cited require a European facilitator to obtain).

Pure Bacillus Mixture

First, in terms of lactic acidosis, there are no major lactic acid producing species (i.e. no lactobacillus). I received an email from the manufactorer stating that it contained

• Bacillus Indicus, HU36
• Bacillus Subtilis, HU58
• Bacillus Clausii (no strain specified)
• Bacillus Coagulans (no strain specified)
• Bacillus Licheniformis (no strain specified)

Histamine Risk

Two of the above (no strain specified) are known to be high histamine producers [2013] and thus if you are in (or close to) the subset of CFS patients with histamine issues, this should be a DO NOT USE.

Alternative Sources

There are actually many manufacturers who have licensed some of these(HU36,HU58) from from Royal Holloway London University

• http://www.viridisbiopharma.com/products/probiotics.htm

• http://nusciencetrading.com/probiotics/ has HU36 & HU58
• http://thriveprobiotic.com/what-exactly-is-bacillus/ – “Just Thrive” has 4 of the above 5… London University
• http://www.viridisbiopharma.com/products/probiotics.htm
• https://www.peakbiotics.com/paleo/
• As well as in bulk from Alibaba
  • http://www.alibaba.com/product-detail/FOOD-GRADE-100-Bacillus-subtilis-HU58_118902042.html
  • http://www.alibaba.com/product-detail/FOOD-GRADE-95-Bacillus-indicus-spores_139484826.html?spm=a2700.7724838.30.1.3M5lli

Bacillus Indicus HU36

• A pigmented marine bacteria [2015]
• “carotenoids from Bacillus indicus HU36 and Bacillus firmus GB1 were found to be interesting antioxidants to fight postprandial oxidative stress in the stomach.”[2013]
• “suggests that the two pigmented Bacilli are adapted to the intestinal environment and are suited to grow in and colonize the human gut.” [2011]
• No Wikipedia or MicrobeWiki page on family

Bacillus Subtilis, HU58

• “B. subtilis examined here were HU58, a human isolate…Compared to a domesticated laboratory strain of B. subtilis both isolates carried traits that could prove advantageous in the human gastro-intestinal tract. This included full resistance to gastric fluids, rapid sporulation and the formation of robust biofilms.” [2012]

Bacillus Licheniformis

• “The optimal temperature for enzyme secretion is 37°C.” – 98.6F (from wikipedia)
• “has proven to be an unexpected tooth decay fighter as it has the ability to cut through plaque or a layer of bacteria
• “Bacillus licheniformis is commonly associated with food spoilage and poisoning. It causes bread spoilage, or more specifically, a condition called “ropy bread” (1). Contamination with this bacterium will make the bread sticky and stringy; the ropy bread will also start to develop a strong odor after contamination. Rope spores is what causes the spoilage; unfortunately these spores do not get killed during the baking process.B. licheniformis can also cause food-borne gastro-enteritis, which is infection of the gut that can lead to a life threatening condition called septicaemia. Septicaemia is blood poisoning, and is classified as having a large amount of bacteria in the blood. Dairy products are at increased risk of being contaminated with toxin-producing isolates of B. licheniformis. Cooked meats, raw milk, vegetables, and processed baby foods are also at risk. (4)The symptoms include stomach pains, (acute) diarrhea, and possible vomiting. These have an onset time of 2-14 hours and last no longer than 36 hours.B. licheniformis, although usually associated with the gut and gastrointestinal tract, can also cause distress in other parts of the body. It can cause ophthalmitis, which is the inflammation of the eye. It can even go as far as causing abortions in pregnancies and impair sperm motility. The toxins produced by B. licheniformis can cause damage to cell membranes, deplete cellular ATP, and cause the acrosome to swell; it is not found to have any damaging effects on the mitochondria.” microbewiki

Bacillus Coagulans

• is a lactic acid-forming bacterial species…separately isolated in 1935 and described as Lactobacillus sporogenes in the fifth edition of Bergey’s Manual, [wikipedia]
• No MicrobeWiki page

Bacillus Clausii

• Bacillus clausii, has been found to produce antimicrobial substances that are active against gram positive bacteria including but not limited to Staphylococcus aureus, Enterococcus faecium, and Clostridium difficile. [wikipedia]
• “The protease from Bacillus clausii strain 221, the H-221 protease, was the first enzyme to be identified in an alkaliphilic Bacillus. [1] The alkaliphilic nature of the organism has also proved it to be useful in preventing and treating various gastrointestinal disorders as an oral bacteriotherapy. [2] This organism can be found in many alkaline environments, including soil and marine habitat…Bacillus clausii resistance to many antibiotics makes it seem capable of harm to humans, but Bacillus clausii sporulated strains are actually used in the treatment of gastrointestinal illnesses to restore intestinal flora because of their antibiotic resistance and ability to stimulate immune activity” [WikibeWiki]

Bottom Line

The two strains that are listed are newly discovered which carries the risk of unknown side-effects (just like a new drug carries the same risks). I prefer strains that have been in use for 20+ years. Bacillus Licheniformis (without strains) raises the question whether any herx like effect is actually a herx and not toxins or histamines that some people may be sensitive to. Bacillus Coagulans being the rare member of the bacillus family that is a lactic acid producer raises concern if lactic acidosis is a significant part of CFS for some patients. Bacillus Clausii (without strain) has the appearance of being safe and good.

My preference is the 4 bacillus Clausii mixture, Enterogermina. Far less uncertainty and risk of unexpected side-effects.

In terms of closeness in genetic distance

I came across a diagram showing how close (or far) apart the different ones are from each other in terms of genetics, The best one (IMHO) is clausii and it is a considerable distance from the rest.

Genetic Distance Apart

Diagram source: Genomic analysis of thermophilic Bacillus coagulans strains: efficient producers for platform bio-chemicals [2014]

A niece happen to be vacationing in Italy and every time that a friend or family goes to a different country, I start looking for established probiotics that may be marketed only in that country which has PubMed studies. Enterogermina in Italy is one such treasure (in theory). Originally, the species was classified as Bacillus subtilis, which was later corrected to Bacillus clausii [“Bacillus clausii sporulated strains are actually used in the treatment of gastrointestinal illnesses to restore intestinal flora because of their antibiotic resistance and ability to stimulate immune activity…They have shown that B. clausii in Enterogermina can in fact colonize for brief periods of time on the intestinal wall of the gut, and provoke immune response in mice to rid of pathogenic bacteria. “]

• Bacillus clausii treatment showed a significant decrease of IL4 levels (p=0.004) and a significant increase of IFNgamma (p=0.038), TGFbeta (p=0.039), and IL10 (p=0.009) levels. In conclusion, this study shows that the Bacillus clausii may exert immuno-modulating activity by affecting cytokine pattern in allergic subjects and confirms previous study conducted in allergic children. [2005]
• “In conclusion, this study shows that the B. clausii may exert immunomodulating activity by affecting cytokine pattern at nasal level in allergic children with recurrent respiratory infections.” [2004]
• “DNA led to the finding that all of the Enterogermina strains belong to a unique genospecies, which is unequivocally identified as the alkalitolerant species Bacillus clausii…in contrast to several reference strains of B. clausii, the strains constituting Enterogermina are characterized by a notable low level of intraspecific genome diversity and that each strain has remained the same for the last 25 years.” [2001]
• “This review describes the therapeutic activity of Bacillus subtilis spores (Enterogermina) in the treatment of intestinal disorders associated with alterations in the qualitative and quantitative composition of the normal human intestinal flora.” [1994]
• “The immunomodulatory and stabilizing effect of Bacillus subtilis spores on the intestinal flora is probably responsible for this improvement.” [1985]
• “We examined two commercial B. subtilis probiotic preparations, Enterogermina and Biosubtyl. Surprisingly, physiological and genetic characterization of the bacteria contained in each of these preparations has shown that neither contains B. subtilis.” [1999]
• “Bacillus clausii spores survive transit through the human gastrointestinal tract. They can undergo germination, outgrowth and multiplication as vegetative forms. Bacillus clausii strains can have different ability to survive in the intestinal environment.” [2015]
• “B. clausii strains release antimicrobial substances in the medium. Moreover, the release of these antimicrobial substances was observed during stationary growth phase and coincided with sporulation. These substances were active against Gram-positive bacteria, in particular against Staphylococcus aureus, Enterococcus faecium, and Clostridium difficile.” [2004]
• Bacillus clausii as a treatment of small intestinal bacterial overgrowth [2009].

This is the latest discovery of an unusual probiotic, it is used for acute adult diarrhea. Availability is in Germany (unfortunately Amazon.de does not carry it). On line German pharmacies do,  for example at this site.

What do we know about it? There are 13 PubMed articles:

• “Probiotic enterococci a widely used by pediatricians and infection diseases doctors in Russia as means for the treatment of dysbiosis, irritated bowel syndrome and in the treatment and prevention of different functional and chronic intestinal diseases. Strains E. faecium M74 and E. faecium SF-68 are included in several probiotic drugs and have been proved as effective and safe.” [2013]
• “Enterococcus faecium SF 68 (sensitive to penicillin, tetracycline, virginiamicin and tylosin, but resistant to streptomycin)” [1994]
• “An antagonistic activity of Enterococcus faecium SF 68 towards Plesiomonas shigelloides, Aeromonas sp., enteropathogenic Escherichia coli and Yersinia enterocolitica has been studied and demonstrated.’ [1990]

• Efficacy of SF 68 in the treatment of acute diarrhea. A placebo-controlled trial.[1996]

• “All treatments were continued for 7 days. Enterococcus SF 68 was shown to be effective in reducing the incidence of antibiotic-associated diarrhoea in comparison with placebo (8.7% compared with 27.2%, respectively). Patients with acute enteritis showed a significantly faster resolution of bowel abnormalities during treatment with Enterococcus SF68 compared with placebo.” [1989]

NOTE: It appears to be available in the US as a probiotic for dogs — “FORTIFLORA® CANINE NUTRITIONAL SUPPLEMENT”

When I last looked at Miyarisan, it was available in Japan only. In the last month I discovered that it is now available in the US and EU — thus it is a good time to revisit it.

2020 Update

• Clostridium Butyricum Modulates the Microbiome to Protect Intestinal Barrier Function in Mice With Antibiotic-Induced Dysbiosis [2020]
• Supplemental Clostridium butyricum Modulates Lipid Metabolism Through Shaping Gut Microbiota and Bile Acid Profile of Aged Laying Hens [2020]
• The Impact of Probiotic Clostridium Butyricum MIYAIRI 588 on Murine Gut Metabolic Alterations [2019] ” treatment resulted in a dramatic increase in Firmicutes phylum compared to non-… treated groups (control and CBM 588-treated group)”
• The Effect of Gut Microbiota and Probiotic Organisms on the Properties of Extended Spectrum Beta-Lactamase Producing and Carbapenem Resistant Enterobacteriaceae Including Growth, Beta-Lactamase Activity and Gene Transmissibility [2019] “. The growth of antimicrobial resistant organisms was suppressed by the supernatant of C. butyricum, C. difficile, C. perfringens, E. faecium and L. plantarum in a dose dependent manner but not by that of B. fragilis and B. longum.”
• The Impact of Clostridium Butyricum MIYAIRI 588 on the Murine Gut Microbiome and Colonic Tissue [2018] “CBM 588 treatment modulated the gut microbiota composition under dysbiosis due to the use of an antimicrobial with strong activity against anaerobes and significantly reduced epithelial damage.”

One of the characteristics that is connected with a lot of the stuff that my model suggests, is that they are often used for diarrhea and other digestive discomfort. In other words, been show effective against common disruptive bugs in the gut. Mutaflor (E.Coli Nissle 1917) and Miyarisan are both traditionally used for that — not as regular daily probiotics, but as probiotics when symptoms require the gut to be fixed. The interesting aspect is this:

• Mutaflor — the only E.Coli probiotic (and many E.Coli are nasty)
• Clostridium butyricum – the only Clostridium probiotic that I am aware of (and many Clostridium are Difficult (i.e. difficile))

Clostridium butyricum MIYAIRI 588® (CBM 588®), an anaerobic spore-forming bacterium, has been developed as a probiotic for use by humans and food animals.

• Safe – “the absence of genes for encoding for α, β, or ε toxins and botulin neurotoxins types A, B, E, or F.”
  [2015]

• Prevention of antibiotic-associated diarrhea in children by Clostridium butyricum MIYAIRI. [2003]

• [Prevention of experimental antibiotic-associated diarrhea by Clostridium butyricum].[1988]

• [Antagonistic interaction between Clostridium butyricum and enterohemorrhagic Escherichia coli O157:H7]. 1999

• “The bactericidal effect of butyric acid on H. pylori was stronger than that of lactic, acetic or hydrochloric acids…Cure of persistent infection with H. pylori in the gnotobiotic mice was demonstrated following infection with C. butyricum. [2000]

• Effectiveness of probiotic therapy for the prevention of relapse in patients with inactive ulcerative colitis. [2015]

• A breakthrough in probiotics: Clostridium butyricum regulates gut homeostasis and anti-inflammatory response in inflammatory bowel disease [2015].

• Clostridium butyricum combined with Bifidobacterium infantis probiotic mixture restores fecal microbiota and attenuates systemic inflammation in mice with antibiotic-associated diarrhea.

• “Clostridium butyricum might change the vitamin K production in the intestinal bacterial flora and attenuated the anticoagulation effect of warfarin.” [2014]

• [Multicenter, randomized, controlled clinical trial on preventing antibiotic-associated diarrhea in children with pneumonia using the live Clostridium butyricum and Bifidobacterium combined Powder [2012].

Do NOT take with E.Coli Probiotics

“1.1 C. butyricum MIYAIRI antagonistic effects on toxinogenic Escherichia coli and 20 E. coli strains isolated from live stocks (cows, pigs and chickens) were evaluated by the plating method. C. butyricum MIYAIRI inhibited the growth of all E. coli strains tested” [Source]

Anxiety

• “Reduced anxiety levels from 19.8 to 10.2 in the HAMA Attenuated the increase in CRF and HR pre op” [2015] [2014]

Histamines

This probiotic produces butyric acid (BTA) which is a histamine antagonist [source].

“An important mechanism by which butyrate causes biological effects in colon carcinoma cells is the hyperacetylation of histones by inhibiting histone deacetylase” [2011]

“In humans, the effects of BA can be subdivided into intestinal and extra-intestinal. Intestinal effects include: regulating transepithelial transport, improving the inflammatory and oxidative states of the intestinal mucosa, reinforcing the mucosal barrier, modulating visceral sensitivity and motility, and preventing and inhibiting colon carcinoma. Extraintestinal effects are less well known; they have been studied in vitro and in animal models and sometimes even in humans. Currently investigated effects include: haemoglobinopathies, hypercholesterolaemia, reducing resistance to insulin (in animal studies), and reducing ischemic stroke (in animal studies).” [2012][2011]

Butyrate Studies with IBS

Butyrate is produced by Miyarisan.

“Butyrates represent a potential new IBS therapy. To date, a few trials have been performed to evaluate the effectiveness of sodium butyrate on clinical symptoms and quality of life in patients with IBS. Banasiewicz et al. performed a double-blind, randomized, placebo-controlled study in which 66 adult patients with IBS received microcapsulated butyric acid at a dose of 300 mg per day or placebo as an adjunct to standard therapy. At four weeks, there was a statistically significant decrease in the frequency of abdominal pain during defecation in the butyric acid group (p = 0.0032). At 12 weeks, decreases in the frequency of spontaneous abdominal pain (p = 0.0132), postprandial abdominal pain (p = 0.0031), abdominal pain during defecation (p = 0.0002) and urge after defecation (p = 0.0100) were observed [9, 10]. In a preliminary report, Tarnowski et al. demonstrated an improvement of abdominal pain, abdominal discomfort and defecation rhythm in patients with IBS treated with microcapsulated sodium butyrate for 6 weeks, compared to those treated with placebo. In the same study, higher quality of life was noted in patients treated with butyrate [11].” [2013]

Addendum on Brain Injury

• Clostridium butyricum attenuates cerebral ischemia/reperfusion injury in diabetic mice via modulation of gut microbiota [2016].
• Clostridium butyricum exerts a neuroprotective effect in a mouse model of traumatic brain injuryvia the gut-brain axis. [2018]

Personal Observations

Both my wife and I found we slept hard when we started taking this. By hard, I mean sleeping thru four(4) alarm clocks. For myself, I woke with less adrenalin than usual, more relaxed. As usual, your experience may be different due to different microbiome.