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Probiotics in Gastrointestinal Problems
Badriul HegarDepartment of Pediatric, University of Indonesia
GASTROINTESTINAL TRACT
100.000 billion bacteria80% of all antibody producing cells
barrier between in- and out-side world
GALT Gut Associated Lymphoid Tissue
The immune system of gastrointestinal tract The largest mass of lymphoid tissue in the human bodyimportant element of the total immunologic capacity
Microorganisms and food are necessary for development of GALT
Ruthlein. 1992
Microflora in Gastrointestinal Tract
Gibson, GR & Roberfroid, MB; 1994
Lactobacilli
EubacteriaBifidobacteria
Ps-AeruginosaProteus
Staphylococci
Veillonellae
EnterococciE. coli
Streptococci
Bacteroides
Clostridia
Production of toxin;diarrhea, constipation;
Infection; liver demage;cancer; encephalopathy
Production of carcinogenic
Intestinal putrefaction
Inhibition of growth of exogenous and/or harmful bacteria
Stimulation of immune function
Aid in ingestion and/or absorption of food ingridient/minerals
Synthesis of vitamins
Health promoting functionPathogenic effects
Probiotic Concept
( Fuller & Gibson, 1997 )
‘mothers’ milk does not contain probiotic bacteria
FAO/WHO recommended definition:Probiotics: ‘Live microorganisms which when administered in adequate amounts confer a health benefit on the host’
Importance of Probiotics
Activation of the immune system
Synthesis of vitamins, enzymesLowering
pH in environmentCompetitive bindingon intestinal mucosa
• more resistance to enteric infections• the development of a immune system - adequate oral tolerance
The Immune System Defence
Mechanical defenceskin, mucosa, mucus layer
Biological defencemicro flora
Chemical defenceSCFA, acidic pH
Immunological defenceantibodies, cytokines,
WBC, macrophages
Main Objective of Probiotic Therapy
“to restore colonization resistance until the normal flora becomes reestablished”
Probiotics: Clinical Evidence
• Multiple randomized trials, meta-analysis1. Treatment of acute gastroenteritis2. Prevention of antibiotic-associated diarrhea
• Small or single randomized trials1. Prevention of Ulcerative Colitis relapse2. Alleviation of symptoms associated with IBS3. Necrotizing enterocolitis prevention and reduced severity4. Atopic dermatitis & allergies
Probiotics for treating infectious diarrheaEffects of probiotics in proven or presumed infectious diarrhea
Infectious diarrhea
Allen S. Cochrane Database Syst Rev. 2004;2:CD003048
23 studies met inclusion criteria (randomised, blind) • 1917 participants/countries with low overall mortality rates• varied in probiotic(s) tested
dosage, methodological qualitydiarrhea definitions, outcome
Probiotics reduce the risk of diarrhea at 3 days relative risk 0.66, 95% confidence interval 0.55 to 0.77, random effects model; 15 studies
and the mean duration of diarrhea by 30.48 hours 95% confidence interval 18.51 to 42.46 hours, random effects model, 12 studies
Adherence of probiotic bacteria to human intestinal mucus in healthy infants and during ROTAvirus infection Juntunen M. Clin Diagn Lab Immunol 2001;8:293-6
20 infants with ROTA / 10 control infantsAdherence L. Rhamnosus GG 34 %
Bifidobacterium Bb12 31 % L. Acidophilus LA5 4 %L. Paracasei F19 3 %
• Adherence pattern not influenced by ROTA• Adherence of Bb12 in presence of L. rhamnosus GG (synergetic!) in healthy infants 31 39 % (p = 0.018)
in diarrhea episodes 26 44 % (p = 0.001)
Infectious diarrhea
ORS +/- Lact. GG (clinical, previous AB, pathogen, ORS intake: NS)
Lactobacillus Placebo pAll 147 140Duration diarrhea 110.4 + 28.1 122.9 + 33.0 < 0.03
Rotavirus only 56 45Duration diarrhea 114.7 + 16.2 136.3 + 29.0 < 0.008
Invasive causes only 27 26Duration diarrhea 124.0 + 46.4 120.8 + 44.1 NS
weight gain : NS; no side effects
Randomized double blind studies with LactobacillusS. Guandalini et al. JPGN 2000;30:54-60
Probiotics in prevention of nosocomial diarrhea in infantsSzajewska H. J Pediatr 2001;138:361-5
81 children ; 1 - 36 months, hospitalized (reason: not diarrhea)Lactobacillus GG -- placebo
risk LGG Placebonosocomial diarrhea (> 3 loose stools / 24 hrs) 6.7 33 %relative risk 0.2 (95 % CI 0.06 - 0.6)
prevalence rota-pos 20 27.8%relative risk 0.72 (95 % CI 0.33 - 1.56)
risk ROTA-Gastroenteritis 2.2 17%relative risk 0.13 (95% CI 0.02 - 0.79)
reduction nosocomial ROTA-gastroenteritis
Efficacy of probiotic use in acute diarhea in children: a meta-analysisHuang JS. Dig Dis Sci 2002;47:2625-34
pooled effects : - 0.8 days (- 1.1 to – 0.6 days) (p<0.001)
Lactobacillus therapy for acute infectious diarrhea in children: a meta-analysis. C.W. Van Niel. Pediatrics 2002;109:678-84
pooled effects: - 0.7 days (16.8 hrs) (95 % CI 0.3 - 1.2 days)
Probiotics in the treatment and prevention of acute infectious diarrheain infants and children. Szajewska H. JPGN 2001;33(Suppl2):S17-25
pooled effects: - 20.1 hours (95 % CI - 26.1 / -14.1 hrs)
Multispecies Synbiotic mixture on the duration of diarrhea and length of hospital stay in children with acute diarrhea in Turkey: Single blinded randomized study (Dinleyici EC, Vandenplas Y, Eur J Pediatr, 2012)
Abstract • a prospective randomized, multicenter single blinded clinical trial in hospitalized
children with acute watery diarrhea.• Lactobacillus acidophilus, Lactobacillus rhamnosus, Bifidobacterium bifidum,
Bifidobacterium longum, Enterococcus faecium, and 625 mg fructooligosaccharide) for 5 days
Result • The duration of diarrhea was significantly shorter ( 36 h) in children receiving the ∼
synbiotic group than the controls (77.9±30.5 vs. 114.6± 37.4 h, p<0.0001). • The duration of hospitalization was shorter in children receiving the synbiotic group
(4.94±1.7 vs. 5.77±1.97 days, p00.002).
Treatment of Acute Diarrhea
Probiotics reduce diarrhea duration and frequency
Dose-dependent with 1010 CFU/day effective Pediatr 2002;109:678-684 (meta-analysis)
Reduced diarrhea by 30.5 hours
The Cochrane Library, Issue 2, 2005. (meta-analysis)
Early use of probiotics greater benefit Pediatr Infect Dis J 2002;21:417-419
Probiotics in Prevention of Antibiotic Associated Diarrhea
• AAD : rate : 5 to 39 %• uncomplicated diarrhoea <--> severe colitis (pseudomembranes)• pathogenesis: disruption of normal flora
overgrowth pathogensmetabolic imbalances
Aliment Pharmacol Ther 2002;16:1461-67; Aliment Pharmacol Ther. 2005 Sep 1;22(5):365-372
Meta-analyses : Probiotics benefit for prevention of antibiotic-associated diarrhea
Probiotics for the Prevention and Treatment of Antibiotic-Associated DiarrheaA Systematic Review and Meta-analysis. JAMA. 2012;307(18):1959-1969
Results : A total of 82 RCTs met inclusion criteria. The majority used Lactobacillus based interventions alone or in combination with other genera; strains were poorly documented.
Conclusions• The pooled evidence suggests that probiotics are associated with
a reduction in AAD. • More research is needed to determine which probiotics are associated with the
greatest efficacy and for which patients receiving which specific antibiotics.
RR (95%CI) Lactobacillus GG Arvola (n=119) 0.3 [0.09, 1.1]
Vanderhoof (n=188) 0.3 [0.13, 0.6] 0.30 [0.15, 0.6] NNT 7 (5-13)
L. acidophilus/B. infantis Jirapinyo (n=18) 0.5 [0.18, 1.21]
L. acidophilus/L. bulgaricus Tankanow (n=38) 0.96 [0.61, 1.50]
B. lactis/Str. thermophilus Correa (n=80) 0.5 [0.29, 0.95] NNT 7 (4-62)
Prevention of antibiotic-associated diarrhea in children
1
77 subjects with IBS : Lactob saliv UCC4331; Bifidobact infantis 35624; placeboin a dose of 1 x 1010 live bacterial cells, 8 weeks
Patient with IBS showed an abnormal IL-10/IL-12 ratio, indicative of a pro-inflammatory, Th-1 state. this ratio was normalized by B infantis 35624 feeding alone.
Conclusions - B infantis 35624 alleviates symptoms in IBS; - Suggesting an immune-modulating role in this disorder
Probiotics in Irritable Bowel Syndrome (IBS): symptom responses and relationship to cytokine profiles.
O'Mahony L. Gastroenterology. 2005;128:541-51
Probiotics in IBS in children
• RCT, N=50, age 6-20 years, IBS (Rome criteria) • Intervention : LGG or placebo, 6 weeks • Gastrointestinal Symptom Rating Scale
Response rate • 44% vs. 40%, p=0.8• Lower incidence of perceived abdominal distention in
LGG group
Bausserman J Pediatr 2005;147:197-201
Clinical evidence for bacteria in the pathogenesis of Inflamatory Bowel Diseases
CD UC PouchitisDisease in area of bacterial concentration
Terminal ileum, colon
Colon Ileal pouch
Mucosal adherence + + ? Mucosal invasion + + ? Inflammation by bowel rest + - +Response to antibiotics Colon - +Pathogenetic immune response to bacteria
+ + ?
Exacerbation by pathogens + + ?
Sartor Gastroenterology 2004; 126: 1620-33
N : 75 (5-21 years)CD in remission Follow-up 2 years
Relapse LGG 31% vs. placebo 17%RR 1.9 (0.8 to 4.4)
Time to relpase - 9.8 vs. 11 months (p=0.24)
Bousvaros et al. Inflamm Bowel Dis 2005;11:833-9
LGG vs placebo in addition to standard maintenance therapy for children with IBD (Crohn’s disease)
PROBIOTICS and H.pylori
• Attachment inhibition to stomach mucosa (L.salivarus)
• Antagonistic activity in vitro
• Inhibition related to the acid production
• Higher eradication rate by triple therapy plus L. acidophilus (87% vs. 70%)
Lorca GL. Curr Microbiol 2001;42:39-44
Probiotics can be added to all of the regimensto improve compliance by decreasing adverse events.
Update on Therapeutic Options for Helicobacter pylori related Diseases
Benefit for H. pylori in patients related to better tolerance of antibiotics
Megraud F. Curr Infect Dis Rep. 2005 Mar;7(2):115-120; Aliment Pharmacol Ther 2002;16:1669-1675
Effect of different probiotic preparations on anti-H. pylori therapy-related side effects. Cremonini F. Am J Gastroenterol. 2002;97:2744-
85 H. pylori positive, asymptomatic patients randomized in 4 groupsprobiotic or placebo both during and for 7 days after a 1-wk triple therapy scheme omeprazole 20 mg b.id
clarithromycin 500 mg b.i.d.tinidazole 500 mg b.i.d.
Group I (n = 21) Lactobacillus GGGroup II (n = 22) Saccharomyces boulardiiGroup III (n = 21) Lactobacillus spp. and bifidobacteriaGroup IV (n = 21) placebo
H. pylori eradication rate almost identical between the probiotic and placebo groups
Effect of longterm consumption of Bifidobacteria on stool patterns
Saavedra, JPGN 2000;31(Suppl 2)
High suppl Low suppl Placebo
Hard Stool 37.8 (°) 29.4 (#) 42.5
Soft Stool 62.0 (°) 70.3 (#) 56.7 Loose Stool 2.7 3.0 3.3
# : p < 0.001 vs placebo; ° : < 0.03 vs placebo
84 children (2-16 years) with constipation (<3 bowel movements /wk) > 12 weeks
1 mL/kg/day of 70% lactulose + 109 CFU of LGG + placebo 2x/day, 12 weeks
n : 43 41treatment success (>3 BMs/week with no fecal soiling)
at 12 weeks 28/41 [68%] 31/43 [72%] (p 0.7) at 24 weeks 27/41 [65%] 27/42 [64%] (p 1.0)
Ineffectiveness of Lactobacillus GG as an adjunct to lactulose for the treatment of constipation in children
(DBPCR trial)
Constipation
Banaszkiewicz A. J Pediatr 2005;146:364-9.
What makes a good probiotic strain?
• Be safe for the consumer
• Be delivered alive to the gut Process technology to stabilize microbes for long-term storage
• Remain alive in the gutResist gastric acid and bile and other microbes
• Have proven efficacy Documentation on pharmacodynamics, pharmacokinetics and clinical efficacy.
A proven bacteria effect of one strain or species cannot be transferred to another
controlled clinical studies comparing different types of bacteria for a specific indication
are warranted
Functionality of a multistrain/ Multispecies Probiotics could be more effective than that of a monostrain
(Timmerman et al, Int. J. Food Microbiol. 96, 2004)
Strains used in multistrain probiotics should be compatible & synergistic,
so the design and use of multistrain probiotics need to be studied well before use.
(Kosin & Rakshit, Food Technol. Biotechnol. 44 (3). 2006)
All probiotics appear equal,just some strains
are more equal than others
‘All animals are equal, just some animals
are more equal than others’George Orwell
Probiotics in GI disease COMBINATION - INTERACTION
Mechanismsof action
Clinical studies
Quality of the gastrointestinal health
Composition of intestinal flora
Contact with the “good” microbes…
Thank you