This document discusses the role of probiotics and prebiotics in children. It begins by defining probiotics as live microorganisms that provide health benefits when consumed in adequate amounts. The document then reviews evidence on the use of probiotics for conditions like infectious diarrhea, antibiotic-associated diarrhea, pouchitis, ulcerative colitis, and necrotizing enterocolitis in preterm infants. It finds that probiotics can shorten the duration of infectious diarrhea, prevent antibiotic-associated diarrhea, help maintain remission of pouchitis, and reduce the risk of necrotizing enterocolitis in preterm infants. It emphasizes the need for further research to identify the most effective probiotic strains, doses, and treatment durations

1. Role of Probiotic & prebiotic
in children
Dr. Vishnu Biradar
Pediatric Gastroenterologist, Pune
Mobile no. 08600800123
E Mail ID : vishnubiradar@gmail.com

2. Outline
 What are probiotics and how do they work
 Clinical efficacy of probiotics and review of evidence
 Issues in prescribing their use
 What are prebiotics and review of evidence

3. What are Probiotics
and how do they work

4. Probiotics: definitions
 World Health Organization:
 “live microorganisms which when administered in adequate amounts
confer a health benefit on the host”
 Criteria:
 Human origin
 Nonpathogenic
 Resistance to processing
 Survives the stomach acid and bile
 Adheres to intestinal lining
 Grows and establishes temporary residence in the intestines
 Imparts health benefits
R Fuller. Probiotics: The Scientific Basis. London: Chapman and Halls. 1992

5. Probiotics
 Lactobacillus sp.
 reuteri
 casei
 Ramnosus GG
 acidophilus
 Streptococcus sp.
 Bifidobacterium sp.
 infantis
 lactis
 longum
 breve
 bifidum
 Sacharomyces boulardii
(non-human)
 VSL # 3
 4 strains of Lactobacillus
 3 strains of Bifidobacterium
 1 strain of Streptococcus

6. What’s the mechanism?
 The mechanism for the benefits of probiotics are incompletely
understood.

7. Mechanism of Action
 Suppression of growth or
epithelial binding/invasion by
pathogenic bacteria
 1. Decrease luminal pH
 2. Secrete antimicrobial
peptides
 3. Inhibit bacterial
invasion
 4. Block bacterial
adhesion to epithelial
cells
 5. Competition for
nutrients
 Enhancement of intestinal
barrier function.
 1. Increase mucus
production
 2. Decrease chloride and
water secretion
 3. Bind epithelial cells at
their apical junctions
through tight junction
proteins

8. Mechanism of Action
 Modulation of the immune
system.
 1. Induce protective
cytokines (IL-10 and
TFG-beta)
 2. Suppress
proinflammatory
cytokines (TNF)

9. Clinical efficacy of
probiotics and review
of evidence

10. 1. Infectious diarrhea
Van Niel et al. 2002
Systematic review of 9 studies (all outside US, 1-36 months)
Various probiotics (4 used L GG)
Mean reduction in diarrhea of 0.7 days (95% CI: 0.3-1.2)
1.6 fewer stools in L GG groups (95% CI: 0.7-2.6)
Dose response curve with higher L GG dose
Lactobacillus is most effective above a threshold dose ( 10
billion CFU ) during first 48 hours on onset of diarrhea
Van Niel et al. Lactobacillis therapy for acute watery diarrhea
in children: A Meta-analysis. Pediatrics 2002;109;678-84

11. Infectious diarrhea
Van Niel et al. Lactobacillis therapy for acute watery diarrhea
in children: A Meta-analysis. Pediatrics 2002;109;678-84

12. Infectious diarrhea
 Szajewska et al. 2007
 Five RCT (619) participants
 Age group 2 – 12 yrs
 S boulardii 250-750 mg daily for 5-6 days
 significant reduction in duration of diarrhea by – 1.1 day and
reduction in risk of diarrhea lasting > 7 days (RR 0.25, 95%
CI: 0.08–0.83; NNT 5, 95% CI: 3–20).
Szajewska et al.Meta-analysis : S boulardii for treating
acute diarrhea in children. Aliment Pharmaco Ther 25,257-64

13. Szajewska et al. Meta-analysis
Szajewska et al.Meta-analysis : S boulardii for treating
acute diarrhea in children. Aliment Pharmaco Ther 25,257-64

14. Issues of probiotics in infectious
diarrhea
 Limitations
 Studies funded by
pharmaceutical and food
companies, so possible
role of publication bias
 Methodological limitation
 No ITT analysis
 No proper blinding
 No objective assessment
of stool volume and
consistency
 Future directions for further
studies
 Assessment of diarrhea
output by quantitative
measurement
 Further delineate groups
(OPD vs IPD, older vs younger,
viral vs other etiologies of
diarrhea)
 To address cost effectiveness
of probiotics
 To determine the most
effective dosing schedule

15. Indian studies of probiotics in
infectious diarrhea :evidence
 S basu et al. 2003
 646 children, over 1 yr period
 LGG ~ 60 million
 Rotavirus ~ 75.85%
S basu et al. Efficacy of Lactobacillus rhamnosus GG in acute watery diarrhoea of Indian children:
A randomised controlled trial Journal of Paediatrics and Child Health 43 (2007) 837–842

16. S Basu et al. LGG in AWD in
Indian children: A RCT
 Reason being very low dose (60 milliion) of LGG used as compared to 1010
S basu et al. Efficacy of Lactobacillus rhamnosus GG in acute watery diarrhoea of Indian children:
A randomised controlled trial. Journal of Paediatrics and Child Health 43 (2007) 837–842

17. Indian studies of probiotics in
infectious diarrhea :evidence
 S Basu et al : RCT
 Age < 2 yrs, 622 patients
 Divided in 3 groups (A.ORS, B.ORS + LGG 1010 and C.ORS +
LGG 1012 dose)
 Rotavirus ~ 57%
S Basu et al. J clin Gastroenterology, 2009; 43(3) : 208-13

18. Indian studies of probiotics in
infectious diarrhea :evidence
S Basu et al. J clin Gastroenterology, 2009; 43(3) : 208-13

19. Indian studies of probiotics in
infectious diarrhea :evidence
 Sudipta Mishra et al.
 Randomised double blind placebo controlled trial, 229 infants
admitted for acute diarrhea in rural India given either 109
CFU of LGG or placebo
 Age group < 36 months
 Rotavirus 25.7%, Stool culture positivity ~ 6%, 81.9%
positive for reducing substance
 No difference in duration of diarrhea or number of stools on
day 3, 6 or 10 of Rx
Sudipta Mishra et al. J Pediatr 2009;155:129-32

20. Sudipta Mishra et al.A RCT to evaluate
the efficacy of LGG in infantile diarrhea
Sudipta Mishra et al. J Pediatr 2009;155:129-32

21. Indian studies of probiotics in
infectious diarrhea :evidence
 S Basu et al. A RCT, double blind control of LGG in persistent
diarrhea over 2 yr period
 235 patients, Mean age 4.1 yr
 Inclusion criteria: persistent diarrhea > 14 days, stool pH <
5.5, and stool reducing substance >1%
 LGG dose 60 million cells with ORS, BD for minimum of 7
days or till diarrhea stops
 Stool culture positive in 38.3%
 PEM present in 90% children
S Basu et al. J Clin Gastroenterology, 2007;41 (8) :756-60

22. S Basu et al. A RCT of LGG in
persistent diarrhea
S Basu et al. J Clin Gastroenterology, 2007;41 (8) :756-60

23. S Basu et al. A RCT of LGG in
persistent diarrhea
S Basu et al. J Clin Gastroenterology, 2007;41 (8) :756-60

24. 2.Antibiotic-associated diarrhea
(AAD)
 Johnston et al. Meta-analysis
 6 RCT, 707 children
 Daily probiotic continued till completion of
antibiotics
 4 used Lactobacillus,1 S boulardii
 Favourable results for the efiicacy of probiotics
( RR 0.43, 95% CI 0.25-0.75)
 Subgroup analysis of those studies who used > 5
billion CFU daily showed strong evidence for
prevention of AAD
 NNT is 6 patients to prevent 1 case of AAD
Johnston et al.meta-analysis .CMAJ 2006.175 (4) 377-83

25. Johnston et al.meta-analysis .CMAJ
2006.175 (4) 377-83
Johnston et al.meta-analysis .CMAJ 2006.175 (4) 377-83

26. Johnston et al.meta-analysis .CMAJ
2006.175 (4) 377-83
Johnston et al.meta-analysis .CMAJ 2006.175 (4) 377-83
 Limitation:
 Pooling of different probiotic strain
 Didn’t withstand ITT analysis because of higher losses in f/u
 Future directions:
 Engage probiotic strains and doses
 Determine effect of age
 Ensure adverse events reported
 Decrease lost to f/u cases

27. Antibiotic-associated diarrhea
 Cochrane 2008
(AAD)
 10 studies , 1986 children (aged 0 to 18 yrs)
 9/10 showed statistical significant results favouring
probiotics over active/non active controls (RR 0.49; 95% CI
0.32 to 0.74).
 However, intention to treat analysis showed non-significant
results overall (RR 0.90; 95% CI 0.50 to 1.63)
 None reported serious adverse events

28. C difficile infection
 Lynne McFarland et al. Meta-analysis.
 6 RCT on 354 patients
 Significant efficacy for
CDD (RR = 0.59, 95% CI
0.41, 0.85, p = 0.005
 Only S boulardii showed
significant reductions in
recurrences of CDD
Lynne McFarland et al.Prevention of AAD:Meta-analysis.
Am J Gastroenterol 2006;101:812–822

29. 3.Pouchitis
 T Mimura et al.
 36 patients randomized
 Remission was maintained
in 85 % on VSL # 3 and 6
% on placebo at one year
 QOL remained high in
VSL # 3 group and
deteriorated in placebo
group
T Mimura et al: VSL # 3 in maintaining remission in recurrent or refractory pauchitis
Gut 2004; 53 : 108 -114

30.  Gionchetti P et al.
Pouchitis
 40 adult cases, RCT
 After 9 months, 15 % in VSL #3 group relapsed vs 100 % in
placebo froup
 All patients relapsed after 3 months discontinuation of
VSL # 3
 Significantly fewer episodes of pouchitis (10% vs 40%) if
VSL # 3 started immediately after ileostomy closure
Gionchetti P et al. J pediatr Gastroenterol Nutrition 2004; 38 : 365-74
Gastroenterology 2003; 124 : 1202-9

31. Ulcerative colitis
 Hutnh et al : A pilot study Inflamm Bowel Dis 2009; 15 : 760-8
 18 children, age 3 -17 yr
 VSL # 3 for 8 weeks to patients for remission along with 5-
ASA and corticosteroid
 Remission was achieved in 56 % children
 Miele at al : RCT, double blind
 29 children, 1.7 – 16.1 yr
 VSL #3 along with concomitant steroid induction and
mesalamine maintenance
 Remission in 92% in VSL #3 treated group vs 36.4% in
placebo
 Relapse in 1 yr : 21.4% in VSL #3 group vs 73.3% in placebo
 Both were statistically significant
Huynh et al. Inflamm Bowel Dis 2009; 15 : 760-8
Miele et al. Am J Gastro 2009; 104: 437-443

32. Ulcerative colitis
 Cochrane review 2009
 Convention therapy does not improve overall remission rates
with mild to mod UC
 Limited evidence added to standard therapy provide modest
benefits in terms of reduction of disease activity in mild to
mod severe UC
 But clearly says that no evidence to suggest that probiotics
are superior to aminosalicylates for induction of remission in
UC

33. 4.Necrotising Enterocolitis
 Deshpande et al.
 7 RCT , 1393 infants ( Preterm < 37 weeks, Wt < 1500 gm)
 lower risk of necrotising enterocolitis (relative risk 0·36,
95% CI 0·20–0·65) in the probiotic group than in controls
 Risk of sepsis did not di er significantly ff between groups
(0·94, 0·74–1·20).
 Risk of death was reduced in the probiotic group (0·47, 0·30–
0·73)
Deshpande et al. Probiotics for prevention of necrotising enterocolitis in
preterm neonates with very low birthweight: a systematic review of randomised controlled trials
Lancet 2007 369: 1614-20

34. Necrotising Enterocolitis
Deshpande et al. Probiotics for prevention of necrotising enterocolitis in
preterm neonates with very low birthweight: a systematic review of randomised controlled trials
Lancet vol 369: 1614-20

35. Necrotising Enterocolitis
 Cochrane 2008 meta-analysis : probiotics for prevention of NEC in
preterm infants. Khalid AlFaleh et al.
 9 RCT , 1425 infants
 significantly reduced the incidence of severe stage II -III NEC
[typical RR 0.32 (95% CI 0.17, 0.60); typical RD -0.04 (95% CI
-0.06,-0.02), NNT 25]
 number of deaths was significantly lower in the probiotics group
[typical RR 0.43 (95% CI 0.25, 0.75); typical RD -0.04 95% CI (-
0.06,-0.01), NNT 25]
 No statistical difference in weight gain / sepsis / duration of
hospital stay
Enteral supplementation of probiotics reduces the risk of severe NEC
and mortality in preterm infants > 1000 g at birth

36. Issues in prescribing
use of Probiotics

37. Probiotics: issues
 Which organism to use?
 For what conditions?
 What dose?
 For How long?
 Any side effects to be aware of?
 How much does it cost?
Lactobacillus GG
Saccharomyces boulardii
VSL# 3
Acute infectious diarrhea
Prevention of AAD
Post operative pouchitis
NEC
1010 CFU/day
 Lactobacillus GG - 2% risk bloating/gas
 S boulardii – risk of fungaemia in presence other co-morbid conditions  Lactobacillus GG – not available on India
 Acute diarrhea – 5 day
 AAD – till completion of antibiotics
 Pouchitis – 9-12 months
 NEC - 2 – 4 weeks
 S boulardii –Rs 25/cap or 32/sachets
 VSL# 3 – Rs 25/cap

38. Prebiotics

39. Definition of prebiotics
 Prebiotics is an indigestible
nutrient that confers benefit
on the host by selectively
stimulating one bacterium or
a group of bacteria in the
colon with probiotic
properties.
 Fructo-oligosaccharides
 Inulin
 Gluco-oligosaccharides
 Galacto-oligosaccharides
 Isomalto-oligosaccharides
 Xylo-oligosaccharides
 Lactitol, lactulose and
lactose

40. Review of evidence:
Srinivasjois et al. Clinical nutrition 28 (2009)
237-242
 Prebiotic supplementation of formula in preterm neonates:Meta-analysis
of RCT
 4 RCT, 126 infants
 Prebiotic supplemented formula upto maximum 0.8g/dl
 Given before 40 weeks of gestation to at leat 2 weeks
 Well tolerated, result in higher stool colony counts of
bifidobacteria, reduced growth of pathogenic bacteria,
softer and acidic stools without adversely affecting weight
gain
 None of the studies designed to look for NEC or sepsis
related outcomes
 Weight gain didn’t differed into two groups
 Available evidence doesn’t support routine supplementation of
prebiotic in preterm formula

41. Take home points…
 Good evidence for:
 Acute infectious diarrhea - LGG and S boulardii 1010 dose
 Prevention of AAD - S boulardii
 Post operative pouchitis - VSL #3
 NEC
 The specific strain is important
 The dose is equally important

42. Thank you …

43. Antibiotic-associated diarrhea
(AAD)
 H Szajewska et al: meta-analysis
 Six placebo-controlled, RCTs (766 children)
 reduced the risk of AAD from 28.5% to 11.9% (relative risk,
RR, 0.44, 95% CI 0.25 to 0.77, random effect model)
 For every 7 patients that would develop diarrhea while being
treated with antibiotics, one fewer will develop AAD if also
receiving probiotics
 effectiveness of probiotics in preventing AAD in children
treated with antibiotics for any reason (mainly for
respiratory tract infections)
H Szajewska meta-analysis .J Pediatr 2006;149:367-72

44. H Szajewska et al: meta-analysis in AAD
H Szajewska meta-analysis .J Pediatr 2006;149:367-72

45. Crohn’s disease
 Bousvaros et al.
 75 children, age 5 – 21 yr
 RCT
 Follow up 2 yrs
 LGG doest not prolong time to relapse in children with CD
when given adjunct to standard therapy
Inflamm Bowel Dis 2005;11: 833-9

46. Irritable bowel syndrome
 9 RCT, 2 open studies in adults and 1 RCT in children
 10 of 12 studies report amelioration of symptoms such as
cloating, abdominal pain or colonic transit
 Limitation was short follow up
 Need studies with long follow up
Clinical practice Guidelines: JPGN 43: 550-7

47. Thank You