1. Demystifying Probiotics: Role in Health and Disease
Michel Farhat, PhD
Manager, Professional & Technical Affairs
Procter and Gamble Personal Healthcare
Human bodies are highly colonized, with the number of microbial cells outnumbering human cells by a factor of 10 to 1. Recognizing the profound impact of microbes to human health, global initiatives are currently underway to study native microbial communities and how they correlate with human health and disease.
Although a common perception is that microbes are bad—an idea fueled by an abundance of information about pathogenic bacteria, yeast, and viruses and their associated morbidity and mortality, a growing body of research is documenting the diverse ways that certain other microbes, called probiotics, can contribute to human health.

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
Probiotics are not only making an impact in research, but they are also becoming a growing trend in the global marketplace. The global market for commercial probiotic products is now estimated at billions of dollars per year (Stanton, et al., 2001). Hundreds of probiotic foods and dietary supplements are available and claim to offer a variety of health benefits in different parts of the body including the gastrointestinal system. Probiotics have also been included in skin care products and pet food.

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
In the VMS category in 2008, probiotics constituted about 9% of total sales accounting for over $400 million in revenue. But the category continues to grow
Probiotic supplements in 2009 estimated at $405 million
Source: Nutrition Business Journal estimates (consumer sales)
Based on NMI’s 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.

7. Clinical Research Activities Trended
(Number of published clinical studies on probiotics)
Polynomial trend line shows uniform, consistent growth
Source:

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
>500 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
Exposure to this microbiome appears to be critical for the development and maturation of a healthy immune system. Colonization of the gastrointestinal tract begins immediately after birth, and occurs within a few days. Mode of delivery (i.e. natural birth versus caesarean section), initial diet (i.e. breast versus formula feeding), geographical location (i.e. developed country vs developing country) and type of delivery (i.e. home birth versus hospitalized birth) all contribute to the colonization pattern. As we mature, the population of Bifidobacterium decreases to about 3–6% of the fecal flora, then declines even further with advanced age.

12. Taxonomic distribution of microorganisms in mother and baby.
Immediately after birth, humans become colonized by a range of microorganisms, particularly on the skin, oronasopharyngeal area, gastrointestinal tract and urogenital tract. The host and its microbiome have developed mechanisms to not only protect against infection, but also restore microbial homeostasis, even without pharmaceutical therapy. The genus-level distributions are shown for a sample of mothers and their babies, grouped according to the delivery method of the babies (vaginal or by Caesarian section
(C-section)). The data shown are averaged for each group.
Reid et al, Nature Reviews Microbiology 2010

13. Functions of the Intestinal Flora
The native colonizing bacteria perform various protective, structural, and metabolic functions on the intestinal mucosa, leading to the concept of the microbiota as a “virtual organ within an organ.” In fact, the microbiota have been called a “metabolic organ,” exquisitely tuned to our physiology that performs functions that we have not had to evolve on our own.”
Although the myriad functions of the native microbes colonizing humans are just beginning to be understood, it is believed that certain other microbes that are consumed and added to our microbial mix—known as probiotic bacteria—may use these same mechanisms to enhance or stabilize normal colonizing microbes

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”
The concept of healthy bacteria has been documented as far back as Early Roman History (Plinio, 76AD) and was advocated by the nobel prize winner Eli Metchnikoff in 1907

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 committee of FAO and WHO have provided a definition of probiotics which is now widely accepted. They define probiotics as live microorganisms ……..on the host”
These Probiotics organisms could be found in foods and beverages or delivered through a supplement.
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
This is a list of the different groups of microorganisms which have been identified as having probiotic properties. The most widely studied and commonly used probiotics are the Lactobacilli and Bifidobacteria.
Lactobacillus: Gram positive facultative anaerobe. In humans they are present in the vagina and the gastrointestinal tract, where they are symbiotic
Bifidobacteria are Gram-positive procaryotes that naturally inhabit the gastrointestinal tract of humans and other warm-blooded animals. In breast-fed newborn infants, bifidobacteria constitute 95% of total gut bacterial population. As we mature, the population of Bifidobacterium decreases to about 3-6% and declines further with advanced age
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
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
Schematic depiction of potential mechanisms of action by which probiotics can promote GI health. Probiotics (PB) and surface-layer proteins (slp) competitively exclude microbial pathogens from mucosal surfaces. Tight junction proteins, such as zona occludins (ZO)-1 and claudin1, remain intact and thereby prevent both uptake of intact macromolecules and translocation of viable organisms to mesenteric lymph nodes. Probiotic strains possess the ability to modulate signal transduction pathways to block activation and translocation to the nucleus of the transcription factor, nuclear factor-kappa B (NF-κB), interferon-γ (IFNγ), and mitogen-activated protein kinases (MAPK). Through a cascade of signaling events, probiotics can enhance production and secretion of anti-inflammatory cytokines, including interleukin-10 (IL-10) and transforming growth factor-β (TGF-β) by a subset of immune cells, referred to as T regulatory cells (Tregs). Humoral immune system responses to probiotics include enhanced production of immune globulins, including secretory immunoglobin A (sIgA). Innate immune responses to probiotics include increased mucin and trefoil factor production by goblet cells (G) and enhanced production of antibacterial defensins by Paneth cells (PC) and intestinal epithelia. DC, dendritic cell; P, pathogen; TC, T lymphocyte.
Sherman et al. Nutr Clin Pract, 2009; 24(1):10-14

23. Study subjects: 13 self-reported IBS and 10 healthy individuals.
Treatment regimen: Subjects in both populations were fed daily with 4-ounce milk (containing 1010 cfu Bifidobacterium infantis 35624) for 3 weeks.
Systemic cytokine profile: Before and after B. infantis feeding, one PBMC (peripheral blood mononuclear cell) from each individual was cultured in vitro with either vehicle or a stimulant (LPS, B. infantis 35624) for 3 days. Culture supernatants were collected for cytokine analyses by bead-based ELISA assay.
Baseline (Pre-feeding with Bifantis)
Results:
Spontaneous (without stimulation) production: Cells isolated from IBS showed a similar cytokine level as those from the healthy individuals.
With LPS stimulation: Cells isolated from IBS revealed an aberrant cytokine pattern of:
Decreased ratio of anti-/pro-inflammatory cytokines (IL10/IFNg, TGFb/IL12).
Increased pro-inflammatory cytokines (IL12, TNFa, IFNg);
Without stimulation: Cells isolated from IBS continued to show a similar cytokine level as the cells isolated from healthy individuals.
Post-feeding with Bifantis:
With LPS or B. infantis stimulation: Cells isolated from IBS showed a more normal balance of cytokines:
Decreased pro-inflammatory cytokines (IL12, TNFa, IFNg).
Increased anti-inflammatory cytokine (IL10).
Increased ratio of anti-/pro-inflammatory cytokines (IL10/IL12, IL10/IFNg, TGFb/IL12).
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
Although information about the microbial composition of the intestinal ecosystem in health and disease remains incomplete, the intestine contains extensive microbiota—100,000 billion bacteria, located mainly in the colon and comprising hundreds of species of bacteria
Probiotic research suggests a range of clinical applications for various probiotics in GI disorders
Although the use of probiotics in diarrheal disease has been most extensively studied to date, a growing number of studies have explored the use of probiotics for use in IBD, with particularly promising data in pouchitis; constipation; lactose intolerance; and for use as adjuntive therapy in H. pylori eradication
Reference:
World Gastroenterology Organisation. Probiotics and prebiotics. May 2008.
Lactose Intolerance
IBD
Ulcerative colitis
Crohn’s 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
Although the mechanisms of action of probiotics are largely unknown at the molecular level, a probiotic can act:
Within the gut lumen by direct interaction with the complex ecosystem of the gut microbiota;
By interaction with the gut mucus and epithelium, including barrier effects, digestive processes, mucosal immune system, and enteric nervous system; and
Through signaling to the host beyond the gut to the liver, systemic immune system, and other potential organs such as the brain
Reference:
Rijkers GT, Bengmark S, Enck P, et al. Guidance for substantiating the evidence for beneficial effects of probiotics: current status and recommendations for future research. J Nutr. 2010;140:671S-676S.
Affect systemic immune system
Adapted from Rijkers GT, et al. J Nutr. 2010;140:671S-676S.

28. Summary of Key Randomized Controlled Trials of Probiotics in IBS
An increasing number of randomized controlled trials (RCTs) have evaluated the efficacy of probiotics in patients with IBS. Unfortunately,many of the available studies are encumbered by methodological limitations such as small sample sizes, lack of adequate blinding, short study duration, use of non-validated study endpoints, and failure to report an intention-to-treat analysis. Furthermore, results between studies are difficult to compare owing to variations in design, probiotic dose and strain and results from these trials should therefore be interpreted with some caution. Nevertheless, some positive results have been noted. Overall, studies have typically included strains of Lactobacillus species or Bifidobacterium species, along with different probiotic combinations such as VSL#3 and SCM-III
William D Chey, Reviews in Gastroenterol 2010

29. RCTs of Probiotics for Treatment of C. difficile Disease
Probiotics in C. Difficile-Associated Disease
RCTs of Probiotics for Treatment of C. difficile Disease
Meta-analysis of 6 RCTs in adults with prior antibiotic exposure from 1977 to 2005 indicated that probiotics have a significant protective effect for C. difficile diarrhea (RR=0.59, 95% CI=0.41, 0.85)1
A funnel plot indicated the absence of publication bias
5 of 6 studies were treating patients with established C. difficile disease and the probiotic was combined with standard antibiotics
The duration of probiotic treatment varied from 3-5 weeks
Types of probiotics used included S boulardii, L. rhamnosus GG, L. plantarum 299v, and a mixture of L. acidophilus and B. bifidum
Of the strains tested, only S. boulardii showed significant reductions in recurrences of C. difficile disease1
This analysis has been criticized for combining the results from 1 study of preventing C. difficile diarrhea with results from 5 treatment studies, and other methodologic flaws (eg, pooling data on different antibiotics, different conditiions)3
Despite these results, a recent Cochrane review of 4 RCTs of probiotics with conventional antibiotics (vancomycin or metronidazole) concluded that there is insufficient evidence to support the use of probiotics alone in the treatment of C. difficile colitis2
References:
MacFarland LV. Meta-analysis of probiotics for the prevention of antibiotic-associated diarrhea and the treatment of Clostridium difficile disease. Am J Gastroenterol. 2006;101:
Pillai A, Nelson R. Probiotics for treatment of Clostridium difficile-associated colitis in adults. Cochrane Database Syst Rev. 2008;23:CD
Wolvers D, Antoine JM, Myllyluoma E, et al. Guidance for substantiating the evidence for beneficial effects of probiotics: prevention and management of infections by probiotics. J Nutr. 2010;140:698S-712S.
BB=Bifidobacterium bifidum; LA=Lactobacillus acidophilus; LGG=Lactobacillus
rhamnosus GG; LP=Lactobacillus plantarum 299v; SB=Saccharomyces boulardii
MacFarland LV. Am J Gastroenterol. 2006;101:

30. S. boulardii Is Effective in Patients with Recurrent C
S. boulardii Is Effective in Patients with Recurrent C. difficile Disease
Initial CDD
Recurrent CDD
P=NS
P=0.04
CDD recurrence, %
CDD recurrence, %
In the largest study to date, S. boulardii in combination with vancomycin or metronidazole was associated with a significant decrease in CDD recurrence in patients who had a history of at least 1 CDD episode.
In this double-blind, randomized, placebo-controlled, parallel-group study, 64 patients with an initial episode of CDD and 60 with a history of at least 1 prior CDD episode received S. boulardii 1 g/day for 4 weeks or placebo in combination with either vancomycin or metronidazole.
S. boulardii was effective in patients with recurrent CDD, but not in patients with initial CDD.
Reference:
McFarland LV, Surawicz CM, Greenberg RN, et al. A randomized placebo-controlled trial of Saccharomyces boulardii in combination with standard antibiotics for Clostridium difficile disease. JAMA. 1994;271:
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:

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):

32. L. acidophilus NCFM and/or B
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
Outside the gut, probiotics have been shown to protect and reduce flu symptoms. This is a study published last year looking at the effect of 2 bacterial strains on symptoms of cold and flu in chinese children, and you can see that there was a signidicant reduction in symptom duration, fever, cough, antibiotic use and absenteeism with probiotic administration. The combination of strains was more effective that the lactobacillus strain alone.
Leyer et al Pediatrics;124(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 (0.50–1.16)
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)
Episodes of diarrhea
0.31 (0.22–0.40)
0.13 (0.05–0.21)
0.02 (0.01–0.05)
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
Similarly another study also published in Pediatrics looked at the effect of feeding infants formula supplemented with the probiotic strain Lactobacillus reuteri, on the rate of infections in child care centers. They found that the duration of fever and diarrhea were significantly reduced with probiotic feeding vs placebo.
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 J Allergy Clin Immunol.

35. “Human gut microbes associated with obesity”
The study shows that the relative proportion of Bacteroidetes is decreased in obese people by comparison with lean people, and that this proportion increases with weight loss.
The findings indicate that obesity has a microbial component, which might have potential therapeutic implications.
Ley, et al. NATURE 2006

36. Resistance to diet-induced obesity in germ-free mice
GF animals are protected from diet-induced obesity
Adult male C57BL/6J mice were conventionalized 3 weeks before they were switched to a high-fat Western diet. Initial weight was recorded ( and g for GF and conventionalized mice, respectively). Weight gain was monitored weekly for 8 weeks and compared with GF mice (n5 per group).
Comparisons of the distal gut microbiota of genetically obese mice and their lean littermates, as well as those of obese and lean human volunteers have revealed that obesity is associated with changes in the relative abundance of the two dominant bacterial divisions, the Bacteroidetes and the Firmicutes. Here we demonstrate through metagenomic and biochemical analyses that these changes affect the metabolic potential of the mouse gut microbiota.
Backhed et al., PNAS , 104 (3): 979–984

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
Despite the growing interest in probiotics, there are a number of common misconceptions about these products. Probiotics are not the same as live active cultures, which are microbes associated with foods as food fermentation agents, or starter cultures, but have not necessarily been tested for health effects. Some live active cultures, however, have demonstrated health effects, and can be called probiotics. Thus, despite potential overlap, these terms are not synonymous.
Additionally, probiotics are not native commensal bacteria from humans, although they are commonly isolated from this source. Once they are shown to have health effects when administered to humans, members of our normal, commensal bacteria can be called probiotics.   
Another key concept essential to understanding probiotics is that the effects of these agents are strain-, not genus-, specific. Despite the range of potential health benefits observed with probiotics, the effects described can only be attributed to the strain or strains tested, and not to the group of probiotics as a whole.

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.
The dose of probiotics is usually expressed as the number of colony forming units (CFUs), or the number of viable microbe, per serving. The required dose of probiotics may vary greatly for different strains and the specific health effect under investigation, with health benefits ranging from 50 million to more than 1 trillion CFU/day. Further, dose-response studies regarding probiotics are not common. Thus, probiotic effects should be considered dose-specific, and it is not possible to make general recommendations about the minimum dose of probiotics that is needed for an effect. Accordingly, studies documenting the efficacy of specific strains at a specific dosage cannot be used as evidence to support health effects at a lower dosage, and the 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 Nov;53(11):

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)
Long term safety in at-risk individuals
Long-term safety to be evaluated for:
Translocation
Case reports of endocarditis and abscesses
Systemic sepsis
Ulcerative colitis
Crohn’s disease
Utrecht pancreatitis
Increased mortality in probiotic group
Mesenteric ischemia

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.
Like their health effects and dosage, the safety of probiotics should be considered to be strain-specific. The genus and species of the microbe being used should be assessed with respect to genetic stability, metabolic activities, and the potential for pathogenicity or toxicogenicity. Additional factors important for assessing the safety of a probiotic
include the method of administration, the level of exposure, the health status of the users, and the physiologic functions they are intended to perform.
In general, few correlations between probiotic use and adverse events have been demonstrated; however, few studies have specifically addressed the safety of these probiotics. Commenting on this observation, Dr. Sanders added that “health care professionals are “extremely receptive to safe interventions, those they feel are associated with possible benefit without being a risk. Consumers should also understand that 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.
So since dietary supplements do not undergo a preapproval for safety by the FDA; assurance of safety is the responsibility of product manufacturers. A health care professional should be consulted before using probiotics for young infants or people with compromised immune systems or other major underlying illnesses.

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”
The US government regulates dietary supplements on the basis of the Dietary Supplement Health and Education Act (DSHEA) of
1994, which was enacted to provide the legal framework specifically for dietary supplements. This regulation allows for structure/function claims and claims of general well-being. Most supplements currently on the market make structure/function claims, which describe the role of the dietary ingredient intended to affect a structure or function in humans. Examples of such claims on probiotics include those suggesting that the product “supports a healthy immune system,” “helps keep your microflora in balance,” or “helps build and maintain a healthy digestive system.” Thus, structure/function claims should “promote, support, maintain a healthy body system” rather than claim that the product can treat, cure, or prevent a disease. Under DSHEA, structure/function claims must be accompanied by the disclaimer that “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 nature of the claims they should be truthful and substantiated by 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:
Most supplements currently on the market make structure/function claims, suggesting that the product “supports a healthy immune system,” “helps keep your microflora in balance,” or “helps build and maintain a healthy digestive system.” These claims are intended to promote, support and maintain a healthy body system.
Under DSHEA, structure/function claims must be accompanied by the disclaimer that “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.”
Despite this required disclaimer and although structure/function claims do not require pre-approval from the FDA, the manufacturer is responsible for the accuracy and truthfulness of all claim(s).
*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 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

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

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

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.
In conclusion, the intestinal flora may impact health through a number of protective, structural, and metabolic functions. Although
these mechanisms have not been fully characterized, probiotic bacteria are believed to confer health benefits by bolstering these effects.
However, it is essential to understand that not all probiotics are created equal, as the benefits of these agents are both
strain-specific and dose-specific. Although the range of probiotic products is expanding, making clinical recommendations can be complicated by misinformation as well as the frequent disconnect between scientific evidence and allowable claims on these products. Consumers and health care professionals choosing probiotics should ensure that the health claim(s) regarding the product are substantiated with well-controlled studies and that the product has been adequately characterized for content and stability.