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.

Finding probiotics free of lactobacillus is a challenge. This probiotic is not available in Canada, but fortunately most Canadians live close to the border with the US.

Probiotic-3 contains:

• Streptococcus (Enterococcus) faecalis T-110
• Clostridium butyricum TO-A
• Bacillus mesentericus TO-A

So what do we know about these species/strains? (My earlier notes are here)

Clostridium butyricum

• [Preventive effect of Clostridium butyricum M588 against the proliferation of Clostridium difficile during antimicrobial therapy].[1990]
• “35 strains of bacteria were detected, but 3 days after administration [of Probiotic-3], 16/30 strains of Gram-positive bacteria, and 2 strains of Gram-negative bacteria disappeared.” [1998]
• [Observation on intestinal flora in patients of irritable bowel syndrome after treatment of Chinese integrative medicine].[2004]
  • C.Butyricum was combined with Tong xie Yao fang. C.B. by itself had impact, just not as much
• Probiotic Bio-Three induces Th1 and anti-inflammatory effects in PBMC and dendritic cells[2010].
• Oral administration of Clostridium butyricum for modulating gastrointestinal microflora in mice[2011].
• “The use of perioperative probiotics[Probiotc-3] reduced postoperative infectious complications after pancreaticoduodenectomy, making it a promising potential adjunct therapy for patients” [2007]
• “This probiotics mixture[Probiotic-3] reduced the severity of diarrhea and length of hospital stay in children with acute diarrhea. In addition to restoring beneficial intestinal flora, probiotics may enhance host protective immunity such as down-regulation of pro-inflammatory cytokines and up-regulation of anti-inflammatory cytokines.”[2010]
• last, but not least, it is a butyric acid producer which is believed to help with “Gut inflammation in chronic fatigue syndrome[2010]“

Bacillus mesentericus

A lot of this literature comes out of Russia/East Europe.

• An antibiotic from Bacillus mesentericus.[1948]
• [Antibiotic properties of Bacillus mesentericus].[1971]
• [Treatment of diarrheas with filtrates and lysates of Bacillus subtilis, Bacillus brevis and Bacillus mesentericus].[1952]
• [Fibrinolytic activity of natural variants of Bacillus mesentericus]. [1987]
• [Fibrinolytic activity of Bacillus mesentericus strains].[1986]

Streptococcus (Enterococcus) faecalis

• Effectiveness of probiotic therapy for the prevention of relapse in patients with inactive ulcerative colitis [2015].
  • “The relapse rates in the Bio-Three and placebo groups were respectively 0.0% vs 17.4% at 3 mo, 8.7% vs 26.1% at 6 mo”

Bottom Line

While there have not been studies for it’s effect on CFS, there is one study showing that it improves IBS (co-morbid with CFS often), and very good results for UC.