1. Wake Forest University School of Medicine
Probiotics
Kathi J Kemper, MD, MPH
Wake Forest University School of Medicine
“You’ve been fooling around with alternative medicine, haven’t you?”

2. 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.

3. Objectives By the end of this session, participants will be able to:
Define and give two examples of probiotics and prebiotics and foods that contain them
Summarize studies about the effectiveness and safety of using probiotics to prevent/treat
Diarrhea, constipation, NEC, and colic
Eczema
Identify one potential side effect and one contraindication to using probiotics

4. 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)

5. 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

6. Synbiotics
Products containing BOTH
Prebiotics
Probiotics

7. 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

8. Initial Intentional Probiotic Use
Eli Metchnikoff - early 20th 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

9. 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

10. 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

11. 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.

12. Probiotics: infectious diarrhea
Treatment:
Systematic review > 9 studies in 1-36 month old children; significant reduction in diarrhea days (0.7, 95% CI: ) and fewer stools with L GG (95% CI: ); 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

13. *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

14. * 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

15. 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!

16. 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

17. * 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 < ).” 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)

18. *FIGURE 2 Effect of probiotics on NEC
Deshpande, G. et al. Pediatrics 2010;125:
Copyright ©2010 American Academy of Pediatrics

19. *FIGURE 4 Effect of probiotics on all-cause mortality
Deshpande, G. et al. Pediatrics 2010;125:
Copyright ©2010 American Academy of Pediatrics

20. *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)

21. 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

22. 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: ); at 4 years, relative risk reduction for atopic eczema of 0.57 (95% CI: ); at 7 years, RR reduction: 0.58 (95% CI, ; 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

23. 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

24. 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

25. *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)

26. 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?

27. 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

28. *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

29. 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

30. Probiotics: common products
Florastor
Nature’s Way enteric coated 35
Culturelle
Organisms
Saccharomyces 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

31. Probiotics: what’s 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 )
L acidophilus
? others
L casei Immunitatis (casei, DN )
Bifidus
L acidophilus, casei, bulgaricus, reuteri
B. Lactis Bb-12 + inulin

32. 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!

33. 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

34. 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:

35. Extra Information

36. 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