www.wholefoodsmagazine.com/blogs/1-wholefoods-magazine/post/13694-probiotics-101-it-s-not-about-the-billions
Probiotics 101: It’s Not About the Billions
December 13, 2018
This article was written by Sid Shastri, product development manager for Kaneka Nutrients and Jordi Espadaler, Ph.D., director of innovation at A. B. Biotics
Probiotics are drastically becoming one of the preferred types of supplements in the US. According to a recent study from Research and Markets, functional food ingredients’ market was globally valued at USD 64.75 billion in 2017 (1). In this scope, probiotics market is estimated to provide 45.64 billion and projected to reach a value of USD 64.02 billion by 2022 (2). Factors such as rapid urbanization hand in hand with higher incomes and rising costumer’s interest in healthcare rank the Asia Pacific region as leaders of the probiotics ’global market. However, North America is predicted to be the fastest expanding market for probiotic products, with a predicted CAGR of 11.4 % for the 2015-2020 period (3). Noteworthy, despite growing probiotics’ popularity, the term probiotic is frequently misunderstood.
What is really a probiotic?
The International Scientific Association for Probiotics and Prebiotics (ISAPP) together with the World Health Organization (WHO) and the Food and Agriculture Organization (FAO) describes probiotics as live microorganisms which when administered in adequate amounts confer a health benefit on the host (4,5). This means that fermentative bacterial strains with no clinically-proven impact on consumer’s wellness or which are not alive in sufficient amounts in the final product are not probiotics. Therefore, probiotics must simultaneously meet two conditions: 1) have clinical proof of effectiveness at an explicit number of live bacteria, stated in colony-forming units (CFUs), and 2) same determined dosage must be specified in the package labelling and verified to be effective at the end of its shelf life.
Most commonly used probiotics include a wide range of Bifidobacteria and Lactobacilli species. Some strains that have been clinically researched in randomized, double-blinded trials include: L. rhamnosus GG ATCC53103 (6,7) B.longum 35624 (8), the combination of L.plantarum strains CECT7527, CECT7528 and CECT7529 (9), L.reuteri NCIMB 30242 (10,19) B.lactis Bb12 (11), the combination of P.acidilactic CECT7483 and L.plantarum CECT7484 and CECT748512 (12), L.plantarum 299v (13,14), S.boulardii CNCMi745 (15) and L.reuteri DSM1793 (16, 17, 18) among others.
What probiotics can do for you.
A healthy human hosts around 10 trillion microorganisms in the large intestine. With over thousand different species, gut microbiota consisting of bacteria, fungi, protists and viruses/phages adds an average of 600,000 genes to a typical human compared to 20,000 genes in the human genome (20), although alternative splicing may significantly raise the number of final gene products). The intestinal ecosystem plays a very important symbiotic role in human health. Most important functions involve host nutrition, metabolism regulation, immune system training, regulation of intestinal transit, gut’s epithelial regeneration and resistance to intestinal pathogens (21,22). Furthermore, increasing evidence proves the role of intestinal microbiota in the regulation of gut-brain axis (23).
Due to constant changes in lifestyle such as nutrition, stress and antibiotics, the gut microbiota undergoes significant alterations over lifetime, and such fluctuations may impact human health. Furthermore, modern lifestyle has resulted in a significant shrinking of its diversity, thus reducing its genetic load and its resilience to environmental challenges (31). Over a century ago, Nobel laureate Eli Metchnikoff postulated “the majority of diseases begin in the digestive tract when ‘good’ bacteria are no more able to control ‘bad’ bacteria” calling this dysbiosis. Nowadays, the scientific community is increasingly aware of the importance of maintaining a balanced gut microbiota to avoid dysbiosis and keep a healthy status. The augmenting amount of evidence is pushing healthcare industry to develop new strategies to counterbalance dysbiosis.
Today, the main therapeutic aims of microbiota modulation include: (i) probiotic intake consisting of bacteria able to displace pathogenic organisms, normalize gut transit, improve the epithelial barrier to reduce intestinal hypersensitivity, downregulate inflammation, increase the immune response to future infections, reduce allergic response, or to improve lipid metabolism; (ii) intake of prebiotics to stimulate the growth of bacteria already in the gut, with similar aims to probiotic administration; and (iii) combination of aforementioned approaches (symbiotics). Thus, success of probiotic treatment depends on their ability to survive gut passage and effect in the intestinal microbiota by interacting with commensal or potential pathogenic microorganisms, impacting the host’s mucosal immune mechanisms and/or metabolic signaling.
From Infants to Elderly
Biodiversity and complexity of microbiota is quite confined in the early life stages. After the depletion of oxygen by facultative anaerobes, Bifidobacteria is the most abundant genus in infants (24). Their presence is positively correlated to health status in childhood. Interestingly, several extrinsic factors determine the initial colonization of Bifidobacterial populations: gestational age, delivery mode and feeding (32). Bifidobacteria are predominant in breastfed and vaginal delivered babies. In contrast, cesarean delivered, formula-fed and preterm infants share an increase in Bacteroides species and Escherichia coli.
Given their dominance in the healthy baby gut, Bifidobacteria are gaining acclaim among parents and physicians. Indeed, they are widely used in the treatment and prevention of several infant health problems. Some pathologies with proven positive outcome comprise infant colic (16,17,18) acute diarrhea (6), infections (25) and allergies (30).
Intestine’s microbiota evolves and naturally stabilizes at approximately 3 years of age, although antibiotic intake and dietary patterns might influence microbiota’s variability throughout life. In adulthood, the amounts of Bifidobacteria decrease compared to childhood (2–14% relative abundance) and tend to remain stable. Among a wide range of factors, lactase non-persisters merged with dairy products consumption seems to be one of the parameters orchestrating Bifidobacteria growth, being increased in this scenario (26).
Regardless different concerns associating Lactobacilli to western diet, their presence in the small intestine and colon has been demonstrated in some populations with non-western lifestyle by metagenomic population studies (27, 28). Moreover, mucosa-associated bacterial characterization using culture-independent quantitative methods have revealed the presence of Lactobacilli and Bifidobacterium in terminal ileum, ascending, transverse and descending colon biopsy samples (29).
Both Bifidobacterium and Lactobacilli have been extensively used as probiotics to treat gastrointestinal (8, 12, 13), lipidic metabolism (9,10,19), respiratory, urinary, vaginal and dermatologic diseases, disorders in oral health, gut-brain axis and allergies (34,35).
About the billions- Why more is not necessarily better.
Of crucial importance when consuming probiotics is to know the exact genus, species and clinical documentation of the strain. On one hand, it has been repeatedly demonstrated that some probiotic effects appear to be general species benefits (e.g.: capability of Bifidobacteria to stimulate the immune system seems to be species specific), while other benefits appear to be strain-specific. For instance, L.rhamnosus GG strain ATCC53103 has a high capacity to adhere to intestinal epithelium, but scientific research has shown that generic strains of L.rhamnosus GG may be devoid of epithelium-binding genes because of genomic deletions spanning dozens of genes (33). Clearly, intake of billions of bacteria devoid of genes producing a health benefit can be rather useless. As probiotics for human usage demand substantiation of efficacy by a clinical trial, clinical data will reveal optimal strain specific dosage. In this regard, it is worth noting that clinical trials with specific strains have shown a saturation effect (12). The best analogy I’ve heard on this comes from Jordi Espadaler, Ph.D.: If you have a plot of land where you can plant 10 trees, there is no reason to believe that if you plant the seeds of 100 trees in the same given area of a much better outcome. In a similar way, the CFU inflation counts that we see may not be providing the intended beneficial effect. Without mentioning company names, the number #1 probiotic advertised at 25 Billion count. A decade later, the best-selling claim has a 50 Billion CFU value--a doubling of count in one decade. Our approach is to find the minimum CFU count that exerts the clinically significant benefit.References:
Probiotics are drastically becoming one of the preferred types of supplements in the US. According to a recent study from Research and Markets, functional food ingredients’ market was globally valued at USD 64.75 billion in 2017 (1). In this scope, probiotics market is estimated to provide 45.64 billion and projected to reach a value of USD 64.02 billion by 2022 (2). Factors such as rapid urbanization hand in hand with higher incomes and rising costumer’s interest in healthcare rank the Asia Pacific region as leaders of the probiotics ’global market. However, North America is predicted to be the fastest expanding market for probiotic products, with a predicted CAGR of 11.4 % for the 2015-2020 period (3). Noteworthy, despite growing probiotics’ popularity, the term probiotic is frequently misunderstood.
What is really a probiotic?
The International Scientific Association for Probiotics and Prebiotics (ISAPP) together with the World Health Organization (WHO) and the Food and Agriculture Organization (FAO) describes probiotics as live microorganisms which when administered in adequate amounts confer a health benefit on the host (4,5). This means that fermentative bacterial strains with no clinically-proven impact on consumer’s wellness or which are not alive in sufficient amounts in the final product are not probiotics. Therefore, probiotics must simultaneously meet two conditions: 1) have clinical proof of effectiveness at an explicit number of live bacteria, stated in colony-forming units (CFUs), and 2) same determined dosage must be specified in the package labelling and verified to be effective at the end of its shelf life.
Most commonly used probiotics include a wide range of Bifidobacteria and Lactobacilli species. Some strains that have been clinically researched in randomized, double-blinded trials include: L. rhamnosus GG ATCC53103 (6,7) B.longum 35624 (8), the combination of L.plantarum strains CECT7527, CECT7528 and CECT7529 (9), L.reuteri NCIMB 30242 (10,19) B.lactis Bb12 (11), the combination of P.acidilactic CECT7483 and L.plantarum CECT7484 and CECT748512 (12), L.plantarum 299v (13,14), S.boulardii CNCMi745 (15) and L.reuteri DSM1793 (16, 17, 18) among others.
What probiotics can do for you.
A healthy human hosts around 10 trillion microorganisms in the large intestine. With over thousand different species, gut microbiota consisting of bacteria, fungi, protists and viruses/phages adds an average of 600,000 genes to a typical human compared to 20,000 genes in the human genome (20), although alternative splicing may significantly raise the number of final gene products). The intestinal ecosystem plays a very important symbiotic role in human health. Most important functions involve host nutrition, metabolism regulation, immune system training, regulation of intestinal transit, gut’s epithelial regeneration and resistance to intestinal pathogens (21,22). Furthermore, increasing evidence proves the role of intestinal microbiota in the regulation of gut-brain axis (23).
Due to constant changes in lifestyle such as nutrition, stress and antibiotics, the gut microbiota undergoes significant alterations over lifetime, and such fluctuations may impact human health. Furthermore, modern lifestyle has resulted in a significant shrinking of its diversity, thus reducing its genetic load and its resilience to environmental challenges (31). Over a century ago, Nobel laureate Eli Metchnikoff postulated “the majority of diseases begin in the digestive tract when ‘good’ bacteria are no more able to control ‘bad’ bacteria” calling this dysbiosis. Nowadays, the scientific community is increasingly aware of the importance of maintaining a balanced gut microbiota to avoid dysbiosis and keep a healthy status. The augmenting amount of evidence is pushing healthcare industry to develop new strategies to counterbalance dysbiosis.
Today, the main therapeutic aims of microbiota modulation include: (i) probiotic intake consisting of bacteria able to displace pathogenic organisms, normalize gut transit, improve the epithelial barrier to reduce intestinal hypersensitivity, downregulate inflammation, increase the immune response to future infections, reduce allergic response, or to improve lipid metabolism; (ii) intake of prebiotics to stimulate the growth of bacteria already in the gut, with similar aims to probiotic administration; and (iii) combination of aforementioned approaches (symbiotics). Thus, success of probiotic treatment depends on their ability to survive gut passage and effect in the intestinal microbiota by interacting with commensal or potential pathogenic microorganisms, impacting the host’s mucosal immune mechanisms and/or metabolic signaling.
From Infants to Elderly
Biodiversity and complexity of microbiota is quite confined in the early life stages. After the depletion of oxygen by facultative anaerobes, Bifidobacteria is the most abundant genus in infants (24). Their presence is positively correlated to health status in childhood. Interestingly, several extrinsic factors determine the initial colonization of Bifidobacterial populations: gestational age, delivery mode and feeding (32). Bifidobacteria are predominant in breastfed and vaginal delivered babies. In contrast, cesarean delivered, formula-fed and preterm infants share an increase in Bacteroides species and Escherichia coli.
Given their dominance in the healthy baby gut, Bifidobacteria are gaining acclaim among parents and physicians. Indeed, they are widely used in the treatment and prevention of several infant health problems. Some pathologies with proven positive outcome comprise infant colic (16,17,18) acute diarrhea (6), infections (25) and allergies (30).
Intestine’s microbiota evolves and naturally stabilizes at approximately 3 years of age, although antibiotic intake and dietary patterns might influence microbiota’s variability throughout life. In adulthood, the amounts of Bifidobacteria decrease compared to childhood (2–14% relative abundance) and tend to remain stable. Among a wide range of factors, lactase non-persisters merged with dairy products consumption seems to be one of the parameters orchestrating Bifidobacteria growth, being increased in this scenario (26).
Regardless different concerns associating Lactobacilli to western diet, their presence in the small intestine and colon has been demonstrated in some populations with non-western lifestyle by metagenomic population studies (27, 28). Moreover, mucosa-associated bacterial characterization using culture-independent quantitative methods have revealed the presence of Lactobacilli and Bifidobacterium in terminal ileum, ascending, transverse and descending colon biopsy samples (29).
Both Bifidobacterium and Lactobacilli have been extensively used as probiotics to treat gastrointestinal (8, 12, 13), lipidic metabolism (9,10,19), respiratory, urinary, vaginal and dermatologic diseases, disorders in oral health, gut-brain axis and allergies (34,35).
About the billions- Why more is not necessarily better.
Of crucial importance when consuming probiotics is to know the exact genus, species and clinical documentation of the strain. On one hand, it has been repeatedly demonstrated that some probiotic effects appear to be general species benefits (e.g.: capability of Bifidobacteria to stimulate the immune system seems to be species specific), while other benefits appear to be strain-specific. For instance, L.rhamnosus GG strain ATCC53103 has a high capacity to adhere to intestinal epithelium, but scientific research has shown that generic strains of L.rhamnosus GG may be devoid of epithelium-binding genes because of genomic deletions spanning dozens of genes (33). Clearly, intake of billions of bacteria devoid of genes producing a health benefit can be rather useless. As probiotics for human usage demand substantiation of efficacy by a clinical trial, clinical data will reveal optimal strain specific dosage. In this regard, it is worth noting that clinical trials with specific strains have shown a saturation effect (12). The best analogy I’ve heard on this comes from Jordi Espadaler, Ph.D.: If you have a plot of land where you can plant 10 trees, there is no reason to believe that if you plant the seeds of 100 trees in the same given area of a much better outcome. In a similar way, the CFU inflation counts that we see may not be providing the intended beneficial effect. Without mentioning company names, the number #1 probiotic advertised at 25 Billion count. A decade later, the best-selling claim has a 50 Billion CFU value--a doubling of count in one decade. Our approach is to find the minimum CFU count that exerts the clinically significant benefit.References:
- Research and Markets, 2018. Functional Food Ingredients Market by Type (Probiotics, Prebiotics, Proteins & Amino Acids, Phytochemical & Plant Extracts, Omega-3 Fatty Acids, Carotenoids, Fibers & Specialty Carbohydrates), Application, Source, and Region - Global Forecast to 2023.
- Research and Markets, 2017. Probiotics Market by Application (Functional Food & Beverages (Dairy, Non-dairy Beverages, Baked Goods, Meat, Cereal), Dietary Supplements, Animal Feed), Source (Bacteria, Yeast), Form (Dry, Liquid), End User (Human, Animal), and Region - Forecast to 2022.
- Probiotic Products - A Global Market Overview, 2015.
- FAO-WHO, 2002. Guideline for the Evaluation of Probiotics in Food.
- ISAPP, 2017. Probiotics.
- Szajewska et al., 2013. Meta-analysis: Lactobacillus GG for treating acute gastroenteritis in children--updated analysis of randomised controlled trials. Aliment Pharmacol Ther.;38(5):467-76.
- Khailova et al., 2017. Lactobacillus rhamnosus GG treatment improves intestinal permeability and modulates inflammatory response and homeostasis of spleen and colon in experimental model of Pseudomonas aeruginosa Q3 pneumonia. Clin Nutr.; 36(6):1549-1557.
- Whorwell et al., 2006. Efficacy of an encapsulated probiotic Bifidobacterium infantis 35624 in women with irritable bowel syndrome. Am J Gastroenterol 2006;101:1581-90.
- Fuentes et al., 2013. Cholesterol-lowering efficacy of Lactobacillus plantarum CECT 7527, 7528 and 7529 in hypercholesterolaemic adults. Br J Nutr.;109(10):1866-72.
- Sung et al. 2018. Lactobacillus reuteri to Treat Infant Colic: A Meta-analysis. Pediatrics; volume 141/ issue 1.
- Mohan et al., 2006. Effects of Bifidobacterium lactis Bb12 Supplementation on Intestinal Microbiota of Preterm Infants: A Double-Blind, Placebo-Controlled, Randomized Study. J Clin Microbiol.; 44(11): 4025–4031.
- Lorenzo-Zúñiga et al., 2014. I.31, a new combination of probiotics, improves irritable bowel syndrome-related quality of life. World J Gastroenterol 20(26): 8709–8716.
- Niedzielin et al., 2001. A controlled, double-blind, randomized study on the efficacy of Lactobacillus plantarum 299V in patients with irritable bowel syndrome. Eur J Gastroenterol Hepatol. 13(10):1143-7.
- Andersson et al., 2016. Oral administration of Lactobacillus plantarum 299v reduces cortisol levels in human saliva during examination induced stress: A randomized, double-blind controlled trial. Int J Microbiol. ;2016:8469018.
- Szajewska et al., 2015. Systematic review with meta-analysis: Saccharomyces boulardii in the prevention of antibiotic-associated diarrhea. Alimentary Pharmacology & Therapeutics; 42(7), 793–801.
- Indrio et al., 2014. Prophylactic use of a probiotic in the prevention of colic, regurgitation, and functional constipation: a randomized clinical trial. JAMA Pediatr. ;168(3):228-33.
- Savino et al., 2010. Lactobacillus reuteri DSM 17938 in infantile colic: a randomized, double-blind, placebo-controlled trial. Pediatrics; 126(3):e526-33.
- Szajewska et al., 2013. Lactobacillus reuteri DSM 17938 for the management of infantile colic in breastfed infants: a randomized, double-blind, placebo-controlled trial. J Pediatr.;162(2):257-62.
- Jones ML et al., 2012. Cholesterol lowering and inhibition of sterol absorption by Lactobacillus reuteri NCIMB 30242: a randomized controlled trial. European journal of clinical nutrition ;66(11):1234–41.
- Turnbaugh et al., 2007. The human microbiome project. Nature; 449, 804–810.
- Flint et al., 2012. The role of the gut microbiota in nutrition and health. Nat Rev Gastroenterol Hepatol.;9(10):577-89.
- Maranduba et al., 2015. Intestinal microbiota as modulators of the immune system and neuroimmune system: impact on the host health and homeostasis. J Immunol Res. 2015;2015:931574.
- Clarke et al., 2013 The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Mol. Psychiatry; 18(6):666-73.
- Favier et al., 2002. Molecular monitoring of succession of bacterial communities in human neonates. Appl Environ Microbiol. ;68(1):219-26.
- Muñoz et al., 2011. Novel probiotic Bifidobacterium longum subsp. infantis CECT 7210 strain active against rotavirus infections. Appl Environ Microbiol.; 77(24): 8775–8783.
- Goodrich et al., 2016. Genetic Determinants of the Gut Microbiome in UK Twins. Cell Host Microbe. ;19(5):731-43.
- De Filippo et al., 2010. Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europa and rural Africa. Proc. Natl. Acad. Sci. USA; 107(33):14691-6.
- Martínez et al., 2015. The gut microbiota of rural papua new guineans: composition, diversity patterns and ecological processes. Cell Rep. ;11(4):527-38.
- Ahmed et al., 2007. Mucosa-associated bacterial diversity in relation to human terminal ileum and colonic biopsy samples. Appl Environ Microbiol. ;73(22):7435-42.
- Di Gioia et al. 2014. Bifidobacteria: their impact on gut microbiota composition and their applications as probiotics in infants. Appl.Microbiol.Biotechnol. 98, 563–577.
- Moeller et al. 2017. Dispersal limitation promotes the diversification of the mammalian gut microbiota. Proc Natl Acad Sci U S A. ;114(52):13768-13773.
- Arboleya et al. 2016. Gut Bifidobacteria populations in human health and aging. Front Microbiol.; 7: 1204.
- Rasinkangas et al. 2014. Genomic Characterization of Non-Mucus-Adherent Derivatives of Lactobacillus rhamnosus GG Reveals Genes Affecting Pilus Biogenesis. Appl Environ Microbiol.; 80(22): 7001–7009.
- Gareau et al. 2010. Probiotics and the gut microbiota in intestinal health and disease. Nat Rev Gastroenterol Hepatol.;7(9):503-14.
- Mahajan et al. 2014. Recent trends in probiotics and health management: a review. IJPSR; Vol. 5(5): 1643-1652.