demystifying probiotics: role in health and disease michel farhat, phd manager, professional &...
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Demystifying Probiotics: Role in Health and Disease
Michel Farhat, PhDManager, Professional & Technical AffairsProcter 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
Source: Nutrition Business Journal estimates (consumer sales)
Based on NMI’s Health and Wellness Trends Database
U.S. Health and Wellness Industry
2009 Sales = $112.3 Billion
U.S. Health and Wellness Industry
2009 Sales = $112.3 Billion
Functional and Fortified Foods and Beverages in 2009 = $40.5 Billion
Functional and Fortified Foods and Beverages in 2009 = $40.5 Billion
Vitamins, Minerals, Herbals and supplements in 2009 = $23.3 Billion
Vitamins, Minerals, Herbals and supplements in 2009 = $23.3 Billion
Probiotic supplements in 2009 estimated at $405 million
Probiotic supplements in 2009 estimated at $405 million
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/
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(Number of published clinical studies on probiotics)
Polynomial trend line shows uniform, consistent growth
Clinical Research Activities Trended
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
Sherman et al. Nutr Clin Pract, 2009; 24(1):10-14
Potential Mechanisms of Action of Probiotics
IFNg
IL10(Bif)
IL10/IL12(LPS)
IL10/IL12(Bif)(LPS)
IL10/IFNg(Bif)(LPS)
IL10/IFNg(Bif)(LPS)
healthysubject
TNFa(LPS)
TNFa(Bif)(LPS)
IL12(LPS)
IL12(Bif)(LPS)
IFNg(LPS)
IFNg(Bif)(LPS)
Pro-inflammatorycytokines
Pro-inflammatorycytokines
Anti-inflammatorycytokines
Anti-inflammatorycytokines
IBS at pre-feeding stage IBS at wk-3 feeding stage
B. infantis 35624 modulates systemic immune state of I BS toward healthy subject
Higher Level than healthy
Lower Level than healthy
TNFa
IL12
IL10(LPS)
IL10(LPS)
TGFb/IL12(LPS)
TGFb/IL12(LPS)
Chen et al, Gastroenterology 2005; 128 (4 suppl 2): A661Gastroenterology 2005; 128 (4 suppl 2): A661
Probiotics in Health and Disease
• Gut Microbiota• What are Probiotics?• Potential Mechanisms of Action• Therapeutic Targets of Probiotics• Strain Specificity• Quality Control• Regulatory Guidelines
Gut functionAcute diarrheaAAD, travelers diarrheaC. difficileLactose digestionIBS symptomsColicInflammatory bowel conditionsGut pain sensation
AllergyAtopic dermatitisAsthma
Oral microbiologyDental caries
Colds, respiratory infections
Skin microbiology, inflammation
Vaginal infectionsMetabolic syndromeObesity, Diabetes
Encompassing effects•Growth parameters of undernourished children•Reduced absences from work, daycare•QOL
Diverse Targets for Probiotics
Probiotics in the Treatment of Gastrointestinal Disorders
IBDUlcerative colitisCrohn’s diseasePouchitis
Constipation
Lactose Intolerance
H. pylori Eradication
DiarrheaAcute infectiousAntibiotic-associated C. difficile
Levels of Probiotic Activity
Adapted from Rijkers GT, et al. J Nutr. 2010;140:671S-676S.
Interfere with growth or survival
of bacteria in gut lumen
Improve mucosal barrier function and
mucosal immune system
Affect systemic immune system
Summary of Key Randomized Controlled Trials of Probiotics in IBS
William D Chey, Reviews in Gastroenterol 2010
Probiotics in C. Difficile-Associated 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.
RCTs of Probiotics for Treatment of C. difficile Disease
S. boulardii Is Effective in Patients with Recurrent C. difficile Disease
CDD=Clostridium difficile-associated diseaseMcFarland L, et al. JAMA. 1994;271:1913-1918.
Initial CDD
CDD
recu
rren
ce, %
S. boulardii(n=31)
Placebo(n=33)
P=NS
Recurrent CDD
Control(n=34)
P=0.04
Patients received standard antibiotics (vancomycin or metronidazole) and S. boulardii 1 g/day or placebo for 4 weeks.
CDD
recu
rren
ce, %
S. boulardii(n=26)
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
Parameter Controls BB-12 L reuteri P Value
n 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
L reuteri versus BB-12 supplemented Infant Formula and Infections in Child Care Centers
Weizman et al, Pediatrics, Jan 2005; 115: 5 - 9
Impact of Probiotics on prevention of eczema
Wickenset et al. 2008. J Allergy Clin Immunol.
6 mo treatment of mother from 35 wks gestation to 6 months of age; infants through 2 years of age
“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.
Regardless of the claim, it must be substantiated
There are no generic probiotic claims
Claim substantiation must be based on a specific strain
Probiotic claims
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.