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