Probiotics and the Biotic Industry

Since first defined by the World Health Organization in 2001, probiotics have played an increasingly more expansive role in dietary supplementation. One of the most critical and understated roles that probiotics have played is in prompting scientists to study and more thoroughly understand the vital functions that the trillions of native bacteria that reside on our skin, in our oral cavity, and throughout our intestinal tracts perform in keeping us healthy. We now have a fuller appreciation of how the use of antibiotics and other medications, certain disease conditions, genetics, and our diet can influence the make-up of our microbiome and how disruption of our indigenous microbial balance can have far-reaching consequences.

One of the most familiar uses for probiotic supplementation is to repopulate the intestinal tract with healthy bacteria after a round of antibiotics, and it is a recognized protocol for many healthcare professionals. These probiotics essentially serve as placeholders until the body’s native strains have re-established, ideally inhibiting colonization by opportunistic pathogenic strains that can enter the body and more easily colonize after destruction of beneficial strains by broad-spectrum antibiotics. But probiotic supplementation can do so much more.

Digestive support is one of the largest general areas for which consumers seek out probiotics in the form of dietary supplements or fermented foods such as yogurt, kefir or miso. Within the area of digestive support is a growing interest in the benefits of probiotics for protein digestion and utilization, especially for individuals consuming a high protein diet. Probiotics can support the microflora by inducing digestive protease and peptidase activity for facilitating optimal protein digestion; and by helping to improve the intestinal absorption of small peptides and amino acids.(1) Efficient protein digestion in turn prevents the accumulation of undigested protein in the colon, thus reducing protein fermentation and production of toxic metabolites.(2)

Probiotics can also be integral in supporting optimal immune health. The digestive tract, extending from the mouth through the colon provides the main conduit through which substances, both good and bad enter and exit our bodies. Throughout the digestive tract, the native bacteria interact directly and indirectly with the immune system, making them an integral part of a healthy immune response. Probiotic bacterial strains of several Lactobacillus and Bifidobacterium species such as L. rhamnosus, L. casei, L. plantarum and B. infantis as well as Streptococcus thermophilus can provide important support to the body’s microbiota in the gut by increasing the activity of immune system cells, such as macrophages and natural killer T cells, helping to modulate the secretion of immunoglobulins or cytokines, by enhancing the intestinal epithelial barrier and by competitively inhibiting the colonization of pathogenic bacteria.(3).

Most of the pathogens that enter our bodies do so through the nose and mouth, and this is where probiotics can have a significant impact. Within the oral cavity, beneficial bacteria act in several ways to inhibit entry of undesirable microbes. An oral cavity well-populated with beneficial species, such as Streptococcus salivarius, provide a physical barrier against invading pathogens, but they are also protective in other ways as well. Some strains also produce bacteriocins (BLIS), proteins that actively inhibit specific strains of closely related bacteria.(4) BLIS-producing strains are an extremely beneficial part of the natural protective mechanisms in the oral cavity and upper respiratory tract; but unfortunately, the most beneficial strains are rare (present in 2% or less of the general population). The development of probiotics from these beneficial strains can provide an impressive level of protection, especially in individuals who naturally have low levels of BLIS-producing bacteria in their mouths. Probiotics derived from strains such as S. salivarius K12 have been studied for over 30 years for their benefits in supporting upper respiratory health in adults and in children.(5)(6)(7) They can also play an important role in the treatment for chronic halitosis,(8) and as part of a dental hygiene regimen for protection against the bacteria causing tooth decay.(9) Some BLIS-producing oral cavity bacterial strains also interact directly with immune system cells on oral surfaces and in saliva.(10)(11)

Prebiotics encompass a group of nondigestible food ingredients that are degraded by and serve as a nutrient media for the gut microbiota. When consumed by gut bacteria, they produce metabolites that include short-chain fatty acids, which not only exert a beneficial effect within the GI tract (particularly the colon) but when absorbed through the intestinal wall can have a positive systemic effect as well.(12) Probably the two most familiar groups of prebiotics are the nondigestible carbohydrates, fructo-oligosaccharides and galacto-oligosaccharides. Formulations that combine probiotics with select prebiotics have become more popular in recent years, leading to the advent of the term, “synbiotics,” to indicate their potential synergism.

Two of the newest areas of “biotic” research are Psychobiotics and Postbiotics. Psychobiotics are usually defined as live bacteria that directly or indirectly engender positive effects on neuronal functions by colonizing and interacting with the intestinal microbiota.(13) They are thought to affect the central nervous system and its functions mediated by the gut-brain axis via immune (anti-inflammatory effects), and by modulating the actions of neurotransmitters and the hypothalamic-pituitary-adrenal (HAP) axis.(14) Most of the preliminary research has concentrated on their anxiolytic and antidepressant activities. The current research has concentrated on various species of Lactobacilus and Bifidobacteria. Prebiotics that influence commensal gut bacteria could also be included in this category if they are shown to influence emotional or cognitive functions.

The terms postbiotic or paraprobiotics have arisen because of the recognition that there are physiological benefits in inactivated (killed) probiotic bacteria, and the metabolic byproducts secreted by live bacteria or released after bacterial lysis. They have drawn attention because they have some distinct benefits over their live counterparts. They have a clear chemical structure, well defined safety dose parameters, a long shelf life and they contain distinct signaling molecules that have anti-inflammatory, immunomodulatory, anti-obesogenic, antihypertensive, hypocholesterolemic, anti-proliferative and antioxidant activities.(15)(16) They also overcome some of the concerns with the use of live bacteria, particularly in immune-compromised individuals since they reduce the risk of probiotic sepsis and antibiotic resistance.

There hasn’t been a tremendous amount of clinical research yet focusing on specific benefits of heat-killed or inactivated probiotic bacteria. However, one ingredient, Lactobacillus LB, a custom blend of two heat-treated probiotic species (Lactobacillus fermentum and L. delbrueki), has been studied extensively for its benefits in ameliorating acute persistent diarrhea and gastritis in children and adults. This research includes in vitro, in vivo, non-RCT and RCT, demonstrating that a concentrated, neutralized spent culture medium exhibits good biotherapeutic agent to treat several gastrointestinal disorders.(17)

Few other segments within the dietary supplement and functional foods industries have expanded and diversified to the extent that the “-biotics” segment has. This has presented tremendous opportunities for continued growth, and at the same time has resulted in the expected challenges such as the need for NDI notifications in the case of heat-treated and other derivatives of probiotic bacteria, to the splitting of the Lactobacillus genus. At the same time, this expansion provides exciting opportunities for the introduction of new ingredients that will safely and effectively provide tremendous benefits that can potentially be customized to meet specific needs in the end-consumer.

References

(1) Wang, J. & Haifeng, J. (2019) Influence of probiotics on dietary protein digestion and utilization in the gastrointestinal tract. Current Protein & Peptide Science, 20(2),125-131.

(2) Amaretti, A., Gozzoli, C., Simone, M., Raimondi, S., Righini, L., Pérez-Brocal, V., García-López, R., Moya, A. & Rossi, M. (2019) Profiling of protein degraders in cultures of human gut microbiota. Frontiers in Microbiology, 10,2614

(3) La Fata, G., Weber, P. & Mohajeri, M.H. (2018) Probiotics and the gut immune system: indirect regulation. Probiotics and Antimicrobial Proteins, 10(1),11-21.

(4) Walls, T., Power, D. & Tagg, J. (2003) Bacteriocin-like inhibitory substance (BLIS) production by the normal flora of the nasopharynx: potential to protect against otitis media? Journal of Medical Microbiology, 52,829-833.

(5) Di Pierro, F., Adami, T., Rapacioli, G., Giardini, N. & Streitberger, C. (2013) Clinical evaluation of the oral probiotic Streptococcus salivarius K12 in the prevention of recurrent pharyngitis and/or tonsillitis caused by Streptococcus pyogenes in adults. Expert Opinion on Biological Therapy, 13(3),339-343.

(6) Marini, G., Sitzia, E., Panatta, M.L. & De Vincentiis, G.C. 2019) Pilot study to explore the prophylactic efficacy of oral probiotic Streptococcus salivarius K12 in preventing recurrent pharyngo-tonsillar episodes in pediatric patients. International Journal of General Medicine, 12,213-217.

(7) Di Pierro, F., Colombo, M., Giuliani, M.G., Danza, M.L., Basile, I., Bollani, T., Conti, A.M., Zanvit, A. & Rottoli, A.S. (2018)Use of Streptococcus salivarius K12 to reduce the incidence of pharyngo-tonsillitis and acute otitis media in children: a retrospective analysis in not-recurrent pediatric subjects. Minerva Pediatrica,70(3),240-245.

(8) Jamali, A., Aminabadi, N.A., Samiei, M., Deljavan, A.S., Shokravi, M. & Shirazi, S. (2016) Impact of chlorhexidine pretreatment followed by probiotic Streptococcus salivarius strain K12 on halitosis in children: a randomized controlled clinical trial. Oral Health & Preventive Dentistry, 14(4),305-313.

(9) Di Pierro, F., Zanvit, A., Nobili, P., Risso, P. & Fornaini, C. (2015) Cariogram outcome after 90 days of oral treatment with Streptococcus salivarius M18 in children at high risk for dental caries: results of a randomized controlled study. Clinical, Cosmetic and Investigational Dentistry, 7:107-113.

(10) Cosseau, C., Devine, D., Dullaghan, E., Gardy, J., Chikatamaria, A., Gellatly, S., Yu, L., Pistolic, J., Falsafi, R., Tagg, J. & Hancock, R. (2008) The commensal Streptococcus salivarius K12 downregulates the innate immune responses of human epithelial cells and promotes host-microbe homeostasis. Infection and Immunity, 76(9),4163-4175.

(11) Chilcott, C., Crowley, L., Kulkarni, V., Jack, R., McLellan, A., & Tagg, J. (2005) Elevated levels of interferon gamma in human saliva following ingestion of Streptococcus salivarius K12. Joint Meeting of New Zealand Microbiological Society and New Zealand Biochemistry and Molecular Biology, Dunedin.

(12) Davani-Davari, D., Negahdaripour, M., Karimzadeh, I., Seifan, M., Mohkam, M., Masoumi, S.J., Berenjian, A. & Ghasemi, Y. (2019) Prebiotics: definition, types, sources, mechanisms, and clinical applications. Foods, 8(3),92.

(13) Evrensel, A., Ünsalver, B.Ö. & Ceylan, M.E. (2019) Psychobiotics. Advances in Experimental Medicine and Biology, 1192,565-581.

(14) Cheng, L., Liu, Y., Wu, C., Wang, S. Tsai, Y. (2019) Psychobiotics in mental health, neurodegenerative and neurodevelopmental disorders. Journal of Food and Drug Analysis, 27(3),632-648.

(15) Auilar-Toalá, J.E., Garcia-Varela, R., Garcia, H.S., Mata-Haro, V., González-Córdova, A.F., Vallejo-Cordoba, B and Hernández-Mendoza, A. (2018) Postbiotics: an evolving term within the functional foods field. Trends in Food Science & Technology, 75,105-114.

(16) Akter, S., Park, J. & Jung, H. (2020) Potential health-promoting benefits of paraprobiotics, inactivated probiotic cells. Journal of Microbiology and Biotechnology, 30(4),477-481.

(17) Liévin-Le Moal, V. (2016) A gastrointestinal anti-infectious biotherapeutic agent: the heat-treated Lactobacillus LB. Therapeutic Advances in Gastroenterology, 9(1),57-75.