Download Probiotics - Mary Ellen Sanders

Probiotics: Benefits and Applications
Presented to American Dietetics Association
September 19, 2006
Honolulu HI
Mary Ellen Sanders, Ph.D.
Consultant, Dairy and Food Culture Technologies
www.mesanders.com
[email protected]
www.usprobiotics.org
Probiotics
Live microorganisms which when
administered in adequate
amounts confer a health benefit
on the host
L. acidophilus NCFM
Photo by Alan Servin
FAO/WHO (2001) Expert Consultation
http://www.fao.org/es/ESN/Probio/probio.htm
Lactobacillus
Bifidobacterium
Saccharomyces
S. thermophilus
Enterococcus
E. coli
recombinant microbes
Bacillus subtilis
(“L. sporogenes”
sporogenes”)
B. longum 536
Photo by Morinaga
1
Human bodies are highly colonized
1014 microbial cells on
human body: mouth,
intestine, vagina, skin
1013 human cells
comprise human
body
Up to 1000 different bacterial species
The combined microbial gene pool is
estimated to be 100 times greater than the
human genome
Laid end to end, the bacteria on our bodies
would circle the earth 2.5 times
“It appears that there are very few physiological parameters of the
human or animal body that are not in some way affected by the
presence of the indigenous microflora” (Rolf Freter)
Colonizing Microbes Are Important
„
„
Inhibits infection by potentially pathogenic microorganisms
-“colonization resistance”
resistance”
Alteration of chemistry and biochemistry of colonized
environments
– SCFA, vitamins, ↓ or ↑ pH, ammonia, digestion of nonnon-digested
polysaccharides/mucin
polysaccharides/mucin,, deconjugation of bile acids, etc.
„
Critical to postpost-natal immune system development - The
gut has the largest number of immune cells of any organ
in the body
– Downregulation of inflammation
– Oral tolerance to antigens in gut
– Balance Th1/Th2 response involved with autoimmune and allergic
conditions
2
Once we appreciate the complexity and
range of biological functions of the
colonizing microbiota it’s not so difficult to appreciate how
influencing the microbiota may have a
wide range of health effects
Probiotics use many of the same mechanisms used by
other commensal bacteria to mediate health benefits
Published targets for probiotics
Oral microbiology
• Dental caries
• S. mutans
• Halitosis
Allergy
• Atopic dermatitis
• Asthma
Inflammatory bowel
disease
Colorectal cancer
Vaginal infections
Colds, respiratory infections
H. pylori
Deliver of cloned components
active in gut
Diarrhea
• AAD, travelers diarrhea
• C. difficile
• rotavirus
Lactose digestion
IBS symptoms
Systemic effects
• Immune function
• Growth parameters of
undernourished children
• Reduced absences from
work, daycare
3
Effect of probiotic formula on infections in
child care centers
Weizman et al. Pediatrics 115:5115:5-9
Control
B. lactis BBBB-12 L. reuteri
Fever (d)
0.83
0.86
0.17*
Fever
(episodes)
0.41
0.27*
0.11*
Diarrhea (d)
0.59
0.37*
0.15*
Diarrhea
(episodes)
0.31
0.13*
0.02*
Clinic visits
0.55
0.51
0.23*
Absences
from CCC
0.43
0.41
0.14*
Ab
prescriptions
0.19
0.21
0.06*
N=60 control
N=73 Bb12
N=68 L. reuteri
RDBPC
No differences in days with or episodes of respiratory illness
% of subjects reporting sick during study
Workplace
absences
N=181 healthy adults
108/d L. reuteri ATCC 55730 powder
RDBPC
Study duration: 80 d
Tubelius P, et al. 2005.
Environ Health. 7;4:25.
Placebo
L. reuteri
% subjects
reporting sick
days
26%
11%
Median # sick
days per
absence
3 days
3 days
# sick
days/total
study days (%)
0.9%
0.4%
4
L. rhamnosus GR-1 and L. reuteri RC14 improves
metronidazole treatment of bacterial vaginosis
30 – day follow up
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
Normal
Intermediate
BV
BV
Probiotic +
AB
96% vs. 53% o
women taking
probiotics had
>105
lactobacilli/gm
vaginal fluid
AB only
Anukam, et al. Microbes and Infection 8 (2006) 1450-1454
1010
108
106 cfu/d
Irritable Bowel Syndrome
„
„
„
„
„
B. infantis 35624
Subjects’ Global Assessment at
wk 4. Subjects responded “yes”
or “no” to the following question:
“Please consider how you felt in
the past week in regard to your
IBS, in particular your general
well-being, and symptoms of
abdominal discomfort or pain,
bloating or distension and altered
bowel habit. Compared to the
way you felt before beginning
the medication, have you had
adequate relief of your IBS
symptoms?” (42% placebo vs.
62% 108 cfu/d)
106 or 108 or 1010 cfu/d
N=362 diagnosed IBS of any subtype
2 wk run in, 4 wk treatment, 2 wk washout
RDBPC multicenter dose ranging trial
Whorwell et al. 2006. Amer J Gastroenterol. 101:1581
5
Effect of probiotic bacteria 5x107/d
B. longum, B. bifidum, L. gasseri on
episodes of colds in healthy adults
Probiotic +
Vitamin/mineral
Vitamin/mineral
supplement
Duration (days)
7.0±
7.0±0.5
8.9±
8.9±1.0 (p=0.045)
Bronchial symptoms
symptom score – points
13.2±
13.2±2.1
19.1±
19.1±2.7 (p=0.011)
Days with fever
0.24±
0.24±0.1
1.0±
1.0±0.3 (p=0.017)
Total symptom score
79.3±
79.3±7.4
102.5±
102.5±12.2 (p=0.056)
Study duration – >3 months
N=479
de Vrese et al. 2005. Clin Nutr 24:481-91.
Fermented milk with yogurt
starters and L. casei DN114-001
Jellied milk
D a y s d ia r r h e a
10
8
L. casei
Yogurt
8
„
„
„
6 fermented milk 5.3
„
4
„
4.3
2
N=287 healthy children, 66-36
months
12 day care centers in France
6 mo duration (Nov(Nov-May)
Monthly intervals, on and off
supplementation
RBPC, 3 arms: milk, yogurt, L.
casei (3(3-6x1010/d) fermented
milk
0
Pedone et al. 2000. Int J Clin Pract 54:568-571
6
Prevention of hospital-acquired diarrhea in
hospitalized infants, 1-36 mos
Szajewska,
Szajewska, et al., 2001. J. Pediatr.
Pediatr. 138:361
138:361--5
# Subjects
Incidence of
diarrhea
P=002
LGG
46
Placebo
36
3 (6.67%)
12 (33.3%)
DoubleDouble-blinded, placeboplacebo-controlled,
6x109 dried Lactobacillus GG/2x/day
Note: June 06 ConAgra sold Culturelle business to Amerifit Nutrition Inc
Probiotics in maintenance of remission in pouchitis
Estimates of relapse during treatment with VSL#3 or placebo
Remission
Dose: 1.8x1012/d total
VSL#3 comprised of 8 different species of probiotic,
predominantly S. thermophilus
VSL#3
Placebo
Months after treatment
Gionchetti et al. 2000. Gastroenterology 119:305-309.
7
Effects Are Strain-Specific
„
Not all strains of the same species can be expected to have the same effects
„
Clinical data must be viewed as applicable only to the strain or strain
combinations tested
– Other strains of the same species MAY have the same effect.
– It cannot be assumed, for example, that because one L. rhamnosus has a certain
effect, that all do.
„
No one strain should be expected to have all effects
– Strain blend approach
– Targeted strain approach
„
Future research will determine what phenotypic traits are important
important for
certain effects
– Genome sequencing
Strain is important:
Same species, but different “strains” =
different use, different performance
Not all strains of the same species will be the same
For example:
Bifidobacterium lactis DR10 vs. Bifidobacterium lactis BbBb-12
Same Genus: Bifidobacterium
Same Species: lactis
But different strain: DR10 and BbBb-12
8
What Levels of Probiotics Need to be Delivered
in Products
„
Many studies have tracked acute endpoints
– What benefits are achieved at lower, long term doses is not known
known
„
Required levels for therapeutic endpoints (e.g., IBD remission or
or
IBS symptoms) may be higher than prophylactic (e.g., resisting
infections) endpoints
„
In general: a few studies document effects at 108/d; most
studies use 109-1010/d.
„
Synergism has not been studied
– What levels of probiotics are necessary when combined with other
foods functional in the GI tract?
– What about multiple dietary sources of probiotic bacteria?
– What about strain interactions as part of blends?
Levels used should be based on levels found to be efficacious in human studies
Effects are dose specific
MetaMeta-Analysis of Lactobacillus as therapy for acute infectious
diarrhea in children
“Lactobacillus is safe
and effective as a
treatment for children
with acute infectious
diarrhea”
Van Niel, et al. 2002. Lactobacillus therapy for acute infectious
diarrhea in children: a meta-analysis. Pediatrics 109:678-684
9
Probiotic Product Format Options in USA
„
Food (e.g., Activia
Activia)
„
Supplement (e.g., Culturelle
Culturelle, Align
Align)
„
Medical Food (VSL#3)
„
Pharmaceutical (none for human use but IBD,
pouchitis,
pouchitis, IBS, BV are possibilities)
– Under jurisdiction of Department of Biologics as “Biologic
Drugs”
Drugs”
In theory, the same probiotic strain could be used in any of these formats
Probiotic Food Products
„
Yogurt is the most common carrier for probiotics
„
Good fit in mind of consumer – ‘live, active cultures’
cultures’
and healthy image fit with dairy products
„
Good option for incorporating ‘beneficial bacteria’
bacteria’ into
daily diet
„
But...many yogurts not formulated optimally
– Unknown levels of probiotics in dairy products
– Little communication to consumer about probiotics
– Strains not optimally chosen
10
Potential advantages of dairy products as
delivery vehicles for probiotics
“Functional Nutrition Package”
Stability
Functionality
In Product
Many dairy foods are
short shelf life,
refrigerated products,
which encourages
probiotic survival in
product
Gastrointestinal Physiological
Transit
Activity
Buffer stomach acid
Compliance
Food vs. pills
Dairy products
deliver functional
nutrition along with
probiotic bacteria
What does the “live active culture” seal
tell us about probiotics?
Nothing!
„
Minimum level of cultures –
107/g at end of shelf life
„
Doesn’
Doesn’t specifically apply to
probiotic content
„
Starter cultures usually
~108-9/g
„
Probiotic bacteria target
~106/g, and levels at end of
shelf life are not published
11
Probiotic labels
„
What should the label say:
– Identify probiotics used
„
Genus, species and strain(s)
strain(s) contained
– What levels will be present at end of shelf
life – based on studies showing efficacy
– Statements of nutritional support (S/F
statements)
Must be truthful and not misleading
„ Must be based on human studies
„
Labeling of Probiotic Products
„
Dairy foods: generally no claims made in US
– DanActive:
DanActive: “strengthens your body’
body’s natural
defenses”
defenses”
– Web sites: contain much more information
„
„
www.stonyfield.com
Supplements:
– Culturelle:
Culturelle: “Clinically proven at major US and
European institutions to maintain a healthy intestinal
tract”
tract”
– Align: “promote a healthy, balanced digestive
system”
system”
12
Indication
Strain or Product
Dose
Infant diarrhea
L. rhamnosus GG (www.culturelle.com)
L. casei DN114001 (strain “Defensis”)
(www.danactive.com)
~1010/d
~1010/d
Inflammatory bowel
conditions
VSL#3 (www.vsl3.com )
~1012/d 3x/d
Antibiotic associated
diarrhea
S. boulardii (www.florastor.com)
L. rhamnosus GG
500 mg 4x/d
~1010/d
GI symptoms
B. infantis 35624 (www.aligngi.com)
B. animalis DN-173 010 (“Bifidus regularis”;
www.activia.com )
109/d
~1010/d
“Keeping healthy”
L. reuteri (www.stonyfield.com; www.biogaia.com)
L. casei DN114001
108-109/d
~1010/d
Allergy in infants
L. rhamnosus GG
~1010/d
Lactose intolerance
L. bulgaricus and/or S. thermophilus
(all strains)
~1010/d
(~108/ml milk)
Immune support
B. lactis HN019 (HOWARU™ or DR10
www.danisco.com)
B. lactis Bb12 (www.bradpharm.com)
L. casei DN114001
~1010/d
~1010/d
~1010/d
Vaginal applications
L. rhamnosus GR-1; L. reuteri RC-14
(www.urexbiotech.com; Fem-Dophilus
www.jarrow.com)
~1010/d
Irritable bowel syndrome
B. infantis 35264 (“Bifantis”; www.aligngi.com)
109/d
“Probiotic” containing foods
Cheese
Cereal
Kashi
Frozen yogurt
Yogurt
Kefir
Daily
dose
drinks
Candy
Juice
Infant formula
13
Probiotic supplements
„
„
Dozens of different probiotic
supplement brands
Available to US market
– Health food stores
– On line
– Warehouse stores
– Grocery/drug stores
„
„
„
„
Different strains, doses, added
active ingredients
Different degrees and types of
substantiated benefits
Many with little or no efficacy
data
Many not meeting label claim
for amount or types of bacteria
through end of shelf life
Safety: Lactobacillus and Bifidobacterium
„
„
„
Generally considered very low pathogenic potential
– Normal commensals
– Some species present in high numbers in foods
– History of safe use for some species in foods, supplements
and pharmaceuticals
Dozens of infections documented due to lactobacilli and
bifidobacteria
– Only in patients with underlying illness
– Source of microbe in most cases thought to be commensal
Lactobacilli isolated from clinical infections are usually L.
rhamnosus, L. casei/paracasei and L. plantarum
– Is this due to some inherent higher risk of causing infection
or because they grow more easily on clinical media often
used in clinical labs?
Safety considerations for other genera used as probiotics will be different
14
Conclusions
„
„
Probiotics are promising healthful dietary ingredients.
They may play a role in helping to keep people
healthy as well as serve as therapeutic agents for
certain conditions.
There is very little risk from probiotics comprised of
Lactobacillus and Bifidobacterium species, although
people who are immunocompromised should
certainly consult with a physician prior to using.
„
More research needs to be done to confirm extent of
health effects and mechanisms of effects.
„
As the industry grows, probiotic products will become
more consumerconsumer-friendly, with guarantees of product
shelfshelf-life, scientifically accurate labeling of contents
and truthful descriptions of documented benefits.
15