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
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Gut Microbiota
What are Probiotics?
Potential Mechanisms of Action
Therapeutic Targets of Probiotics
Strain Specificity
Quality Control
Regulatory Guidelines
Probiotics in Health and Disease
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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
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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
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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.
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Oligosaccherides
Inulin
Fructose oligosaccherides
Fiber
Fiber supplements
Prebiotic vs Probiotic
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Prebiotic
Usually carbohydrate
Not alive
Beneficial health effect
Food ingredient
• Act on microbiota
• Focus is colon, but broader
effects also seen
Probiotic
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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
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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
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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
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The safety of probiotics is strain-specific.
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The genus and species of the microbe being used should be assessed with respect
to:
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Genetic stability,
Metabolic activities,
Potential for pathogenicity or toxicogenicity
Method of administration
Level of exposure,
Health status of the users
Physiologic functions
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Few correlations between probiotic use and adverse events have been
demonstrated
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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
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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
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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.