Demystifying Probiotics: Role in Health and Disease

1
Demystifying Probiotics Role in Health and
Disease

• Michel Farhat, PhD
• Manager, Professional Technical Affairs
• Procter and Gamble Personal Healthcare

2
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

3
Awareness of Probiotics in the Current Marketplace
Natural Marketing Institute (NMI) 2009
Supplement/OTC/Rx Database
4
Probiotics in the Current Marketplace
Natural Marketing Institute (NMI) 2009
Supplement/OTC/Rx Database
5
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 NMIs Health and Wellness Trends
Database
6
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/
7
Clinical Research Activities Trended
(Number of published clinical studies on
probiotics)
Polynomial trend line shows uniform, consistent
growth
Source www.ncbi.nlm.nih.gov/pubmed
8
Probiotics in Health and Disease

• Gut Microbiota
• What are Probiotics?
• Potential Mechanisms of Action
• Therapeutic Targets of Probiotics
• Strain Specificity
• Quality Control
• Regulatory Guidelines

9
Probiotics in Health and Disease

• Gut Microbiota
• What are Probiotics?
• Potential Mechanisms of Action
• Therapeutic Targets of Probiotics
• Strain Specificity
• Quality Control
• Regulatory Guidelines

10
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
gt500 different bacterial species in intestine
11
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

12
Taxonomic distribution of microorganisms in
mother and baby.
Reid et al, Nature Reviews Microbiology 2010
13
Functions of the Intestinal Flora
14
Probiotics in Health and Disease

• Gut Microbiota
• What are Probiotics?
• Potential Mechanisms of Action
• Therapeutic Targets of Probiotics
• Strain Specificity
• Quality Control
• Regulatory Guidelines

15
Probiotics

• First described by Metchnikoff in 1908
• Live microbial food ingredients that alter the
  microflora and confer health benefit

16
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
17
Different types of microbes used as probiotics

• Lactobacillus
• Bifidobacterium
• S. thermophilus
• Saccharomyces
• Propionibacterium
• Bacillus
• Enterococcus
• E. coli

Images courtesy of Prof. Lorenzo Morelli
18
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

19
Prebiotic vs Probiotic

• Prebiotic

• Probiotic

• Usually carbohydrate
• Not alive
• Beneficial health effect
• Food ingredient
• Act on microbiota
• Focus is colon, but broader effects also seen

• Microorganism
• Alive
• Beneficial health effect
• Food, dietary supplement, drugs
• May act on microbiota, but other mechanisms
• Can act on numerous sites around the body

20
Synbiotic Probiotic Prebiotic
21
Probiotics in Health and Disease

• Gut Microbiota
• What are Probiotics?
• Potential Mechanisms of Action
• Therapeutic Targets of Probiotics
• Strain Specificity
• Quality Control
• Regulatory Guidelines

22
Potential Mechanisms of Action of Probiotics
Sherman et al. Nutr Clin Pract, 2009 24(1)10-14
23
Chen et al, Gastroenterology 2005 128 (4 suppl
2) A661
24
Probiotics in Health and Disease

• Gut Microbiota
• What are Probiotics?
• Potential Mechanisms of Action
• Therapeutic Targets of Probiotics
• Strain Specificity
• Quality Control
• Regulatory Guidelines

25
Diverse Targets for Probiotics

• Gut function
• Acute diarrhea
• AAD, travelers diarrhea
• C. difficile
• Lactose digestion
• IBS symptoms
• Colic
• Inflammatory bowel
• conditions
• Gut pain sensation

Encompassing effects Growth parameters of
undernourished children Reduced absences from
work, daycare QOL

• Allergy
• Atopic dermatitis
• Asthma

Colds, respiratory infections
Skin microbiology, inflammation

• Oral microbiology
• Dental caries

• Metabolic syndrome
• Obesity, Diabetes

Vaginal infections
26
Probiotics in the Treatment of Gastrointestinal
Disorders
Diarrhea Acute infectious Antibiotic-associated
C. difficile
H. pylori Eradication
Lactose Intolerance
IBD Ulcerative colitis Crohns disease Pouchitis
Constipation
27
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.
2010140671S-676S.
28
Summary of Key Randomized Controlled Trials of
Probiotics in IBS
William D Chey, Reviews in Gastroenterol 2010
29
Probiotics in C. Difficile-Associated Disease
RCTs of Probiotics for Treatment of C. difficile
Disease
BBBifidobacterium bifidum LALactobacillus
acidophilus LGGLactobacillus rhamnosus GG
LPLactobacillus plantarum 299v
SBSaccharomyces boulardii MacFarland LV. Am J
Gastroenterol. 2006101812-822.
30
S. boulardii Is Effective in Patients with
Recurrent C. difficile Disease
Initial CDD
Recurrent CDD
PNS
P0.04
CDD recurrence,
CDD recurrence,
S. boulardii (n31)
Placebo (n33)
Control (n34)
S. boulardii (n26)
Patients received standard antibiotics
(vancomycin or metronidazole) and S. boulardii 1
g/day or placebo for 4 weeks.
CDDClostridium difficile-associated
disease McFarland L, et al. JAMA.
19942711913-1918.
31
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.
32
L. acidophilus NCFM and/or B. animalis Bi-07
reduces symptoms of colds/flu in Chinese
children.

• DBPC study
• N326 children (35 years of age)
• Probiotic NCFM or NCFMBi-07, dried powder mixed
  in milk
• Daily dose 1010cfu/d
• 6 months administration

Leyer et al. 2009. Pediatrics124(2)e172-9
33
L reuteri versus BB-12 supplemented Infant
Formula and Infections in Child Care Centers
Parameter Controls BB-12 L reuteri P Value

n 60 73 68
Days with fever 0.83 (0.501.16) 0.86 (0.331.39) 0.17 (0.040.30) lt.001
Episodes of fever 0.41 (0.280.54) 0.27 (0.170.37) 0.11 (0.040.18) lt.001   
Days with diarrhea 0.59 (0.340.84) 0.37 (0.080.66) 0.15 (0.120.18) lt.001   
Episodes of diarrhea 0.31 (0.220.40) 0.13 (0.050.21) 0.02 (0.010.05) lt.001   
Days with respiratory illness 0.60 (0.310.89) 0.68 (0.171.19) 0.38 (0.100.66) .169
Respiratory illness episodes 0.24 (0.130.35) 0.25 (0.150.35) 0.17 (0.080.26) .457
Clinic visits 0.55 (0.420.68) 0.51 (0.340.68) 0.23 (0.120.34) .002
Absences from child care 0.43 (0.220.64) 0.41 (0.190.63) 0.14 (0.070.35) .015
Prescriptions of antibiotics 0.19 (0.090.29) 0.21 (0.120.30) 0.06 (0.010.12) .037
Weizman et al, Pediatrics, Jan 2005 115 5 - 9
34
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.
35
Human gut microbes associated with obesity
Ley, et al. NATURE 2006
36
Resistance to diet-induced obesity in germ-free
mice
Backhed et al., PNAS 2007 , 104 (3) 979984
37
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

38
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.

39
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

40
Maintaining remission of ulcerative colitis with
Escherichia coli Nissle 1917
Kruis et al., Gut. 2004 Nov53(11)1617-23
41
Effect of Different Probiotic Strains on
Cytokine Production
42
Comparative Claims

• Comparative claims among products cannot be made
  unless a product contains
• Same probiotic strain
• Same dose
• Same formulation

43
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)

44
Dose listed on label should accurately reflect
dose in product at the end of shelf life
45
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.

46
Probiotics in Health and Disease

• Gut Microbiota
• What are Probiotics?
• Potential Mechanisms of Action
• Therapeutic Targets of Probiotics
• Strain Specificity
• Quality Control
• Regulatory Guidelines

47
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

48
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)

49
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.
50
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

51
Challenges for consumers

• Lots of misinformation
• Consumers dont 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

52
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
53
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
54
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.