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Probiotic-3: More than what meets the eye

This is my rebuttal to the article written October 3, 2018 by by Mr. John Brisson, at FixYourGut – his original article can be found here: https://www.fixyourgut.com/why-i-do-not-recommend-aor-probiotic-3-a-review/

Everyone is certainly entitled to their own opinion, however this article highlights some of the misinformation regarding the pathogenic potential of strains in AOR’s Probiotic-3.

First, let us start with the definition of probiotics – according to the World Health Organization and The International Scientific Association for Probiotics and Prebiotics, the internationally endorsed definition of probiotics are as “live microorganisms, which when administered in adequate amounts, confer a health benefit on the host”. This definition and the research behind probiotics has made probiotics a viable option in the line of treatment by gastroenterologists and other health care practitioners. AOR has followed the very definition accepted internationally in the formulation of Probiotic-3, which is a clinically tested, characterized and proven probiotic formula.

Some of the criticism relating to the safety of strains may be alleviated by understanding the regulatory and manufacturing processes involved in bringing products to market in Canada. For over five years, evidence was submitted to Health Canada to demonstrate the safety, and efficacy of the strains of probiotics in AOR’s Probiotic-3, in order to obtain a product license (Natural Product Number) for sale in Canada. No other AOR product took anywhere as long for license approval.

It is very important to highlight the different specific strains and alphanumeric strain designations under a particular probiotic umbrella and as such, their pathogenic potential and efficacy for gut health can vary widely, not all probiotics strains are created equal. Strain desigation is essential in determining the effect of a probiotic and the mechanism by which a probiotic exerts its benefits will vary significantly by specific probiotic strain and health indication. For example, Clostridium butyricum may indeed be a virulent strain, but C butyricum is a wide group and has strains specified by a number e.g. C butyricum AOR1234 vs. C buytricum NHP4321. Each may have different properties and effects on health, the former may be helpful while the latter may be harmful.

In order to provide a most comprehensive response to this article, here is some Probiotic-3 specific information.

A little background on Probiotic-3:

Probiotic-3 is a combination of three proprietary strains of bacteria that TOA Japan developed over 50 years ago. The strains in this product are Clostridium butyricum TO-A, Bacillus subtilis TO-A (old nomeclature: Bacillus mesentericus TO-A) and Enterococcus faecium T-110. These three strains of probiotics have been characterized and studied for their synergistic benefits in balancing intestinal flora. Probiotic-3 was granted a manufacturing approval in Japan, since 1963 and has been clinically proven to resolve various indications caused by abnormal intestinal flora, while improving bowel movement disorders. This combination of ingredients is referred to as “Synbiotics”. This term refers to a combination of prebiotics and probiotics that synergistically promote gastrointestinal health. AOR’s Probiotic-3 contains no external prebiotic – but contains a bifidobacterium promoting bacteria – Bacillus subtilis TO-A. In other words, one of the strains acts as a food for the other two strains so they grow and multiply quickly.

Clinical evidence over the past 50 years have evaluated the efficacy of Probiotic-3 in various health indications, including Irritable Bowel Syndrome, Inflammatory Bowel Disease, Ulcerative Colitis, Acute Diarrhea, H. pylori infections and many more indications. The study populations include infants, three months old and older, with sufficient peer-reviewed, published data to back up the safety of this product.

Safety Information on Probiotic-3:

It is important to note that this article, in no way, is disputing the lack of dangerous bacterial strains. However, there are several important criteria for selecting a safe probiotic, which are outlined below:

  1. What is the origin of the bacteria?
  2. Does the strain have clinical validation in humans?
  3. Is there virulence testing available for the specific bacterial strain?
  4. What about genomic sequencing of the bacterial strains?
  5. What is the potential for horizontal gene transfer?

Probiotic-3 has a long history of use and its safety and efficacy has been the subject of intense testing, with over 30 human clinical studies and over a double that number in animal trials. The strains are proprietary strains developed by a number of Japanese companies who are world leaders in fermentation and probiotics, and TOA is one of these companies that has been active in fermentation technology for over 70 years. The bacterial strains in this product are isolated from safe sources – E. faecium and C. butyricum are isolated from human microbiome, while B. subtilis is isolated from potato skins. Probiotic-3 has had extensive use, multiple decades in fact, in a number of Asian countries aimed at treating a whole host of conditions including antibiotic associated diarrhea, Traveller’s diarrhea, colon polyps, atopic dermatitis, IBD and IBS and other conditions. This information provides evidence of origin, safety and clinical validation of Probiotic-3.

For the licensing of this product in Canada, Health Canada wanted evidence of safety of this product and requested the following;

  1. Evidence of virulence testing and lack of horizontal gene transfer:

Clinical evidence and long-term use were used to support the safety of this synergistic combination of bacteria in humans, however AOR had to engage the help of 3rd party researchers at the University of Calgary to sequence and provide evidence of the virulence factor of the strains in Probiotic-3. The strain sequence is available in the links below. Bioinformatics was used to analyze the sequence of the three strains to confirm the absence of known pathogenic clostridial toxin genes in the species. Polymerase Chain Reaction (PCR) and Southern Blot analysis were used to detect the presence or absence of DNA isolated from the three strains – test samples were negative for virulence. Toxicity analysis in cell models, showed no toxicity

Additional Safety Information:

Safety considerations from the Office of Dietary Supplements on general probiotic use by Health care professionals: “Given the large quantities of probiotics consumed around the world, the numbers of opportunistic infections that result from currently marketed probiotics are negligible”. The case reports that have shown potential serious adverse events remain inconclusive as to the role of the probiotics in the adverse reaction. It should also be noted that none of these reports have pointed a finger at any of the strains used in AOR’s Probiotic-3.

Safety considerations from AOR on Probiotic-3: Probiotic-3 has been licensed in Canada since 2016 and has been on the market since then, in Canada and the US. AOR monitors its products closely, especially for adverse events in its consumers, in order to remain compliant with Health Canada’s regulations of natural health products. Since its introduction to the market, AOR has only received 7 adverse reaction returns – these are all related to mild gastrointestinal upset that resolved either with continued use or discontinuation of use. Additionally, this product has ≥ 4.4 star rating on every e-commerce site where we market it, with customer satisfaction and safety, being the paramount criteria of the reviews –

https://www.amazon.com/product-reviews/B0082DDQH6/ref=acr_dpproductdetail_text?ie=UTF8&showViewpoints=1
https://www.amazon.ca/product-reviews/B01MR7G979
https://ca.iherb.com/r/Advanced-Orthomolecular-Research-AOR-Probiotic-3-90-Capsules/43463

 Specific rebuttals to article:

  1. The author states: Though C. Butyricum has been used as a probiotic in Asian countries, it is also known to cause opportunistic infections including dysbiosis, chronic diarrhea, sepsis, foodborne illness, and rarely botulism and necrotizing enterocolitis.2 3 4 5 6

Response: C. butyricum is a potentially dangerous and pathogenic strain, but as mentioned above, there are various C. butyricum strains, of which non-toxigenic strains are currently used in various probiotics in Asia – this information, was obtained from one of the articles referenced in the article. Analysis of the papers referenced corroborate the findings despite the title of the articles. See snapshots from references 2-6 below;

 (2) https://www.sciencedirect.com/science/article/pii/S1198743X15009143

(3) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3070119/

(4) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4903954/

(6) https://www.nature.com/articles/s41398-017-0089-z

2. “The strain used in Probiotic 3 is Clostridium butyricum TO-A. C. butyricum TO-A has been shown in one study to potentially reduce inflammation in the colon by deactivating toll-like receptor 4 (TLR4) by the production and utilization of butyrate” AND ” The Clostridium strain that is in Probiotic-3, C. butyricum TO-A, has no virulence testing performed that is published to my knowledge, so it is unknown if the strain is pathogenic or contains the ability to inherit pathogency”

This is incorrect. C. butyricum TO-A has been used in many research studies – both pre-clinical and human studies. Additionally, C. butyricum has been studied in combination with the other bacterial strains in Probiotic-3 to ensure no virulence and a lack of horizontal gene transfer. The evidence is clear – C. butyricum TO-A, as well as the other strains in Probiotic-3 are safe and effective for a healthy gut flora. Toxicological studies have shown no reproductive and developmental toxicity of C. butyricum TO-A in cell and animal models.

An assumption may have been made that the only time the activation of TLR4 is beneficial is if we were dealing with leaky gut, colorectal cancer or uncontrolled intestinal inflammation, even though this is an incorrect assumption. The TLR4 and its family of receptors play a fundamental role in pathogen recognition and activation of immunity and mediate the prodcution of cytokines that are essentail for the development of effective immunity. Additionally, beyond the induction at the transcriptional level of proinflammatory mediators, TLR4 interaction with LPS also orchestrates the induction of mediators such as microRNAs (miRNAs) that post transcriptionally regulate the shutdown of the proinflammatory response.

3.“It might be possible for C. butyricum TO-A to obtain virulence potential from other bacteria through horizontal gene transfer”

As mentioned above, testing at the University of Calgary yielded results to show a lack of horizontal gene transfer and was negative for virulence potential. “It is unknown if Enterococcus faecium TO-A contains any virulence factors associated with E. faecium” AND “Probiotic-3 uses the strain Bacillus subtilis TO-A and it’s virulence potential is unknown currently, therefore I do not recommend it”

4.“It is unknown if Enterococcus faecium TO-A contains any virulence factors associated with E. faecium” AND “Probiotic-3 uses the strain Bacillus subtilis TO-A and it’s virulence potential is unknown currently, therefore I do not recommend it”

All strains in Probiotic-3 have been tested for virulence potential, presence of toxin carrying sequences. Results are negative on the strains for virulence, toxins and horizontal gene transfer. In conclusion, while it’s true that all probiotic products are not alike and do not offer the stated health benefits, research has shown that AOR’s Probiotic-3 offers numerous benefits and is proven to be non-pathogenic, while being shelf stable at room temperature.

I don’t begrudge the author his opinion and his resources for the public. What I do however hope for, in the future, is that experts out there obtain all the necessary, complete and correct information and be as unbiased as possible, when reporting on benefits or concerns associated with anything related to the health of the public.  

 References:

  1. https://ods.od.nih.gov/factsheets/Probiotics-HealthProfessional/
  2. Ciorba M. A. (2012). A gastroenterologist’s guide to probiotics. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association10(9), 960–968. doi:10.1016/j.cgh.2012.03.024
  3. Cassir, N., Benamar, S., & La Scola, B. (2016). Clostridium butyricum: from beneficial to a new emerging pathogen. Clinical Microbiology and Infection, 22(1), 37–45. https://doi.org/10.1016/j.cmi.2015.10.014
  4. Mary Ellen Sanders, Probiotics: Definition, Sources, Selection, and Uses, Clinical Infectious Diseases, Volume 46, Issue Supplement_2, February 2008, Pages S58–S61, https://doi.org/10.1086/523341
  5. Canani, R. B., Costanzo, M. D., Leone, L., Pedata, M., Meli, R., & Calignano, A. (2011). Potential beneficial effects of butyrate in intestinal and extraintestinal diseases. World journal of gastroenterology17(12), 1519–1528. doi:10.3748/wjg.v17.i12.1519
  6. Bourassa, M. W., Alim, I., Bultman, S. J., & Ratan, R. R. (2016). Butyrate, neuroepigenetics and the gut microbiome: Can a high fiber diet improve brain health? Neuroscience letters625, 56–63. doi:10.1016/j.neulet.2016.02.009
  7. Rose, S., Bennuri, S.C., Davis, J.E. et al. Butyrate enhances mitochondrial function during oxidative stress in cell lines from boys with autism. Transl Psychiatry 8, 42 (2018) doi:10.1038/s41398-017-0089-z
  8.  Monica Molteni, Sabrina Gemma, and Carlo Rossetti, “The Role of Toll-Like Receptor 4 in Infectious and Noninfectious Inflammation,” Mediators of Inflammation, vol. 2016, Article ID 6978936, 9 pages, 2016. https://doi.org/10.1155/2016/6978936.
  9. https://www.genecards.org/cgi-bin/carddisp.pl?gene=TLR4
  10. Isono, A., Katsuno, T., Sato, T., Nakagawa, T., Kato, Y., Sato, N., … Saito, Y. (2007). Clostridium butyricum TO-A Culture Supernatant Downregulates TLR4 in Human Colonic Epithelial Cells. Digestive Diseases and Sciences, 52(11), 2963–2971. https://doi.org/10.1007/s10620-006-9593-3
  11. Genichiro, Seo., Masanori, Sasatsu., Megumi, Kono. (1986). Drug Sensitivity and characteristics of Enterococcus isolated from Probiotic products. Clinical Microbiology, 13(3), 359-364, 1986
  12. Chen, C.-C., Kong, M.-S., Lai, M.-W., Chao, H.-C., Chang, K.-W., Chen, S.-Y., … Lin, T.-Y. (2010). Probiotics Have Clinical, Microbiologic, and Immunologic Efficacy in Acute Infectious Diarrhea. The Pediatric Infectious Disease Journal, 29(2).
  13. Tsuda, Y., Yoshimatsu, Y., Aoki, H., Nakamura, K., Irie, M., Fukuda, K., … Suzuki, Y. (2007). Clinical effectiveness of probiotics therapy (BIO-THREE) in patients with ulcerative colitis refractory to conventional therapy. Scandinavian Journal of Gastroenterology, 42(11), 1306–1311. https://doi.org/10.1080/00365520701396091
  14. Yoshimatsu, Y., Yamada, A., Furukawa, R., Sono, K., Osamura, A., Nakamura, K., … Suzuki, Y. (2015). Effectiveness of probiotic therapy for the prevention of relapse in patients with inactive ulcerative colitis. World journal of gastroenterology21(19), 5985–5994. doi:10.3748/wjg.v21.i19.5985
  15. Huang, Y.-F., Liu, P.-Y., Chen, Y.-Y., Nong, B.-R., Huang, I.-F., Hsieh, K.-S., & Chen, K.-T. (2014). Three-Combination Probiotics Therapy in Children With Salmonella and Rotavirus Gastroenteritis. Journal of Clinical Gastroenterology, 48(1).
  16. Chimura, T. (1998). Ecological treatment of bacterial vaginosis and vaginitis with Bio-Three (Article in Japanese). Japanese Journal of Antibiotics,  51(12) : 759-763
  17. Hua, M. C., Lin, T. Y., Lai, M. W., Kong, M. S., Chang, H. J., & Chen, C. C. (2010). Probiotic Bio-Three induces Th1 and anti-inflammatory effects in PBMC and dendritic cells. World journal of gastroenterology16(28), 3529–3540. doi:10.3748/wjg.v16.i28.3529
  18. Rammohan, A., Sathyanesan, J., Rajendran, K., Pitchaimuthu, A., Perumal, S. K., Balaraman, K., … Govindan, M. (2015). Synbiotics in Surgery for Chronic Pancreatitis: Are They Truly Effective? A Single-blind Prospective Randomized Control Trial. Annals of Surgery, 262(1).
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