NavNirat Nibber, ND

Our gut microbiome describes the unique and complex array of microorganisms that inhabit our gut. Imagine in your large intestine there is a fertile landscape ready to welcome a multitude of microbes, including billions of bacteria and yeast. These microbes colonize the lining of the gut and are known as “commensal microbes,” meaning we have developed a “symbiotic” or mutually beneficial relationship with them.¹ In return for hosting these bacteria, they help us digest food, strengthen or calm our immune system, and even send signals to our nervous system impacting mood and mental health, affecting almost every system in our body.¹  

Microorganisms that comprise an individual’s microbiome are determined by a number of factors, including genetics, delivery techniques (vaginal seeding techniques), diet, antibiotic use, environment and more.² When this internal environment gets disrupted, known as dysbiosis, it can lead to gut disorders such as Crohn’s disease, ulcerative colitis, and various gastrointestinal infections.³  

Medicine has long used probiotics to promote gut health. Russian scientist Elie Metchnikoff discovered fermented yogurt in the early 1900s after observing long life and good health in rural Bulgarians who consumed it regularly.⁶As a result of his research, he discovered that probiotics might prevent the toxic effects of gastrointestinal metabolism, which contribute to illness and aging. Investigations into supplemental probiotic support was first described in 1922 and used Lactobacillus acidophilus in 30 patients with chronic constipation, diarrhea or eczema.⁶ Even back then researchers found improvement in all three conditions. It was 10 years later, in 1932, that a study confirmed the effects of L. acidophilus in patients with constipation and mental illness.⁶  

Although most of the research on probiotics has focused on gut health, recent discoveries about the role of gut bacteria and the brain-gut axis have spurred increased interest in understanding how probiotics work in different health conditions.⁵  A study published in 2021 presented probiotics as a potential treatment for constipation in patients with schizophrenia.⁶  Research has also found probiotics beneficial in mental health conditions like anxiety and depression.⁵  

Probiotics have also been studied in the following conditions:

• Ulcerative colitis^2-4
• GI infections (leading to diarrhea and constipation)⁴
• Inflammatory bowel disease⁷
• Irritable bowel syndrome^7I
• GI infections in children (salmonella, rotavirus)⁸
• Autoimmune disease⁹
• Depression⁵
• Anxiety⁵  

We can obtain probiotics from fermented foods, soil, fresh produce, and from regulated dietary supplements.³ When consumed in adequate amounts, they provide a range of health benefits to the host. They work by introducing beneficial bacteria to the gut, helping to maintain microbial balance, and promote a healthy gut environment.  

As interest in probiotics grows, so does the variety of available products each touting the most strains and the best results subsequently confusing consumers.¹⁰ Products that combine many commensal strains in very high doses offer short-term or no benefits at all for three important reasons:  

• A lack of synergy or even competition of strains leading to low potency: While many of the strains exist in the human colon and theoretically are synergistic, they do not operate synergistically in a capsule – a vastly different environment than the human gut. Manufacturers try to offset this uncertainty by adding very high doses (overages) to anticipate the die-off, hoping that some of the bacteria make it to the colon.¹⁰
• Inability to properly colonize the colon: Strains in the probiotic supplement may not be able to withstand the harsh and variable environments that exist along the human gastrointestinal tract. From the highly acidic stomach to the alkaline small intestine, and eventually to the large intestine where they colonize and live. While fermented foods with probiotic capabilities are effective, many supplemental formulations lack the clinical data to confidently conclude that proper colonization is occurring.¹⁰
• Reduced tolerance due to adverse effects: Many probiotic supplements contain prebiotics that are used as fuel which can result in gas, bloating, and uncomfortable reactions.¹¹ Even formulations without these prebiotics can result in a short-term band-aid solution by providing microbial diversity only while continuing to take the probiotics and fewer long-term benefits after stopping.

The Synergy Concept in BIO-Three Probiotics

Synergy refers to the cooperative action of different elements working together to produce a result that is greater than the sum of their individual effects. In the context of probiotics, this means that the selected strains complement each other, enhancing their overall effectiveness.  

BIO-THREE is an exclusive formulation thathas been used to manage ulcerative colitis (UC) and GI infections. This is a combination formula made up of three bacteria species with specific qualities to promote health. Although these are new strains to North America, they have been used medicinally in Asia for more than 70 years.¹² Enterococcus faecium T-110 (E. faecium) is naturally found in the GI tract. It produces lactic acid increasing the acidity in the gut, preventing the growth of harmful bacteria. Clostridium butyricum TO-A (C. butyricum) is also naturally occurring in the gut. It provides protective effects through breaking down dietary fiber into beneficial nutrients, one being butyric acid, feeding cells of the GI tract. Bacillus subtilis TO-A (B. subtilis) supports E. faecium and C. butyricum growth along with growth of some of the Bifidobacterium species, another type of beneficial bacteria that supports a healthy gut environment. BIO-THREE was formulated as a synbiotic agent with all three bacteria to promote a healthy gut and help reduce symptoms of ulcerative colitis and GI infections.¹² 

Advantages of Fewer Strains with Synergy  

    Enhanced Stability. Having fewer strains in a probiotic formulation can lead to increased stability and viability of the product. Each strain requires specific environmental conditions to survive and thrive. With fewer strains, it is easier to ensure that these conditions are met, resulting in a more robust and reliable probiotic product.¹²  

Reduced Competition When It Matters. In probiotics with numerous competing strains, some strains may outcompete others, leading to a less diverse and less effective gut microbiota. In contrast, carefully selected strains should demonstrate growth when in the same media rather than one or more strains degrading. Each strain works together harmoniously, reducing competition when in the capsule in turn leads to a balanced and diverse gut environment that outcompetes bad bacteria in the gut. For example, E. faecium T-110 naturally lives in the human gut. It produces lactic acid, which lowers the pH, preventing the growth of harmful bacteria while still being synergistic with Bifidobacterium species.¹³  

Targeted Benefits. By choosing specific strains that complement each other’s functions, we can address specific health concerns more effectively. For example, certain strains may focus on improving digestion, while others boost immune function. The synergy between the strains amplifies the overall impact on gut health. For example, C. butyricum TO-A also naturally lives in the human gut and breaks down dietary fiber into several beneficial nutrients, one of which is butyric acid, which feeds cells of the GI tract.¹⁴  

Improved Colonization. The ability of probiotic strains to colonize the gut is crucial for their effectiveness. Selected strains should be able to withstand the harsh ecology along the human gastrointestinal tract. Those that are acid resistant, spore forming or inactivated may be more likely to first reach and then establish themselves and finally persist in the large intestine.¹⁴  

Minimized Side Effects. Some individuals may experience digestive discomfort when consuming probiotics with multiple competing strains. This is the result of high metabolic activity resulting in by-products of fermentation irritating the colon or increasing gas production. Strains that can use the by-products of another bacterial strain’s metabolism will thrive—like a chain reaction of growth. An example of this synergy is seen in the strain B. subtilis TO-A , which supports the growth of E. faecium and C. butyricum, as well as the growth of several strains of the beneficial Bifidobacterium species.¹⁵  

Clinical Relevance. As mentioned, many probiotic combinations use theory rather than clinical validation to support formulas. Taking a kitchen sink approach, throwing many strains with little data to support combinations into a capsule and hoping it makes it to and then colonizes the human gut. Rigorous testing of the interaction between strains both in the capsule and in the gut is required to feel confident when taking a probiotic.  Bio-three has a long history of use in clinical and experimental settings. Some clinical studies have shown wide-ranging health benefits, including reducing allergy symptoms, improved immunity, reduced bloating, constipation and diarrhea, and even enhanced detoxification.^15,16  

	MECHANISMS OF ACTION	INTERACTIONS
ENTEROCOCCUS FAECIUM T-110	– A member of the lactic acid family, it is very effective at killing harmful bacteria.  – It can survive the acidity of the digestive process to thrive in the gut.   – It produces three antibacterial peptides, called bacteriocins, which are effective against multiple bacterial species.   – When paired with C. butyricum, the effectiveness of controlling harmful bacteria is significantly higher than either strain alone.	No known drug interactions, however, it is not recommended for people who are immunocompromised.
CLOSTRIDIUM BUTYRICUM TO-A	– Well known as the essential regulator of intestinal homeostasis, or balance within the body.  – Uses fermentation to create short-chained fatty acids (SCFA), lowering the pH in the gut making it inhospitable to many harmful species.  – C. butyricum kills harmful bacteria that settle in the inner lining of the intestine (the intestinal mucosa) by competing with other species and making antibacterial peptides.	No known drug interactions, however, it is not recommended for people who are immunocompromised.
BASCILLUS SUBTILIS TO-A	– B. subtilis attaches to the inner lining of the intestine making it difficult for other harmful bacteria to stick.  – It also produces antibiotics, antimicrobial enzymes, and special digestive enzymes that support gut function and makes essential amino acids and vitamins. B. subtilis produces bacteriocins that combat GI infections caused by harmful bacteria.	No known drug interactions, however, it is not recommended for people who are immunocompromised.

Postbiotics Finally Getting a Boost

While probiotics are the gut microbes in our guts, prebiotics are the soluble and insoluble fibers that probiotics eat. These two are often used together in something called a synbiotic. Postbiotics, however, are the substances made through the metabolic activity of probiotics eating prebiotics. These by-products may have beneficial effects to the person whose gut they live in.¹⁶   

Postbiotics are the substances released or produced through the metabolic activity of probiotics, called “functional fermentation compounds.”¹⁷ They provide a new and interesting take on probiotics as they provide the same health benefits without many risks. Postbiotics are inactive bacteria, so the risk of developing infections is much lower. They are also stable at room temperature making them easier to store and less temperamental. While research using postbiotics is new and developing, there is already promising research suggesting their benefits in metabolic disorders, weight management, and as an antioxidant.    

References

1. Gasbarrini, G., Bonvicini, F. & Gramenzi, A. Probiotics History. J. Clin. Gastroenterol. 50, S116–S119 (2016). 
2. Yoshimatsu Y, Yamada A, Furukawa R, Sono K, Osamura A, Nakamura K, Aoki H, Tsuda Y, Hosoe N, Takada N, Suzuki Y. (2015). Effectiveness of probiotic therapy for the prevention of relapse in patients with inactive ulcerative colitis. World J Gastroenterol. May 21;21(19):5985-94. doi: 10.3748/wjg.v21.i19.5985. 
3. Dhillon, P., Singh K. (2020). Therapeutic applications of probiotics and ulcerative colitis: An updated review. PharmaNutrition. Vol 13. https://doi.org/10.1016/j.phanu.2020.100194. 
4. Bjarnason, I., Sission, G. & Hayee, B. (2019). A randomised, double-blind, placebo-controlled trial of a multi-strain probiotic in patients with asymptomatic ulcerative colitis and Crohn’s disease. Inflammopharmacol 27, 465–473. https://doi.org/10.1007/s10787-019-00595-4 
5. Johnson, D., Thurairajasingam, S., Letchumanan, V., Chan, K.-G., & Lee, L.-H. (2021). Exploring the Role and Potential of Probiotics in the Field of Mental Health: Major Depressive Disorder. Nutrients, 13(5), 1728. MDPI AG. Retrieved from http://dx.doi.org/10.3390/nu13051728 
6. Lynne V. McFarland, From Yaks to Yogurt: The History, Development, and Current Use of Probiotics, Clinical Infectious Diseases, Volume 60, Issue suppl_2, May 2015, Pages S85–S90, https://doi.org/10.1093/cid/civ054 
7. Nagamine, T. (2021). The potential of probiotics in the treatment of schizophrenia. Clinical Neuropsychopharmacology and Therapeutics, 12, 18-22.  
8. Kanai, T., Mikami, Y. & Hayashi, A. (2015). A breakthrough in probiotics: Clostridium butyricum regulates gut homeostasis and anti-inflammatory response in inflammatory bowel disease. J Gastroenterol 50, 928–939. https://doi.org/10.1007/s00535-015-1084-x 
9. Helioswilton Sales-Campos, Siomar Castro Soares & Carlo José Freire Oliveira (2019) An introduction of the role of probiotics in human infections and autoimmune diseases, Critical Reviews in Microbiology, 45:4, 413-432, DOI: 10.1080/1040841X.2019.1621261  
10. Chen CC, Kong MS, Lai MW, Chao HC, Chang KW, Chen SY, Huang YC, Chiu CH, Li WC, Lin PY, Chen CJ, Li TY. (2010). Probiotics have clinical, microbiologic, and immunologic efficacy in acute infectious diarrhea. Pediatr Infect Dis J.Feb;29(2):135-8. doi: 10.1097/inf.0b013e3181b530bf. 
11. Helioswilton Sales-Campos, Siomar Castro Soares & Carlo José Freire Oliveira (2019) An introduction of the role of probiotics in human infections and autoimmune diseases, Critical Reviews in Microbiology, 45:4, 413-432, DOI: 10.1080/1040841X.2019.1621261 
12. Wallace, C. J., & Milev, R. V. (2021). The efficacy, safety, and tolerability of probiotics on depression: clinical results from an open-label pilot study. Frontiers in psychiatry, 12, 618279. 
13. Huang YF, Liu PY, Chen YY, Nong BR, Huang IF, Hsieh KS, Chen KT. (2014). Three-combination probiotics therapy in children with salmonella and rotavirus gastroenteritis. J Clin Gastroenterol. Jan;48(1):37-42. doi: 10.1097/MCG.0b013e31828f1c6e. PMID: 23632352.  
14. Yuan, W., Xiao, X., Yu, X. et al. (2022). Probiotic Therapy (BIO-THREE) Mitigates Intestinal Microbial Imbalance and Intestinal Damage Caused by Oxaliplatin. Probiotics & Antimicro. Prot. 14, 60–71. https://doi.org/10.1007/s12602-021-09795-3
15. 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 gastroenterology, 16(28), 3529–3540. https://doi.org/10.3748/wjg.v16.i28.3529
16. Wegh, Geerlings, Knol, Roeselers, & Belzer. Postbiotics and Their Potential Applications in Early Life Nutrition and Beyond. Int. J. Mol. Sci. 20, 4673 (2019).   

Published October 21, 2023

About the Author

NavNirat Nibber, ND, is a graduate of the Canadian College of Naturopathic Medicine, and a registered naturopathic doctor and recipient of the 2015 Naturopathic Honour Award. In addition to her clinical and consulting work, Dr. Nibber is a senior medical advisor, brand educator, and research liaison for Advanced Orthomolecular Research engaging with international research in the naturopathic field. She is a published health expert in over 25 international publications. Her focus is on providing equitable and accessible heath insights to build empowered communities.