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.