Probiotics

Probiotics
Kathi J Kemper, MD, MPH
Wake Forest University
School of Medicine
“You’ve been fooling around with alternative medicine, haven’t you?”
Disclaimer
 I have the following financial relationships with the
manufacturer of a commercial product and/or
provider of commercial services discussed in this
CME activity:

American Academy of Pediatrics, “Mental
Health, Naturally "Author. Royalties anticipated.
 The presentation will include no description of any proprietary
items for screening, diagnosis, or treatments.
 I do not intend to discuss an unapproved or investigative use of
a commercial product in my presentation.
Objectives
By the end of this session, participants will be
able to:
1. Define and give two examples of probiotics
and prebiotics and foods that contain them
2. Summarize studies about the effectiveness
and safety of using probiotics to prevent/treat
1. Diarrhea, constipation, NEC, and colic
2. Eczema
3. Identify one potential side effect and one
contraindication to using probiotics
Prebiotics (functional food)
 First identified in 1995
 Non-digestible food ingredients that
stimulate the growth and/or activity of
probiotics
 Typically oligosaccharides:
galactooligosaccharides (GOS), fructoOS (FOS), xylo-OS (XOS), Inulin
 Found in: Breastmilk, Jerusalem
artichoke, chicory root, raw dandelion
greens, leeks, onions, garlic, asparagus,
whole grains, beans, banana
 Adding Prebiotics to Probiotics increases
production of gut Short-Chain Fatty Acids
(SCFA)
Probiotics: definition
 World Health Organization:

“live microorganisms which when administered in
adequate amounts confer a health benefit on the
host”
 They:
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Survive stomach acid and bile
Establish residence in the intestines
Impart health benefits
Synbiotics
 Products containing
BOTH
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
Prebiotics
Probiotics
Probiotic examples
 Lactobacillus sp.
reuteri
 casei
 ramnosus
 Acidophilus
Streptococcus sp.
Bifidobacterium sp.
 Infantis (breastmilk)
 lactis
 longum
 breve
 bifidum
Sacharomyces boulardii
Enterococcus sp
Mixtures
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Formulations: drops, chewable tablets, lozenges, capsules, straws, bottle caps
Brands most often recommended on CHIM listserv include BioGaia, Culturelle,
Florastor
Initial Intentional Probiotic Use
 Eli Metchnikoff - early 20th century (Russian Nobel
laureate, professor at Pasteur Institute in Paris)
 Observed
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Bulgarians who drank milk fermented by lactic-acid
producing bacteria had long lives
Lactic acid lowers gut pH and inhibits the growth of
some pathogenic bacteria.
 Metchnikoff began drinking fermented milk and soon
Parisian physicians did likewise.
 Henry Tissier at Pasteur Institute identified bacteria
common in breastfed infant stool: Bifidobacter
 Lactobacillus acidophilus breaks down lactose and
allows lactose intolerant individuals to drink milk
Probiotics- normal source?
 Colonization at birth with
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maternal species
Specific organisms vary by age
in first year
Become established by 1 year
Diet – maternal milk, fermented
milk, pickles, fermented soy
(tempeh), etc.
“Successful” probiotic treatment
leads to temporary colonization
Primary Pediatric Uses of Probiotics
 Manage lactose intolerance (L acidophilus)
 Antibiotic-associated diarrhea and infectious
diarrhea
 Decrease constipation
 Decrease risk of NEC and all cause mortality
in premature infants
 Decrease dental caries
 Treatment of H pylorii infections, UTI
 Decrease colic
 Decrease risk of developing eczema
 Decrease upper respiratory tract infections
Antibiotic-associated Diarrhea
Systematic review of 9 placebo-controlled studies (2 in
children) using various products: 60% reduction in
incidence and duration of antibiotic associated
diarrhea compared with placebo (P<0.01) 2002
9/10 pediatric trials (different products) favored
probiotics (RR 0.49; 95% CI 0.32 to 0.74). None of
the 5 trials monitoring adverse events (n = 647)
reported a serious adverse event.
Johnston BC. Cochrane Database Syst Rev, 2007
D’Souza et al. BMJ, 2002
What I do: recommend 2-4 weeks of probiotics for all
kids who receive an antibiotic prescription.
Probiotics: infectious diarrhea
 Treatment:
Systematic review > 9 studies in 1-36 month old
children; significant reduction in diarrhea days
(0.7, 95% CI: 0.3-1.2) and fewer stools with L GG
(95% CI: 0.7-2.6); Dose response curve with
higher L GG dose . Also S. boulardii and L reuterii
Van Niel et al. Pediatrics, 2002
Allen et al. Cochrane Database Syst Rev, 2004
 Prevention:
2006 systematic review of 5 RCTs in day care and
hospital settings: modest, but significant benefit for
rotavirus or C. Diff. L GG, L reuteri > B lactis
Guandalini. J Clin Gastroenterol, 2008
*Chemotherapy-associated diarrhea
 Benefits for pediatric oncology patients with diarrhea
(incl C diff). Benchimol EI. J Pediatric
Hematology/Oncology, 2004
 Breast cancer and colorectal cancer patients
receiving chemotherapy had markedly less diarrhea
with probiotics El-Atti S.Journal of Parenteral &
Enteral Nutrition, 2009; Osterlund P. Br J Cancer,
2007
 Radiation induced diarrhea attenuated with
probiotics. Delia P.Tumori, 2007; Fuccio L. J Clin
Gastroenterol, 2009; Giralt J. Intl J Rad Onc Bio
Physics, 2008
* Decreased risks in adults
 Recurrent colon and bladder cancer
with probiotics/synbiotics; implications
for pediatrics?
 Perioperative infections in abdominal
surgery with probiotics in adults.
 Implications for pediatrics
Probiotics: constipation
 Meta-analysis of 5 RCTs (3 adults n = 266; )
2 children, n = 111). In adults, data suggest
favorable effects of several probiotics. In
children, L. casei rhamnosus Lcr35, but not L.
rhamnosus GG, showed a beneficial effect.
Chmielewska A. World J Gastroenterol, 2010
 Anecdotally, I’ve had good success. More
research needed on effectiveness for
constipation!
Probiotics: NEC prevention
Meta-analysis of 9 trials randomizing 1,425
premature infants (<37 weeks or < 2500 gms)
to prophylactic probiotics, vs. placebo or TAU;
probiotics significantly reduced severe NEC
by RR 0.32 and mortality by 0.43 (P<0.05);
no impact on nosocomial sepsis or length of
TPN.
Safety: no observed cases of systemic infection
with the probiotic agents.
More research needed in ELBW infants.
Alfaleh K. Neonatology, 2010
* Probiotics reduce all-cause
mortality and NEC
 “A systematic review, …of 11 randomized, controlled
trials (RCTs) in 2176 infants of <34 weeks' gestation
revealed that oral probiotics reduced all-cause
mortality and necrotizing enterocolitis (NEC) by more
than half (P < .00001).” How?
 “Probiotics upregulate local and system immunity,
increase anti-inflammatory cytokines and gut
impermeability to bacteria and toxins, and suppress
pathogens associated with NEC.”
Tarnow-Mordi, et al. Pediatrics, 2010 (editorial)
Soll RF. Pediatrics, 2010 (editorial)
Deshpande G, et al Pediatrics, 2010 (meta-analysis)
*FIGURE 2 Effect of probiotics on NEC
Deshpande, G. et al. Pediatrics 2010;125:921-930
Copyright ©2010 American Academy of Pediatrics
*FIGURE 4 Effect of probiotics on allcause mortality
Deshpande, G. et al. Pediatrics 2010;125:921-930
Copyright ©2010 American Academy of Pediatrics
*Probiotics for Premature Infants:
widespread implementation?
 What about < 1000 gram infants?
 11 studies used 10 different probiotics
 Which strains? Combinations?
 What dose?
 Should strain and dose depend on type of
milk feeding?
 Contraindications? (case report toxicity)
 Routine vs. informed consent?
Soll RF. Pediatrics, 2010 (editorial)
Probiotics: colic
 RCT of L reuteri vs. simethicone for 28 days
in 83 breast-fed infants
 Daily median crying time
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Day 7 P:159 minutes vs S: 177 minutes
Day 28 P: 51 minutes vs S: 145 minutes
(P<0.01)
 Percent responders by 28 days: 95% of
Probiotic vs. 7% of simethicone (P<0.01)
 No adverse effects reported
Savino F. Pediatrics, 2007
Probiotics: eczema
 Probiotic supplements for Finnish pregnant moms with 1st
degree fam hx atopy: L GG 10 bill cfu’s daily for 2-4
weeks before delivery, followed by infants daily for 6
months. At 2 years old, eczema prevalence reduced from
46% to 23% (RR 0.51, CI: 0.32-0.84); at 4 years, relative
risk reduction for atopic eczema of 0.57 (95% CI: 0.330.97); at 7 years, RR reduction: 0.58 (95% CI, 0.35-0.94;
P = .027).
Kalliomaki et al. Lancet 2001; Lancet, 2003; J Allergy Clin Immunol, 2007
 Dutch RdbPCT (B. bifidum, B. lactis, and L. lactis) was
given to pregnant women and to babies for first 12
months. Decreased risk of eczema with active treatment
at 3 months, 6/50 vs 15/52 (P = 0.035) and at 12 months
23/50 vs 31/48.
Niers L. Allergy, 2009
Probiotics and infections
 High risk of allergy 1,018 pregnant mothers
RCT mix (L rhamnosus GG and LC705, B
breve Bb99, P freudenreichii) vs. placebo for 4
weeks before delivery; infants received same
with or without GOS for 6 months.
 Two year follow-up – no difference in neonatal
morbidity, colic, or serious adverse effects;
significantly fewer antibiotics prescribed to
synbiotic group and fewer respiratory
infections
Kukkonen K. Pediatrics, 2008
Probiotics: Respiratory Illness
 Weizman, et al. 12 weeks of B lactis or L
reuteri vs. TAU controls
 Significant reductions, all favoring L reuteri in
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Days with fever (0.17 vs. 0.8, P<0.001)
Episodes of fever (0.1 vs. 0.4, P<0.001)
Antibiotic prescriptions (0.06 vs. 0.19, P<0.05)
Weizman, Pediatrics, 2005
*Nosocomial infections
 L GG to prevent nosocomial GI and
Respiratory infections
 RdbpCT, N=742 hospitalized children
 Dose L GG 109 daily in 100 ml fermented milk
 RRisk of GI infections 0.4 for LGG vs.
placebo; NNT 15; (vomiting RR 0.3; diarrhea
RR 0.24)
 RRisk of Respiratory infections 0.38 for LGG
v placebo, NNT 30
Hojsak I. , et alPediatrics, 2010 (May)
Probiotics: prescribing
 Which organism to use?
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S boulardii, Lactobacillus, and E faecium have
prevented antibiotic-associated diarrhea
L GG and L reuterii reduced infectious
diarrhea
L GG for eczema
L reuteri for colic
 Which product? What dose? How long?
 Side effects? Cost?
Probiotics: recommending
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Lactobacillus rhamnosus GG, reuterii, best
studied to date
Combination products not well studied, but
may work as well
Typical effective “dose”: 10 billion organisms/d
Most require refrigeration
Can give in cool food/drink
*Probiotics: product variability
 1996 BMJ
(Hamilton-Miller JM)
only 2/13 study of
13 British brands
contained quantity
of cfu listed on label
 2004 Can Fam
Physician (Huff BA)
found 0/10 brands
tested matched
microbiologic
specifications on
label; typically, 010% of label
quantities, often not
including any of
stated bacteria
Probiotics: product variability
 ConsumerLab.com tested 25 probiotic products
 19 for general population, 3 for children, 3 yogurts
 8 claimed a specific number of organisms per serving
 13 claimed only a number of organisms at time of
manufacture
 8/25 contained less than 1 percent of the claimed
number of live bacteria or of the expected minimum of
1 billion.
 7 of the 8 that gave expected numbers per serving met
those counts
 None contaminated with bacteria, mold, or fungus
 All enteric-coated capsules passed testing
Probiotics: common products
Florastor
Nature’s Way enteric
coated 35
Culturelle
Organisms
Saccharomyce L rhamnosus, casei,
s boulardii
plantarum,
acidophilus, lactis,
diacetylactis,
bulgaricus, salivarius,
helveticus,
B longum, breve,
infantis
S thermophilus
L. GG
Quantity per
“dose”
10 billion
10 billion
(reliability?)
35 billion
Some products are available as dairy free preparations. Sedona
labs, Klaire labs, Kirkman labs, Pharmax – all recommended by
various members of CHIM listserv
Probiotics: what’s in yogurt?
Product
Activia
Breyers
99% Fat
Free Fruit
on the
Bottom…
Type
B
L
regularis acidophilus
(animalis, ? others
DN-173
010)
DanActive
Stonyfield
Farm
French
Vanilla
Nonfat
Yogurt
YoPlus
L casei
Immunitatis
(casei, DN114 001)
Bifidus
L
acidophilus,
casei,
bulgaricus,
reuteri
B. Lactis
Bb-12 +
inulin
Probiotic safety
 Case reports of bacteremia, fungemia,
endocarditis, meningitis in
immunocompromised children on ventilators
 2% bloating, gas, diarrhea
 Increased allergic sensitization?
 Food is safer than pills!
Take home points…
 Good evidence for:
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Infectious diarrhea, tx
Antibx-assoc diarrhea
NEC; premature mortality
 Promising evidence for:
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Preventiong atopic conditions
Constipation
 In the future we may be using
probiotics as we use antibiotics
today: with specific strains used
for certain clinical situations
guided by controlled studies
 Prescribing
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Lactobacillus GG best
studied to date
Combination products
not well studied, but may
work as well
10 billion organisms/d
Keep refrigerated (except
Culturelle and BioGaia)
Give in cool food/drink
2% risk bloating/gas
Suggested Practice Changes
 Recommend L. acidophilus for patients with lactose intolerance
 For the next 30 days, recommend probiotics for outpatients who
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receive a prescription for antibiotics; monitor rate of diarrhea as
a side effect
Try different probiotic products yourself and monitor your own
gut reaction
Recommend probiotics (L GG) for patients with infectious
diarrhea.
Talk with your local neonatologist about using probiotics to help
reduce risk of NEC.
In the next week, talk with one mother of an infant about
probiotics to help with colic.
Ask your hospital library to subscribe to ConsumerLab.com.
Prepare a handout comparing different probiotic products for
your patients.
Join the AAP SOCIM: www.aap.org/sections/chim/
Extra Information
Probiotics: proposed
mechanisms
 Adherence and subsequent stimulation of gut
immune system
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Up-regulation of mucin gene
Enhance secretory IgA
Maintain normal macrophage function
 Competition for essential nutrients
 Production of antimicrobial factors
 Provide favorable environment for growth of other
beneficial bacteria
 Production of short-chain fatty acids with antiinflammatory properties