Ferdinand Haschke Medical University of Vienna, Austria

Nestle Nutrition Institute, Vevey,Switzerland

Probiotics – Do They Work?

Prevention/Treatment of GI disease in pediatrics?

DISCLAIMER

I would like to thank Prof. Hania Szajewska, Dept. Pediatrics, University Warsaw, Poland, who provided me with charts from her presentation at the Nestle Nutrition Institute Course in Singapore 2013.

10:1There are 10 times more microorganisms in and

on us than we have cells that make up our body

(mainly in the gut)

gut microbiota

Gut microbiota• 1000– Up to 1000 different species of bacteria

• 170– Each individual harbors some 170

bacterial species out of a total of about 1000 that are predominant in the gut

• 150– The gut microbiota encode 150 times

as many genes as our own genomeQin et al. Nature 2010;464:59-65.

Diabetes

Johnson & Versalovic. Pediatrics 2012;129:950-60.

Differences in gut microbiota between healthy controls and disease states

Differences in gut microbiota between healthy controls and obese subjects

Obese subjects have less variability in their microbiota than healthy non-obese subjects.

Gut microbiota might be an essential factor in certain pathological disorders

• Efforts to optimize the intestinal microbial milieu have increased

the interest in probiotics (and/or prebiotics)

Manipulation of the human microbiome

What are probiotics?Definition Live microorganisms which

when administered in adequate amounts confer a health benefit on the host

Examples Lactobacilli Bifidobacteria S boulardii

Joint FAO/WHO Expert Consultation 2001

ProbioticsGenera, species, and strains

Why the stain- not just probiotics?

Genus Species StrainLactobacillus rhamnosus ATCC 53103 (GG)Lactobacillus casei DN-114 001Lactobacillus reuteri DSM 17938Bifidobacterium animalis subsp. lactis HN019

WHO Global Guideline. Probiotics and prebiotics. 2011.

All probiotics are not created equal

Supplement companies make unproven claims !!!!!!

What are the implications of the strain-specifity?

• Documentation

• No extrapolation

• Dosage

WHO Global Guideline. Probiotics and prebiotics. 2011.

Mechanisms of action

• Non-immunologic• Immunologic

O'Toole PW, Cooney JC. Interdiscip Perspect Infect Dis. 2008;2008:175285WHO Global Guideline. Probiotics and prebiotics. 2011.

Effectiveness of interventions. Published RCTs & systematic reviews/

meta-analyses on probiotics

810 Meta-analyses

101 Cochrane Collaboration (search date: Jan 2013)

For infants and children:

Supplementation of infant formula with probiotics

Provide clinically proven supplements

Administration of probiotic-supplemented formula beyond early infancy

B lactis Bb12 3 RCTs

RR 0.5 (0.36-0.8)NNT 7

There is evidence from the trials that supplementation of infant formula with B lactis

Bb 12 is associated with a reduction in the risk of nonspecific GI infections.

J Pediatr Gastroenterol Nutr 2011;52:238-50.

Prevention of Gastrointestinal Infections

ESPGHAN Committee on Nutrition

Administration ≤4 mo Beyond early infancy Growth No safety concerns

Limited evidence No safety concerns Limited evidence

Clinical outcomes

GI infections

Too much uncertainty to draw reliable conclusions

from the results

Reduction in the risk of non-specific GI infections

Other clinical outcomes

Limited evidence Some clinical benefits

Adverse effects NS NS

Supplementation of infant formula with probiotics – term infants

ESPGHAN Committee on Nutrition

Treatment - Acute Gastroenteritis

What is the evidence that probiotics work?

Acute gastroenteritis Duration of diarrhoea

Metaanalysis Probiotic RCT (n) WMD (95% CI) Szajewska et al. J Pediatr Gastr Nutr 2001

Various 8 (773) -20 h (-26 to –14)

Van Niel et al.Pediatrics 2002

Various 7 (675) -17 h (-29 to –7)

Huang et al.Dig Dis Sci 2002

Various 18 (1917) -19 h (-26 to –14)

Allen et al.Cochrane Review 2010

Various 35 (4555) -25 h (-16 to -34)

Reduced duration of diarrhoea

A common criticism

Mixing apples & oranges

Lactobacillus GG11 RCTs, n=2483

Saccharomyces boulardii8 RCTs, n=1052

Update: Szajewska et al. Aliment Pharmacol Therap 2007;25:257-64Szajewska et al. Aliment Pharmacol Ther 2009;30:960-1

Reduced duration of diarrhoea

Acute gastroenteritis Duration of diarrhoea

S boulardii Diarrhea lasting ≤4 days

Cochrane review 2010

6 RCTs (n=606)RR 0.37 (0.21 to 0.65)

NNT 3 (2 to 3)

Treatment of acute gastroenteritisCurrent recommendations

ESPGHAN/ESPID 2008 AAP 2010

Yes YesProbiotics may be an effective adjunct to the management of

AGE. Because there is no evidence of efficacy for many preparations, we suggest the use of probiotic

strains with proven efficacy and in appropriate doses

There is some evidence in otherwise healthy infants and

young children to support the use of probiotics early in the course of

diarrhea from acute viral gastroenteritis.

Examples Lactobacillus GG,

Saccharomyces boulardiiJPGN 2008;46:619-21 Pediatrics 2010;126:1217-31.

Proportion of patients with watery diarrhoea

L reuteri 4 × 108 CFU

Duration of diarrhoea L reuteri 2.1 ± 1.7 d Placebo 3.3 ± 2.1 dMean difference -1.2 d (-2 to -0.3)

Other probioticsalso may be used provided their efficacy is documented in high

quality RCTs (or in meta-analyses).ESPGHAN 2008

Antibiotic-associated diarrhoea

Prevention of AAD

Hempel at al. JAMA 2012;307:1959-1969

Total 63 RCTs

N= 11 811 RR 0.58 (0.5 to 0.68)

Children 16 RCTs

RR 0.55 (0.38 to 0.8)

45% reduction in the risk of AAD

Number needed to treat 11

i.e. you have to treat 11 patients to prevent 1 from AAD

Number needed to treat

Intervention NNTStatins for myocardial infarction for one yearVitamin D for hip fracturesAspirin for cardiovascular protection

Slide from Dan Merenstein

Intervention NNTStatins for myocardial infarction for one year

100-427

Vitamin D for hip fracturesAspirin for cardiovascular protection

100-427

Vitamin D for hip fractures 50Aspirin for cardiovascular protection

100-427

Probiotics for prevention of AAD

AAP recommendation• Prevention of AAD – There is some evidence to support the use of

probiotics to prevent antibiotic-associated diarrhoea

Thomas et al. Pediatrics 2010;126:1217-31.

Prevention of Clostridium difficile-associated diarrhea

Johnston et al. Ann Intern Med. 2012

Probiotics (as a group) reduced risk of C. difficile-diarrhea

20 RCTs N= 3821 RR 0.34 (0.24-0.49)

Johnston et al. Ann Intern Med. 2012RCT, badanie z randomizacją

Johnston et al. Ann Intern Med. 2012

Effect size (example)S. boulardii (n=1232)

1.4% vs. 3.7%RR 0.39 (0.19-0.82)

risk 61%

November2012

TREATMENT OF CLOSTRIDIUM DIFFICILE DIARRHEA

Hot topic: Fecal microbiota transplantation (enema, colonoscopy, nasogastric tube)

• Traditional Chinese medicine (4th cent.)• Transplant «healthy» microbiota• Seems to be safe and works• Randomized clinical trial: van Nood et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med 2013

Questions: dosage, timing, standardized «healthy» microbiota?

IBD – probiotic supplementsfecal microbiota transplantation

• No effect in Crohn`s diease

• VLS#3 probiotic combination + concomindant therapy. Remission rate in ped. UC significantly higher (93 vs 36%)

• Microbiota transplantation: mild-to-moderate UC: N=10 (pediatric); Enema daily for 5 days; Family or close relation. Clinical remission at 1 week (3); clinical response at 1 mo (6); Kunde et al, JPGN, 2013

Nosocomial diarrhoea

Meta-analysis of 20 surveillance studies(Pediatrics 2012;129:e1011)

Incidence per 100 hospitalisations

Overall nRV 2.9 (1.6 – 4.4.)

nRV in children <2 y, hospitalized during the epidemic months

8.1 (6.4 – 9.9)

B. bifidum+Str. therm RR (95% CI) NNT (95% CI)Saavedra Lancet 1994

0.2 (0.06-0.8) 5 (3-20)

L. delbrueckii H2B20PennaPediatria (São Paulo) 2009

1.6 (0.6-4.0) NS

Lactobacillus GG RR (95% CI) NNT (95% CI)

Szajewska J Pediatr 2000

0.2 (0.06-0.6) 4 (2-10)

Mastretta JPGN 2002

0.8 (0.6-1.3) NS

Hojsak Pediatrics 2010

0.4 (0.25-0.7) 15 (9-34)

Prevention of nosocomial diarrhoeaWhat is known on this topic?

3 RCT, n=1043RR 0.5 (0.4 – 0.7)

NNT 13 (95% CI 9 – 28) Szajewska et al. Aliment Pharmacol Therap 2011

What is new on this topic?LGG in the prevention of nosocomial diarrhoea

Meta-analysis

L reuteri DSM 17938 in the prevention of nosocomial diarrhoea

Wanke & Szajewska. J Pediatr 2012;161:40-43.e1

In hospitalized children, the administration of L reuteri DSM

17938 compared with placebo had no effect

on the overall incidence of nosocomial diarrhea, including

rotavirus infection

To use or not to use probiotics for preventing nosocomial diarrhoea?

Lactobacillus GG Study design NNT (95% CI)

Szajewska APT 2011

Meta-analysis of 3 RCTs(n=1043)

13 (9-28)

B. bifidum+Str. thermSaavedra Lancet 1994

RCT (n=55)

5 (3-20)

L. delbrueckii H2B20PennaPediatria (São Paulo) 2009

RCT (n=139)

L reuteri DSM 17938Wanke & SzajewskaJ Pediatr 2012

RCT (n=106)

Prevention of nosocomial diarrhoeaSummary 2013

Infantile colic

• Prevalence – 3 to 40% of infants

• Rationale for the use of probiotics– An aberrant gut microbiota

in colicky infants • Lower counts of intestinal

lactobacilli• Increased concentration of

coliformis

Savino & Tarasco. Curr Opin Pediatr 2010;22:791-7.

Could something as simple as a probiotic supplement stop a colicky baby from crying so much?Newsweek, January 2011

Infantile colicL reuteri DSM 17938

RR (95% CI) NNT (95% CI)Dzień 7 1.6 (1.1-2.2) 3 (2-8)Dzień 14 2.1 (1.2-3.8) 3 (2-9)Dzień 21 1.3 (1.01-1.8) 5 (3-25)

Savino et al. Pediatrics 2010;126:e526-33.

L. reuteri DSM 17 938 at a dose of 108 CFU/d in breastfed infants improved symptoms of infantile colic and was well tolerated and

AAP 2010There may be benefit for treating infantile colic with

probiotics, but further studies are necessary.

Day 0 Day 21 0

Day 7Day 14Day 21

Day 7 Day 14 Day 21

Treatment success Reduction on the daily average crying time ≥50%

Day 7 Day 14 Day 21 Day 28

15 16L reuteri (n=40)Placebo (n=40)

RR (95% CI) NNT (95% CI) P value Day 7 - 7 (4 to 19) 0.026Day 14 4.3 (2.3 to 8.7) 2 (2 to 3) <0.001Day 21 3.2 (1.8 to 4.0) 2 (2 to 3) <0.001Day 28* 1.6 (1.3 to 2.1) 3 (2 to 5) <0.001 * Follow-up visit 1 week after the termination of the intervention

Szajewska, Gyrczuk, Horvath. J Pediatr 2013;162:257-262

Duration of crying

Throughout the study period, the crying time was significantly reduced in the

probiotic group compared with the placebo group

Parental percetion of colic severity Family quality of life

Throughout the study period, in the probiotic group compared with the placebo group:

• reduction in the parental perception of colic severity

• improved parental/family quality of life throughout the study

Conclusion Exclusively or predominantly breastfed infants with infantile colic benefit from

the administration ofL reuteri DSM 17938 compared with

placebo.

Infantile colicL reuteri DSM 17938

Feb2013

How this intervention might work?• ?• The effect of L reuteri on

– gut motility – colonic sensory nerves– colon contractile activity– pain perception

• Additional mechanisms include – anti-inflammatory effects documented both in vitro and in vivo– interaction with altered gut microbiota.

Kunze et al. J Cell Mol Med. 2009;13(8B):2261-70.Wang et al. Neurogastroenterol Motil 2010;22:98-107, e33.Ma et al. Am J Physiol Gastrointest Liver Physiol 2009;296:G868-75Indrio et al. J Physiol Pharmacol 2009;60(suppl 6):27-31.

The use of L reuteri could be discussed with caregivers

Prevention of NEC

Controversy

‘It is time to change practice’‘Probiotics: are we ready for routine use?’

A common criticism

Mixing apples & oranges

Current recommendationsESPGHAN 2009 AAP 2010 ASPEN 2012

No No No Efficacy and safety

should be established for each product.

Further studies are needed.

There is some evidence that

probiotics prevent NEC in VLBW infants

(birth weight between 1000 and 1500 g), but

more studies are needed.

There are insufficient data to recommend the use of probiotics in infants at risk for

NEC.Further research

needed.

JPGN 2009;49:1-9. Pediatrics 2010;126:1217-31. JPEN 2012;36:506-23.

Some researchers consider that the current evidence justifies the

routine use of probiotics

Deshpande et al. BMC Med. 2011;9:92.

Take home messageCan probiotics prevent/treat

disease in pediatrics?Yes, but all probiotics are not

created equal.

Respiratory tract infections

>5 y – 5 episodes/year <5 y – 3 episodes/year

Probiotics for preventing acute upper respiratory tract infections

Cochrane review 2011

Probiotics were better than placebo in reducing

the number of participants experiencing episodes of

acute URTIs

the rate ratio of episodes of acute URTI

antibiotic use

Lactobacillus GG for preventing acute respiratory tract infections

Population Dose Duration Effect

Hatakka BMJ 2001

N=571 1-6 y

≈108 CFU 7 mo (winter)

LGG may reduce RTI and their severity

Kumpu EJCN 2012

N=523 2-6 y

≈108 CFU 7 mo(Oct-Apr)

LGG reduced RTI in the completed cases (in terms of recovery of LGG in fecal samples), but not in the total population

Hojsak Clin Nutr 2009

N=281 1-7 y

109 CFU 3 mo (Nov-Feb)

LGG can be recommended for decreasing the risk of upper RTI

Total 1375

Population Dose Duration Effect

Hatakka BMJ 2001

N=571 1-6 y

≈108 CFU 7 mo (winter)

LGG may reduce RTI and their severity

Kumpu EJCN 2012

N=523 2-6 y

≈108 CFU 7 mo(Oct-Apr)

LGG reduced RTI in the completed cases (in terms of recovery of LGG in fecal samples), but not in the total population

Hojsak Clin Nutr 2009

N=281 1-7 y

109 CFU 3 mo (Nov-Feb)

LGG can be recommended for decreasing the risk of upper RTI

Total 1375Hojsak Clin Nutr 2009

N=742 hospital

109 CFU URTI RR 0.38 (0.2-0.85)

Upper RTI (n=794)RR 0.7 (0.55 to 0.9)

NNT 8 (5 to 15)

All RTI (n=1295)RR 0.8 (0.5 to 1.3)

Szajewska 2012 (unpublished)

Use of antibioticsRR 0.89 (0.78 to 1.02)

Szajewska 2012 (unpublished)

How the intervention might work

Forsythe P. Chect 2011;139:901-908.

Following immune

challenge in the airway, cells

activated in GALT traffic to the respiratory

mucosa where they promote protective and

antiinflammatory responses.

Microbes in the intestine are sampled

by DC directly or following

translocation through M cells to the

Phenotypic changes in the

DC and the production of

Th1 type and/or

regulatory mediators

Activation of IDO

(indolamine 2,3

dioxygenase) and

subsequent production of

KYN (kynurenine)

promotes Tregs and

depletes Th2 cells.

Probiotics for preventing allergyData from (some) RCTs

Probiotic(s) Before delivery

After delivery

Outcome (AD)

Effect

LGG 4 wk 6 mo 2,4,7 y YesLGG 6 wk 6 mo 2 y No LGG From 36 wk of

gestationUntil

delivery 1 y No

L acidophilus LAVRI A1 - 6 mo 2.5 y No L reuteri ATCC 55730

6 wk 12 mo 2 yNo

Yes (IgE eczema)

BL999 + LPR - 6 mo 1 y No L rhamnosus HN001 From 35 wk of

gestation 6 mo 2 y/4 yYes/Yes

B animalis subsp. lactis No/No B bifidum & B lactis & L acidophilus 4-8 wk 6 mo 1 y Yes

BL999 +LPR8 wk 2 mo 2 y Yes

BL999 + ST11 Yes

Probiotics for preventing allergyMeta-analysis

Cochrane review 2007Allergic disease or food hypersensitivity

Insufficient evidence to recommend probiotics

Lee JACI 2008 Atopic dermatitis ✔

Betsi Am J Clin Dermatol 2008Atopic dermatitis ✔ (especially LGG)

Doege Br J Nutr 2012Atopic eczema ✔

Pelucchi Epidemiology 2012Atopic dermatitis ✔

Probiotics supplementation during pregnancy or infancy for the prevention of

atopic dermatitis

Pelucchi et al. Epidemiology 2012:23:402-14.

18 publications based on 14 RCTsRR 0.79 (0.71 to 0.88)

Probiotics supplementation during pregnancy or infancy for the prevention of

atopic dermatitis

Moderate role of probiotics in the prevention of AD and IgE-associated AD in infants.

The favorable effect was similar regardless of the time of probiotic use (pregnancy or early life) or the subject(s) receiving

probiotics (mother, child, or both)

Would you recommend use of probiotics to prevent/treat allergic

disease in your patients?

AAP recommendation• The results of some studies support the

prophylactic use of probiotics during pregnancy and lactation and during the first 6 mo of life in infants who are at risk of atopic disorders

• Further confirmatiory evidence is necessary before a recommendation for routine use can be made.

Thomas et al. Pediatrics 2010;126:1217-31.

All probiotics are not created

What is new?

Design RCT, double-blind Participants Mothers & infants at high risk of allergy

Intervention • L rhamnosus HN001 • B animalis subsp. lactis HN019 From 35 wk gestation until 6 mo if brestfeeding and infant supplementation until 2 y

Comparison • Placebo

Primary outcome Allergic disease & sensitisation at 2 & 4 y (90% participated in follow-up)

L rhamnosus HN001,but not B animalis subsp lactis HN019,

reduced the cumulative prevalence of eczema, but not atopy, by 2 & 4 years.

At 2 years At 4 years

Intervention until 2 y Intervention until 2 y

One of a very few studies to separately evaluate 2 different

probioticsWickens et al. Clin Exp Allergy 2012;42:1071-9.

Maternal supplementation with LPR and BL999 or ST11 and BL999

during pregnancy and breastfeeding reduces the risk of eczema in the

infant

Rautava et al. JACI 2012;130:1355-60.

Ferdinand Haschke Medical University of Vienna, Austria

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