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.

ObjectivesBy the end of this session, participants will be

able to:1. Define and give two examples of probiotics

and prebiotics and foods that contain them2. Summarize studies about the effectiveness

and safety of using probiotics to prevent/treat1. Diarrhea, constipation, NEC, and colic2. 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 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

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, 2007D’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, 2002Allen 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 preventionMeta-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 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: 0.33-0.97); 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 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 30Hojsak 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 Nature’s Way enteric coated 35

Culturelle

Organisms Saccharomyces boulardii

L rhamnosus, casei, plantarum, acidophilus, lactis, diacetylactis, bulgaricus, salivarius, helveticus,B longum, breve, infantisS 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: 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-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