Ferdinand Haschke Medical University of Vienna, Austr Nestle Nutrition Institute, Vevey,Switzerla Probiotics – Do They Work? Prevention/Treatment of GI disease in pediatrics?
Feb 23, 2016
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.
10:1
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.
IBD
Diabetes
NEC
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
RCTs
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
J Pediatr Gastroenterol Nutr 2011;52:238-50.
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
J Pediatr Gastroenterol Nutr 2011;52:238-50.
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
Number needed to treat
Intervention NNTStatins for myocardial infarction for one year
100-427
Vitamin D for hip fracturesAspirin for cardiovascular protection
Slide from Dan Merenstein
Number needed to treat
Intervention NNTStatins for myocardial infarction for one year
100-427
Vitamin D for hip fractures 50Aspirin for cardiovascular protection
Slide from Dan Merenstein
Number needed to treat
Intervention NNTStatins for myocardial infarction for one year
100-427
Vitamin D for hip fractures 50Aspirin for cardiovascular protection
40
Slide from Dan Merenstein
Number needed to treat
Intervention NNTStatins for myocardial infarction for one year
100-427
Vitamin D for hip fractures 50Aspirin for cardiovascular protection
40
Probiotics for prevention of AAD
11
Slide from Dan Merenstein
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.
All probiotics are not created equal
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
All probiotics are not created equal
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)
NS
L reuteri DSM 17938Wanke & SzajewskaJ Pediatr 2012
RCT (n=106)
NS
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
safe
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
5
30
40 40
07
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
Szajewska, Gyrczuk, Horvath. J Pediatr 2013;162:257-262
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
Szajewska, Gyrczuk, Horvath. J Pediatr 2013;162:257-262
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
2012
2001
2009
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
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 1375Hojsak Clin Nutr 2009
N=742 hospital
109 CFU URTI RR 0.38 (0.2-0.85)
Lactobacillus GG for preventing acute respiratory tract infections
Lactobacillus GG for preventing acute respiratory tract infections
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)
NS
Szajewska 2012 (unpublished)
Lactobacillus GG for preventing acute respiratory tract infections
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
GALT.
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
equal
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)
2012
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.
2012
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.
2012