Probiotics in

Gastrointestinal Problems
Badriul Hegar
Department of Pediatric, University of Indonesia

GASTROINTESTINAL
TRACT
100.000 billion bacteria
80% 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 body
important element of the total immunologic
capacity
Microorganisms and food are necessary
for development of GALT
Ruthlein. 1992

Microflora in Gastrointestinal Tract

Pathogenic effects

Health promoting function

Ps-Aeruginosa
Production of toxin;
diarrhea, constipation;
Infection; liver
demage;cancer;
encephalopathy

Proteus

Inhibition of growth of
exogenous and/or
harmful bacteria

Staphylococci
Clostridia
Veillonellae

Production
of carcinogenic

Stimulation of immune
function

Enterococci
E. coli

Lactobacilli

Intestinal putrefaction

Streptococci

Eubacteria
Bifidobacteria
Bacteroides

Aid in ingestion and/or

absorption of food
ingridient/minerals

Synthesis of vitamins

Gibson, GR & Roberfroid, MB; 1994

Probiotic Concept
FAO/WHO recommended definition:
Probiotics: Live microorganisms which when
administered in adequate amounts confer a
health benefit on the host

mothers milk does not contain probiotic bacteria

( Fuller & Gibson, 1997 )

Importance of Probiotics

Competitive
binding
on intestinal
mucosa

Lowering
pH in environment

Synthesis of
vitamins, enzymes

Activation of the immune

system

more resistance to enteric infections

the development of a immune system - adequate
oral tolerance

The Immune System Defence

Mechanical defence
skin,
skin, mucosa, mucus layer

Immunological defence
antibodies,
antibodies, cytokines,
cytokines,
WBC,
WBC, macrophages

Biological defence
micro
micro flora
flora

Chemical defence
SCFA,
SCFA, acidic
acidic pH
pH

Main Objective of Probiotic

Therapy
to restore colonization resistance until the normal
flora
becomes reestablished

Probiotics: Clinical Evidence

Multiple randomized trials, meta-analysis
1. Treatment of acute gastroenteritis
2. Prevention of antibiotic-associated diarrhea
Small or single randomized trials
1. Prevention of Ulcerative Colitis relapse
2. Alleviation of symptoms associated with IBS
3. Necrotizing enterocolitis prevention and
reduced severity
4. Atopic dermatitis & allergies

Infectious
diarrhea
Probiotics for treating infectious
diarrhea
Effects of probiotics in proven or presumed
23 studies met inclusion
criteria (randomised, blind)
infectious
diarrhea
1917 participants/countries with low overall mortality rates
varied in
probiotic(s) tested
dosage, methodological quality
diarrhea 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
Allen S. Cochrane Database Syst Rev. 2004;2:CD003048

Infectious
diarrhea

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 infants

AdherenceL. 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)

Randomized double blind studies with

LactobacillusS. Guandalini et al. JPGN 2000;30:54-60
ORS +/- Lact. GG (clinical, previous AB, pathogen,
ORS intake: NS)
Lactobacillus
Placebo
All
147
140
Duration diarrhea
110.4 + 28.1
< 0.03
Rotavirus only
Duration diarrhea
< 0.008

56
114.7 + 16.2

Invasive causes only

27
Duration diarrhea
124.0 + 46.4

p
122.9 + 33.0
45
136.3 + 29.0
26
120.8 + 44.1

Probiotics in prevention of nosocomial

diarrhea in infants
reduction Szajewska
nosocomial
ROTA-gastroenteritis
2001;138:361-5
Szajewska H.
H. JJ Pediatr
Pediatr
2001;138:361-5

81 children ; 1 - 36 months, hospitalized (reason: not diarrhea)

Lactobacillus GG -- placebo

risk

LGG

Placebo

nosocomial 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
relative risk 0.13 (95% CI 0.02 - 0.79)

2.2

17%

fficacy of probiotic use in acute diarhea in children: a meta-analysis

ang JS.
uang
JS. Dig
Dig Dis
Dis Sci
Sci 2002;47:2625-34
2002;47:2625-34

ooled 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.
C.W. Van
Van Niel.
Niel. Pediatrics
Pediatrics 2002;109:678-84
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 diarrhea
in infantseffects:
and children.
H.
pooled
- 20.1 Szajewska
hours
(95
% 2001;33(Suppl2):S17-25
CI
- 26.1 / -14.1
Szajewska
H. JPGN
JPGN
2001;33(Suppl2):S17-25
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 (77.930.5
vs. 114.6 37.4 h, p<0.0001).
The duration of hospitalization was shorter in children
receiving the synbiotic group (4.941.7 vs. 5.771.97 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 pathogens
metabolic imbalances

Meta-analyses : Probiotics benefit for

prevention of antibiotic-associated
diarrhea
Aliment Pharmacol Ther 2002;16:1461-67; Aliment Pharmacol Ther. 2005 Sep 1;22(5):365-372

Probiotics for the Prevention and Treatment

of Antibiotic-Associated Diarrhea
A Systematic Review and Meta-analysis. JAMA. 2012;307(18):19591969

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.

Prevention of antibiotic-associated
diarrhea
in children
RR (95%CI)
0.3 [0.09, 1.1]
0.3 [0.13, 0.6]

Lactobacillus GG
Arvola (n=119)
Vanderhoof (n=188)

0.30 [0.15, 0.6] NNT 7 (513)

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)

1

Probiotics in Irritable Bowel

Syndrome (IBS):
symptom responses and relationship to
cytokine profiles.
O'Mahony L. Gastroenterology. 2005;128:541-51

77 subjects with IBS : Lactob saliv UCC4331; Bifidobact infantis

35624; placebo
in 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;

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
Terminal ileum,
colon

UC
Colon

Pouchitis
Ileal pouch

Mucosal adherence

Mucosal invasion

Inflammation by bowel rest

Response to antibiotics
Pathogenetic immune response
to bacteria
Exacerbation by pathogens

Colon
+

+
?

Disease in area of bacterial

concentration

Sartor Gastroenterology 2004; 126: 1620-33

LGG vs placebo in addition to standard

maintenance therapy for children with IBD
(Crohns disease)
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

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

Update on Therapeutic Options

for Helicobacter pylori related
Diseases
Probiotics can be added to all of the regimens
to improve compliance by decreasing adverse
Benefit for H. pylori in patients
events.of antibiotics
related to better tolerance

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
Cremonini F.
F. Am
Am JJ
Gastroenterol.
Gastroenterol.
2002;97:274485 H. pylori 2002;97:2744positive, asymptomatic

patients randomized in 4

groups
probiotic 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
Group
Group
Group

I
II
III
IV

(n = 21)
(n = 22)
(n = 21)
(n = 21)

Lactobacillus GG
Saccharomyces boulardii
Lactobacillus spp. and bifidobacteria
placebo

H. pylori eradication rate almost identical

between the probiotic and placebo groups

Effect of longterm consumption of

Bifidobacteria on stool patterns
Saavedra,
Saavedra, JPGN
JPGN 2000;31(Suppl
2000;31(Suppl 2)
2)

Placebo
Hard Stool
Soft Stool
Loose Stool
3.3

High suppl
37.8 ()

Low suppl
29.4 (#)

62.0 () 70.3 (#)

2.7

56.7

3.0

# : p < 0.001 vs placebo; : < 0.03 vs placebo

42.5

Constipation
Ineffectiveness of Lactobacillus GG as an
adjunct to lactulose for the treatment of
constipation in children (DBPCR trial)
84
84children
children(2-16
(2-16years)
years)with
withconstipation
constipation
(<3
(<3bowel
bowelmovements
movements/wk)
/wk)>
>12
12weeks
weeks

11 mL/kg/day
mL/kg/day of
of 70%
70% lactulose
lactulose
9
+
+ 10
109 CFU
CFU of
of LGG
LGG +
+ placebo
placebo 2x/day,
2x/day, 12
12
weeks
weeks
nn ::
43
41
43
41
treatment
treatment success
success (>3
(>3 BMs/week
BMs/week with
with no
no fecal
fecal
soiling)
soiling)
at
28/41
31/43
at 12
12 weeks
weeks
28/41 [68%]
[68%]
31/43 [72%]
[72%]
Banaszkiewicz A. J Pediatr 2005;146:364-9.
(p
(p 0.7)
0.7)

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 gut

Resist 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.

All animals are equal,

just some animals
are more equal than
others
George Orwell

All probiotics appear

equal,
just some strains
are more equal than
others

Probiotics in GI disease
COMBINATION - INTERACTION

Mechanisms
of action

Clinical
studies

Composition of intestinal
flora

Quality of
the gastrointestinal
health

Contact with the good

microbes

Thank you