Demystifying Probiotics: Role in Health and Disease Michel Farhat, PhD Manager, Professional & Technical Affairs Procter and Gamble Personal Healthcare Probiotics in the Current Marketplace • Growing public and scientific interest in probiotics • Global probiotic market estimated at billions of dollars per year • Hundreds of probiotics available as food, dietary supplements, skin and pet products Awareness of Probiotics in the Current Marketplace Natural Marketing Institute (NMI) 2009 Supplement/OTC/Rx Database™ Probiotics in the Current Marketplace Natural Marketing Institute (NMI) 2009 Supplement/OTC/Rx Database™ U.S. Specialty Supplement Sales by Product in 2009 U.S. Health and Wellness Industry 2009 Sales = $112.3 Billion Functional and Fortified Foods and Beverages in 2009 = $40.5 Billion Vitamins, Minerals, Herbals and supplements in 2009 = $23.3 Billion Probiotic supplements in 2009 estimated at $405 million Source: Nutrition Business Journal estimates (consumer sales) Based on NMI’s Health and Wellness Trends Database Human Microbiome Project • The Human Microbiome Project (HMP) aims to characterize the microbial communities found at several different sites on the human body, including nasal passages, oral cavities, skin, gastrointestinal tract, and urogenital tract, and to analyze the role of these microbes in human health and disease. http://commonfund.nih.gov/hmp/ Clinical Research Activities Trended (Number of published clinical studies on probiotics) 564 421 432 2007 453 2006 Polynomial trend line shows uniform, consistent growth 294 271 2002 2003 307 191 127 91 61 7 2008 2005 2004 2001 2000 1999 1998 1997 17 Source: www.ncbi.nlm.nih.gov/pubmed Probiotics in Health and Disease • • • • • • • Gut Microbiota What are Probiotics? Potential Mechanisms of Action Therapeutic Targets of Probiotics Strain Specificity Quality Control Regulatory Guidelines Probiotics in Health and Disease • • • • • • • Gut Microbiota What are Probiotics? Potential Mechanisms of Action Therapeutic Targets of Probiotics Strain Specificity Quality Control Regulatory Guidelines Human bodies are highly colonized 100 trillion microbial cells on/in human body: mouth, intestine, vagina, skin 10x the number of human cells in our bodies >500 different bacterial species in intestine Gut Colonization • Colonization of the gastrointestinal tract begins immediately after birth • Colonization pattern is affected by: – mode and type of birth delivery, – initial diet – geographical location • Initial bacterial colonization (normal) starts from a “Germ free” intrauterine environment and is populated through maternal vaginal/fecal flora and oral feeding (breast milk vs formula) • Complete adult colonization : 18 – 24 months Taxonomic distribution of microorganisms in mother and baby. Reid et al, Nature Reviews Microbiology 2010 Functions of the Intestinal Flora Probiotics in Health and Disease • • • • • • • Gut Microbiota What are Probiotics? Potential Mechanisms of Action Therapeutic Targets of Probiotics Strain Specificity Quality Control Regulatory Guidelines Probiotics • First described by Metchnikoff in 1908 • “Live microbial food ingredients that alter the microflora and confer health benefit” What are Probiotics? FAO/WHO Definition • “Live microorganisms which when administered in adequate amounts confer a health benefit on the host” • Probiotic microorganisms can be found in both supplement form and as components of foods and beverages. The Joint Food and Agriculture Organization/World Health Organization Working Group Different types of microbes used as probiotics • • • • • • • • Lactobacillus Bifidobacterium S. thermophilus Saccharomyces Propionibacterium Bacillus Enterococcus E. coli Images courtesy of Prof. Lorenzo Morelli Prebiotics • “Non-digestible food ingredients that beneficially affect the host by selectively stimulating the growth and activity of one species or a limited number of species of bacteria in the colon” Duggan et al, 2002. – – – – – Oligosaccherides Inulin Fructose oligosaccherides Fiber Fiber supplements Prebiotic vs Probiotic • • • • Prebiotic Usually carbohydrate Not alive Beneficial health effect Food ingredient • Act on microbiota • Focus is colon, but broader effects also seen Probiotic • • • • Microorganism Alive Beneficial health effect Food, dietary supplement, drugs • May act on microbiota, but other mechanisms • Can act on numerous sites around the body Synbiotic = Probiotic + Prebiotic Probiotics in Health and Disease • • • • • • • Gut Microbiota What are Probiotics? Potential Mechanisms of Action Therapeutic Targets of Probiotics Strain Specificity Quality Control Regulatory Guidelines Potential Mechanisms of Action of Probiotics Sherman et al. Nutr Clin Pract, 2009; 24(1):10-14 B. infantis 35624 modulates systemic immune state of IBS toward healthy subject IBS at pre-feeding stage IBS at wk-3 feeding stage Higher Level than healthy TNFa IL12 (LPS) (LPS) (LPS) IFNg IL10 (Bif) TNFa IL12 IFNg IL10/IL12 IL10/IFNg (Bif) (LPS) (Bif) (LPS) healthy subject IL10 (LPS) IL10/IL12 TNFa IL12 (LPS) (Bif) (LPS) IFNg IL10 (Bif) (Bif) (LPS) (LPS) (LPS) TGFb/IL12 Lower Level than healthy IL10/IFNg TGFb/IL12 (Bif) (LPS) Pro-inflammatory cytokines (LPS) Anti-inflammatory cytokines (LPS) Pro-inflammatory cytokines Chen et al, Gastroenterology 2005; 128 (4 suppl 2): A661 Anti-inflammatory cytokines Probiotics in Health and Disease • • • • • • • Gut Microbiota What are Probiotics? Potential Mechanisms of Action Therapeutic Targets of Probiotics Strain Specificity Quality Control Regulatory Guidelines Diverse Targets for Probiotics Gut function Encompassing effects Acute diarrhea •Growth parameters of AAD, travelers diarrhea undernourished children C. difficile •Reduced absences Allergy Lactose digestion from work, daycare Atopic dermatitis IBS symptoms •QOL Asthma Colic Inflammatory bowel conditions Gut pain sensation Colds, respiratory infections Skin microbiology, inflammation Metabolic syndrome Obesity, Diabetes Oral microbiology Dental caries Vaginal infections Probiotics in the Treatment of Gastrointestinal Disorders Diarrhea Acute infectious Antibiotic-associated C. difficile Lactose Intolerance H. pylori Eradication IBD Ulcerative colitis Crohn’s disease Pouchitis Constipation Levels of Probiotic Activity Interfere with growth or survival of bacteria in gut lumen Improve mucosal barrier function and mucosal immune system Affect systemic immune system Adapted from Rijkers GT, et al. J Nutr. 2010;140:671S-676S. Summary of Key Randomized Controlled Trials of Probiotics in IBS William D Chey, Reviews in Gastroenterol 2010 Probiotics in C. Difficile-Associated Disease RCTs of Probiotics for Treatment of C. difficile Disease BB=Bifidobacterium bifidum; LA=Lactobacillus acidophilus; LGG=Lactobacillus rhamnosus GG; LP=Lactobacillus plantarum 299v; SB=Saccharomyces boulardii MacFarland LV. Am J Gastroenterol. 2006;101:812-822. S. boulardii Is Effective in Patients with Recurrent C. difficile Disease Initial CDD Recurrent CDD P=0.04 CDD recurrence, % CDD recurrence, % P=NS Placebo (n=33) S. boulardii (n=31) Control (n=34) S. boulardii (n=26) Patients received standard antibiotics (vancomycin or metronidazole) and S. boulardii 1 g/day or placebo for 4 weeks. CDD=Clostridium difficile-associated disease McFarland L, et al. JAMA. 1994;271:1913-1918. Probiotics for the Prevention of Antibiotic Associated Diarrhea Mixtures included: Lactinex = L. acidophilus and L. bulgaricus; Lactobacillus acidophilus and Bifidobacterium lactis; Lactobacillus acidophilus and Bifidobacterium infantis. McFarland, Am J Gastroenterol 2006; 101(4): 812-822. L. acidophilus NCFM and/or B. animalis Bi-07 reduces symptoms of colds/flu in Chinese children . • DBPC study • N=326 children (3–5 years of age) • Probiotic: NCFM or NCFM+Bi-07, dried powder mixed in milk • Daily dose 1010cfu/d • 6 months administration Leyer et al. 2009. Pediatrics;124(2):e172-9 L reuteri versus BB-12 supplemented Infant Formula and Infections in Child Care Centers Parameter Controls BB-12 L reuteri 60 73 68 Days with fever 0.83 (0.50–1.16) 0.86 (0.33–1.39) 0.17 (0.04–0.30) <.001* Episodes of fever 0.41 (0.28–0.54) 0.27 (0.17–0.37) 0.11 (0.04–0.18) <.001 Days with diarrhea 0.59 (0.34–0.84) 0.37 (0.08–0.66) 0.15 (0.12–0.18) <.001 Episodes of diarrhea 0.31 (0.22–0.40) 0.13 (0.05–0.21) 0.02 (0.01–0.05) <.001 Days with respiratory illness 0.60 (0.31–0.89) 0.68 (0.17–1.19) 0.38 (0.10–0.66) .169 Respiratory illness episodes 0.24 (0.13–0.35) 0.25 (0.15–0.35) 0.17 (0.08–0.26) .457 Clinic visits 0.55 (0.42–0.68) 0.51 (0.34–0.68) 0.23 (0.12–0.34) .002* Absences from child care 0.43 (0.22–0.64) 0.41 (0.19–0.63) 0.14 (0.07–0.35) .015* Prescriptions of antibiotics 0.19 (0.09–0.29) 0.21 (0.12–0.30) 0.06 (0.01–0.12) .037 n P Value Weizman et al, Pediatrics, Jan 2005; 115: 5 - 9 Impact of Probiotics on prevention of eczema 6 mo treatment of mother from 35 wks gestation to 6 months of age; infants through 2 years of age Wickenset et al. 2008. J Allergy Clin Immunol. “Human gut microbes associated with obesity” Ley, et al. NATURE 2006 Resistance to diet-induced obesity in germ-free mice Backhed et al., PNAS 2007 , 104 (3): 979–984 Misconceptions about Probiotics • Probiotics are live active cultures • Probiotics are synonymous with native commensal bacteria • More is not better – Dose (1 billion vs 10 billion vs 450 billion) – Number of strains • The effect of probiotics is genus specific Dosage of Probiotics • The dose of probiotics is usually expressed as the number of colony forming units (CFUs) • The required dose of probiotics may vary greatly for different strains and the specific health effect under investigation • Probiotic effects should be considered dose-specific • Dose listed on the label must be based on studies that show a health effect in humans. Effects are considered strain-specific for most probiotic attributes •Different strains of the same species can be different •Clinical support to substantiate claims must be for each probiotic strain Maintaining remission of ulcerative colitis with Escherichia coli Nissle 1917 Kruis et al., Gut. 2004 Nov;53(11):1617-23 Effect of Different Probiotic Strains on Cytokine Production Comparative Claims Comparative claims among products cannot be made unless a product contains: -Same probiotic strain -Same dose -Same formulation Probiotics: Quality Control • Source (animal vs human; normal vs diseased) • Formulation (vehicle) • Safety (in at risk populations) • Characterization (strain purity) • Viability (Cfu delivered) • Dose (Dose-response studies) • Combinations/cocktails (Different effects of different bacterial strains) Dose listed on label should accurately reflect dose in product at the end of shelf life Safety of Probiotics • The safety of probiotics is strain-specific. • The genus and species of the microbe being used should be assessed with respect to: – – – – – – – Genetic stability, Metabolic activities, Potential for pathogenicity or toxicogenicity Method of administration Level of exposure, Health status of the users Physiologic functions • Few correlations between probiotic use and adverse events have been demonstrated • Although probiotics marketed as foods and dietary supplements should be safe for the generally healthy population, their safety has not been asserted on individuals with underlying health conditions. Probiotics in Health and Disease • • • • • • • Gut Microbiota What are Probiotics? Potential Mechanisms of Action Therapeutic Targets of Probiotics Strain Specificity Quality Control Regulatory Guidelines Regulatory Environment • Probiotics in the US are food or dietary supplements and therefore regulated by the Dietary Supplements Health and Education Act (DSHEA) • Structure/Function Claims for impact on the structure/ functioning of the normal human body • This food can support a healthy immune system • This supplement can help maintain a healthy digestive tract • Claims are required by FDA to be “truthful and not misleading” and supported by “competent and reliable scientific evidence” Not Allowable Claims The FDA does not allow any statements on a food or supplement that would communicate benefits on: Reducing the risk of acute diseases (colds, flu, GI infections) Managing symptoms in people who are not healthy (in-patients or people with a diagnosed condition such as IBS) Improving therapeutic efficacy of a drug Managing side effects of a drug (e.g., antibiotics) (Even if such use is recognized as safe in the target populations) DSHEA: Probiotic Claims Supports a healthy immune system* Helps keep your microflora in balance* Helps build and maintain a healthy digestive system* Disclaimer: *This statement has not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease. Probiotic claims Regardless of the claim, it must be substantiated There are no generic probiotic claims Claim substantiation must be based on a specific strain Challenges for consumers • • • • Lots of misinformation Consumers don’t know what products are good ones Limited third party assessment of health benefit claims Disconnect between scientific evidence available on probiotics and what regulatory authorities will allow to be communicated • All products in USA are foods or supplements not intended for use in non-healthy populations How to choose a probiotic? • Strain: Different strains of even the same species can be different • Clinically proven: Probiotics must be tested in humans and shown to have health benefits – Product web sites should cite efficacy studies • Truthful claims: Any claim made on a product, no matter how general, is supposed to be truthful and not misleading – Not all manufacturers have efficacy substantiation ISAPP guidelines at www.isapp.net How to choose a probiotic? • Safety: Patients should consult their doctor’ if they have health concerns • Dose: Product should match levels used in human studies showing benefits – Different probiotics have been shown to be effective at different levels – It is not possible to provide one count for all “probiotics” • Food or supplements? Probiotic content is generally more important than the way they are consumed. ISAPP guidelines at www.isapp.net Conclusions • Probiotic bacteria confer health benefits by bolstering protective, structural and metabolic functions in the human body. • Not all probiotics are equal. • Disconnect between scientific evidence and allowable claims. • Claims should be substantiated with well-controlled clinical studies. • Products should be characterized for content and stability.