Probiotics

Kathi J Kemper, MD, MPH

Wake Forest University
School of Medicine
Youve been fooling around with alternative medicine, havent 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), fructo-
OS (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:
Survive stomach acid and bile
Establish residence in the intestines
Impart health benefits

Synbiotics
Products containing
BOTH
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

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 20
th
century (Russian Nobel
laureate, professor at Pasteur Institute in Paris)
Observed
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
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
DSouza 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, Ive 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)

Copyright 2010 American Academy of Pediatrics
Deshpande, G. et al. Pediatrics 2010;125:921-930
*FIGURE 2 Effect of probiotics on NEC
Copyright 2010 American Academy of Pediatrics
Deshpande, G. et al. Pediatrics 2010;125:921-930
*FIGURE 4 Effect of probiotics on all-
cause mortality
*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
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 1
st

degree fam hx atopy: L GG 10 bill cfus 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: 0.33-
0.97); 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
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 10
9
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?
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

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
2004 Can Fam
Physician (Huff BA)
found 0/10 brands
tested matched
microbiologic
specifications on
label; typically, 0-
10% of label
quantities, often not
including any of
stated bacteria
1996 BMJ
(Hamilton-Miller JM)
only 2/13 study of
13 British brands
contained quantity
of cfu listed on label
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 Natures Way enteric
coated 35
Culturelle
Organisms Saccharomyce
s boulardii

L rhamnosus, casei,
plantarum,
acidophilus, lactis,
diacetylactis,
bulgaricus, salivarius,
helveticus,
B longum, breve,
infantis
S thermophilus
L. GG
Quantity per
dose
10 billion 35 billion 10 billion
(reliability?)
Some products are available as dairy free preparations. Sedona
labs, Klaire labs, Kirkman labs, Pharmax all recommended by
various members of CHIM listserv
Probiotics: whats in yogurt?
Product Activia Breyers
99% Fat
Free Fruit
on the
Bottom
DanActive Stonyfield
Farm
French
Vanilla
Nonfat
Yogurt
YoPlus
Type B
regularis
(animalis,
DN-173
010)
L
acidophilus
? others
L casei
Immunitatis
(casei, DN-
114 001)
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:
Infectious diarrhea, tx
Antibx-assoc diarrhea
NEC; premature mortality

Promising evidence for:
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
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
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
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 anti-
inflammatory properties