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Probiotics: Benefits and Applications Presented to American Dietetics Association September 19, 2006 Honolulu HI Mary Ellen Sanders, Ph.D. Consultant, Dairy and Food Culture Technologies www.mesanders.com [email protected] www.usprobiotics.org Probiotics Live microorganisms which when administered in adequate amounts confer a health benefit on the host L. acidophilus NCFM Photo by Alan Servin FAO/WHO (2001) Expert Consultation http://www.fao.org/es/ESN/Probio/probio.htm Lactobacillus Bifidobacterium Saccharomyces S. thermophilus Enterococcus E. coli recombinant microbes Bacillus subtilis (“L. sporogenes” sporogenes”) B. longum 536 Photo by Morinaga 1 Human bodies are highly colonized 1014 microbial cells on human body: mouth, intestine, vagina, skin 1013 human cells comprise human body Up to 1000 different bacterial species The combined microbial gene pool is estimated to be 100 times greater than the human genome Laid end to end, the bacteria on our bodies would circle the earth 2.5 times “It appears that there are very few physiological parameters of the human or animal body that are not in some way affected by the presence of the indigenous microflora” (Rolf Freter) Colonizing Microbes Are Important Inhibits infection by potentially pathogenic microorganisms -“colonization resistance” resistance” Alteration of chemistry and biochemistry of colonized environments – SCFA, vitamins, ↓ or ↑ pH, ammonia, digestion of nonnon-digested polysaccharides/mucin polysaccharides/mucin,, deconjugation of bile acids, etc. Critical to postpost-natal immune system development - The gut has the largest number of immune cells of any organ in the body – Downregulation of inflammation – Oral tolerance to antigens in gut – Balance Th1/Th2 response involved with autoimmune and allergic conditions 2 Once we appreciate the complexity and range of biological functions of the colonizing microbiota it’s not so difficult to appreciate how influencing the microbiota may have a wide range of health effects Probiotics use many of the same mechanisms used by other commensal bacteria to mediate health benefits Published targets for probiotics Oral microbiology • Dental caries • S. mutans • Halitosis Allergy • Atopic dermatitis • Asthma Inflammatory bowel disease Colorectal cancer Vaginal infections Colds, respiratory infections H. pylori Deliver of cloned components active in gut Diarrhea • AAD, travelers diarrhea • C. difficile • rotavirus Lactose digestion IBS symptoms Systemic effects • Immune function • Growth parameters of undernourished children • Reduced absences from work, daycare 3 Effect of probiotic formula on infections in child care centers Weizman et al. Pediatrics 115:5115:5-9 Control B. lactis BBBB-12 L. reuteri Fever (d) 0.83 0.86 0.17* Fever (episodes) 0.41 0.27* 0.11* Diarrhea (d) 0.59 0.37* 0.15* Diarrhea (episodes) 0.31 0.13* 0.02* Clinic visits 0.55 0.51 0.23* Absences from CCC 0.43 0.41 0.14* Ab prescriptions 0.19 0.21 0.06* N=60 control N=73 Bb12 N=68 L. reuteri RDBPC No differences in days with or episodes of respiratory illness % of subjects reporting sick during study Workplace absences N=181 healthy adults 108/d L. reuteri ATCC 55730 powder RDBPC Study duration: 80 d Tubelius P, et al. 2005. Environ Health. 7;4:25. Placebo L. reuteri % subjects reporting sick days 26% 11% Median # sick days per absence 3 days 3 days # sick days/total study days (%) 0.9% 0.4% 4 L. rhamnosus GR-1 and L. reuteri RC14 improves metronidazole treatment of bacterial vaginosis 30 – day follow up 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Normal Intermediate BV BV Probiotic + AB 96% vs. 53% o women taking probiotics had >105 lactobacilli/gm vaginal fluid AB only Anukam, et al. Microbes and Infection 8 (2006) 1450-1454 1010 108 106 cfu/d Irritable Bowel Syndrome B. infantis 35624 Subjects’ Global Assessment at wk 4. Subjects responded “yes” or “no” to the following question: “Please consider how you felt in the past week in regard to your IBS, in particular your general well-being, and symptoms of abdominal discomfort or pain, bloating or distension and altered bowel habit. Compared to the way you felt before beginning the medication, have you had adequate relief of your IBS symptoms?” (42% placebo vs. 62% 108 cfu/d) 106 or 108 or 1010 cfu/d N=362 diagnosed IBS of any subtype 2 wk run in, 4 wk treatment, 2 wk washout RDBPC multicenter dose ranging trial Whorwell et al. 2006. Amer J Gastroenterol. 101:1581 5 Effect of probiotic bacteria 5x107/d B. longum, B. bifidum, L. gasseri on episodes of colds in healthy adults Probiotic + Vitamin/mineral Vitamin/mineral supplement Duration (days) 7.0± 7.0±0.5 8.9± 8.9±1.0 (p=0.045) Bronchial symptoms symptom score – points 13.2± 13.2±2.1 19.1± 19.1±2.7 (p=0.011) Days with fever 0.24± 0.24±0.1 1.0± 1.0±0.3 (p=0.017) Total symptom score 79.3± 79.3±7.4 102.5± 102.5±12.2 (p=0.056) Study duration – >3 months N=479 de Vrese et al. 2005. Clin Nutr 24:481-91. Fermented milk with yogurt starters and L. casei DN114-001 Jellied milk D a y s d ia r r h e a 10 8 L. casei Yogurt 8 6 fermented milk 5.3 4 4.3 2 N=287 healthy children, 66-36 months 12 day care centers in France 6 mo duration (Nov(Nov-May) Monthly intervals, on and off supplementation RBPC, 3 arms: milk, yogurt, L. casei (3(3-6x1010/d) fermented milk 0 Pedone et al. 2000. Int J Clin Pract 54:568-571 6 Prevention of hospital-acquired diarrhea in hospitalized infants, 1-36 mos Szajewska, Szajewska, et al., 2001. J. Pediatr. Pediatr. 138:361 138:361--5 # Subjects Incidence of diarrhea P=002 LGG 46 Placebo 36 3 (6.67%) 12 (33.3%) DoubleDouble-blinded, placeboplacebo-controlled, 6x109 dried Lactobacillus GG/2x/day Note: June 06 ConAgra sold Culturelle business to Amerifit Nutrition Inc Probiotics in maintenance of remission in pouchitis Estimates of relapse during treatment with VSL#3 or placebo Remission Dose: 1.8x1012/d total VSL#3 comprised of 8 different species of probiotic, predominantly S. thermophilus VSL#3 Placebo Months after treatment Gionchetti et al. 2000. Gastroenterology 119:305-309. 7 Effects Are Strain-Specific Not all strains of the same species can be expected to have the same effects Clinical data must be viewed as applicable only to the strain or strain combinations tested – Other strains of the same species MAY have the same effect. – It cannot be assumed, for example, that because one L. rhamnosus has a certain effect, that all do. No one strain should be expected to have all effects – Strain blend approach – Targeted strain approach Future research will determine what phenotypic traits are important important for certain effects – Genome sequencing Strain is important: Same species, but different “strains” = different use, different performance Not all strains of the same species will be the same For example: Bifidobacterium lactis DR10 vs. Bifidobacterium lactis BbBb-12 Same Genus: Bifidobacterium Same Species: lactis But different strain: DR10 and BbBb-12 8 What Levels of Probiotics Need to be Delivered in Products Many studies have tracked acute endpoints – What benefits are achieved at lower, long term doses is not known known Required levels for therapeutic endpoints (e.g., IBD remission or or IBS symptoms) may be higher than prophylactic (e.g., resisting infections) endpoints In general: a few studies document effects at 108/d; most studies use 109-1010/d. Synergism has not been studied – What levels of probiotics are necessary when combined with other foods functional in the GI tract? – What about multiple dietary sources of probiotic bacteria? – What about strain interactions as part of blends? Levels used should be based on levels found to be efficacious in human studies Effects are dose specific MetaMeta-Analysis of Lactobacillus as therapy for acute infectious diarrhea in children “Lactobacillus is safe and effective as a treatment for children with acute infectious diarrhea” Van Niel, et al. 2002. Lactobacillus therapy for acute infectious diarrhea in children: a meta-analysis. Pediatrics 109:678-684 9 Probiotic Product Format Options in USA Food (e.g., Activia Activia) Supplement (e.g., Culturelle Culturelle, Align Align) Medical Food (VSL#3) Pharmaceutical (none for human use but IBD, pouchitis, pouchitis, IBS, BV are possibilities) – Under jurisdiction of Department of Biologics as “Biologic Drugs” Drugs” In theory, the same probiotic strain could be used in any of these formats Probiotic Food Products Yogurt is the most common carrier for probiotics Good fit in mind of consumer – ‘live, active cultures’ cultures’ and healthy image fit with dairy products Good option for incorporating ‘beneficial bacteria’ bacteria’ into daily diet But...many yogurts not formulated optimally – Unknown levels of probiotics in dairy products – Little communication to consumer about probiotics – Strains not optimally chosen 10 Potential advantages of dairy products as delivery vehicles for probiotics “Functional Nutrition Package” Stability Functionality In Product Many dairy foods are short shelf life, refrigerated products, which encourages probiotic survival in product Gastrointestinal Physiological Transit Activity Buffer stomach acid Compliance Food vs. pills Dairy products deliver functional nutrition along with probiotic bacteria What does the “live active culture” seal tell us about probiotics? Nothing! Minimum level of cultures – 107/g at end of shelf life Doesn’ Doesn’t specifically apply to probiotic content Starter cultures usually ~108-9/g Probiotic bacteria target ~106/g, and levels at end of shelf life are not published 11 Probiotic labels What should the label say: – Identify probiotics used Genus, species and strain(s) strain(s) contained – What levels will be present at end of shelf life – based on studies showing efficacy – Statements of nutritional support (S/F statements) Must be truthful and not misleading Must be based on human studies Labeling of Probiotic Products Dairy foods: generally no claims made in US – DanActive: DanActive: “strengthens your body’ body’s natural defenses” defenses” – Web sites: contain much more information www.stonyfield.com Supplements: – Culturelle: Culturelle: “Clinically proven at major US and European institutions to maintain a healthy intestinal tract” tract” – Align: “promote a healthy, balanced digestive system” system” 12 Indication Strain or Product Dose Infant diarrhea L. rhamnosus GG (www.culturelle.com) L. casei DN114001 (strain “Defensis”) (www.danactive.com) ~1010/d ~1010/d Inflammatory bowel conditions VSL#3 (www.vsl3.com ) ~1012/d 3x/d Antibiotic associated diarrhea S. boulardii (www.florastor.com) L. rhamnosus GG 500 mg 4x/d ~1010/d GI symptoms B. infantis 35624 (www.aligngi.com) B. animalis DN-173 010 (“Bifidus regularis”; www.activia.com ) 109/d ~1010/d “Keeping healthy” L. reuteri (www.stonyfield.com; www.biogaia.com) L. casei DN114001 108-109/d ~1010/d Allergy in infants L. rhamnosus GG ~1010/d Lactose intolerance L. bulgaricus and/or S. thermophilus (all strains) ~1010/d (~108/ml milk) Immune support B. lactis HN019 (HOWARU™ or DR10 www.danisco.com) B. lactis Bb12 (www.bradpharm.com) L. casei DN114001 ~1010/d ~1010/d ~1010/d Vaginal applications L. rhamnosus GR-1; L. reuteri RC-14 (www.urexbiotech.com; Fem-Dophilus www.jarrow.com) ~1010/d Irritable bowel syndrome B. infantis 35264 (“Bifantis”; www.aligngi.com) 109/d “Probiotic” containing foods Cheese Cereal Kashi Frozen yogurt Yogurt Kefir Daily dose drinks Candy Juice Infant formula 13 Probiotic supplements Dozens of different probiotic supplement brands Available to US market – Health food stores – On line – Warehouse stores – Grocery/drug stores Different strains, doses, added active ingredients Different degrees and types of substantiated benefits Many with little or no efficacy data Many not meeting label claim for amount or types of bacteria through end of shelf life Safety: Lactobacillus and Bifidobacterium Generally considered very low pathogenic potential – Normal commensals – Some species present in high numbers in foods – History of safe use for some species in foods, supplements and pharmaceuticals Dozens of infections documented due to lactobacilli and bifidobacteria – Only in patients with underlying illness – Source of microbe in most cases thought to be commensal Lactobacilli isolated from clinical infections are usually L. rhamnosus, L. casei/paracasei and L. plantarum – Is this due to some inherent higher risk of causing infection or because they grow more easily on clinical media often used in clinical labs? Safety considerations for other genera used as probiotics will be different 14 Conclusions Probiotics are promising healthful dietary ingredients. They may play a role in helping to keep people healthy as well as serve as therapeutic agents for certain conditions. There is very little risk from probiotics comprised of Lactobacillus and Bifidobacterium species, although people who are immunocompromised should certainly consult with a physician prior to using. More research needs to be done to confirm extent of health effects and mechanisms of effects. As the industry grows, probiotic products will become more consumerconsumer-friendly, with guarantees of product shelfshelf-life, scientifically accurate labeling of contents and truthful descriptions of documented benefits. 15