Which probiotic for acute diarrheea in children

Which Probiotic
for
Acute Diarrhea in Children?
GABY FALAKHA
PEDIATRICIAN – NEONATOLOGIST
TRIPOLI JULY 12TH, 2017

Outline
1. Definitions
2. Brief history
3. Ecology of gut microbiata
4. Types of probiotics
5. Mechanisms of action
6. Therapeutic use in Acute Diarrhea in Children
7. Conclusions

Scientific interest in probiotics has grown
significantly since 1997
NIH PubMed database
80

Scientific interest in probiotics has grown
significantly since 1997
NIH PubMed database
80
= 100 publication
per month

Introduction
 Based on our genes we are all 99,9% identical, but based on our
microbiota, we can be 90% different.
 The total number of bacteria in the GI tract is enormous. Approximately
50% of fecal mass is bacteria numbering 1012 organisms per gram.
 Therefore, our long-term destiny might be determined by the bacteria
which co-exist in our body.
 Probiotics are now intensively studied which might in the future
influence or even protect from certain diseases.
 Among those are the metabolic syndrome with diabetes Type 2, obesity,
atherosclerosis, asthma, certain cancers, depression, allergy and
inflammatory bowel disease.

Definitions
 Commensal bacteria (indigenous microbiota) These are the microorganisms that are
present on body surfaces that are covered by epithelial cells and are exposed to the
external environment (gastrointestinal and respiratory tract, vagina, skin, etc.).
Commensal bacteria are considered as self by the host's immune system.
 Intestinal dysbiosis An unnatural shift in the composition of the gut microbiota that
may result from diet (e.g., high fat), psychological or physical stress, infection,
antibiotics, or radiation that is associated with an imbalance between protective and
harmful bacteria.
 Human microbiota(microflora) Refers to the 10–100 trillion microbial cells harbored
by each person, primarily in the gut.
 Human microbiome The entire collection of genes found in all the microbes
associated with a particular host.
 Human metagenome A metagenome is comprised of all the genetic elements of the
host and all those of all the microorganisms (microbiome) that live in or on that host.

Definitions (2)
 Prebiotic A selectively fermented ingredient that allows specific changes both in the
composition and activity in the gastrointestinal microflora that confers benefits upon
host well-being and health.
 Probiotic Live microorganisms that when administered in adequate amounts confer a
health benefit on the host.
 Synbiotic Nutritional supplements combining probiotics and prebiotics in a form of
synergism

History of probiotics
 Hippocrates (460–370BC) stated: “All diseases begin in the gut.”
 The Old Testament “Abraham owed his longevity to the consumption of sour
milk”
 Theodor Escherich, in 1886 described the relationship of intestinal bacteria to
the physiology of digestion in the infant.
 Ludwig Doderlein in 1892 proposed that microorganisms (lactobacilli) could
be used to treat vaginal infections
 Eli Metchnikoff is considered the father of the probiotic concept. In his 1907
book—The Prolongation of life—he proposed that colonic bacteria played a
role in aging and adverse health in adults (Bulgarian peasants)
 In 1908, Henry Tissier, a pediatrician at the Pasteur Institute in Paris, first
reported the isolation of a Y-shaped bacteria(Bifidus) from the stool of a
breast-fed infant. He observed that Bifidus was found in significant numbers
in the stool of healthy infants, whereas children with diarrhea had low
concentrations of this organism.

History of probiotics
 In 1917,during World War I , Alfred Nissle isolated a nonpathogenic strain
of Escherichia coli from the stool of a soldier, who was one of a few who
did not develop enterocolitis during a severe outbreak of Shigellosis. This
strain was named E. coli Nissle 1917 and was subsequently used to treat
gastrointestinal salmonellosis and shigellosis.
 Minoru Shirota recognized the therapeutic potential of using bacteria to
modulate gastrointestinal microflora. In1930,he succeeded in isolating
and culturing a Lactobacillus strain capable of surviving the passage
through the gastrointestinal tract. This bacterium was named
Lactobacillus casei strain shirota.
 Henry Boulard observed in Indochina in 1920 that locals that were
relatively resistant to cholera outbreaks drank an infusion of Lychee and
Mangosteen skins. Later he was able to isolate a yeast that was called
saccharomyces Boulardii

Types of probiotics
 The majority of Probiotics in clinical use are species from
three genera:
1. Lactobacillus
2. Bifidobacterium
3. Saccharomyces
 Both Lactobacilli and Bifidobacteria are saccharolytic bacteria
that can ferment carbohydrates to lactic acid that inhibits
growth of pathogenic bacteria.
 In addition, pyruvate produced from fermentation can be
utilized by certain colonic anaerobes to produce beneficial
SCFA

Types of probiotics
1. Lactobacilli are normally found in healthy gut but are present in
relatively low numbers even in individuals consuming probiotics.
Lactobacilli are also found in the vaginal secretions of healthy women.
Some of the Lactobacilli commonly found in yogurt and probiotic
supplements include L. acidophilus, L. bulgaricus, L. rhamnosus GG, L.
plantarum, L. reuteri, L. salivarius, L. casei, L. johnsonii, and L. gasseri.
2. Bifidobacteria are the constituents of normal gut flora and can also be
found in the vagina and oral cavity. Bifidobacteria tha are used as
probiotics include B. bifidum, B. lactis, B. longum, B. breve, B. infantis,
B. thermophilum, and B. pseudolongum.
3. Saccharomyces boulardii is the only yeast probiotic.
4. Others: Bacillus cereus, Enterococcus faecalis, Enterococcus faecium,
Escherichia coli Nissle, Streptococcus thermophilus

International Code of Nomenclature of Prokaryotes.
 Probiotic identification should include:
 1. Genus: a group of species of microorganisms with similar
qualities, such as physical characteristics, metabolic needs, and
metabolic end products
 2. Species: a group of strains that share numerous stable
properties
 3. Strain: a population of microorganisms that descend from a
single organism or from a pure culture isolate
 Lactobacillus rhamnosus GG, the genus is Lactobacillus,
the specie is rhamnosus and the strain is GG

Ecology of Gut Microbiata
 The healthy human intestinal microbiata is estimated at 1012
organisms
 With approximately 3-4 million genes (150 x the human genome)
 Diverse metabolic activities:
• Extracting energy and nutrients from food, vitamin biosynthesis,
bile salt transformation, developing innate and adaptive
immunity, maintaining gut epithelial integrity, functioning as a
barrier to colonization by microbial pathogens and metabolism of
drug.
• Food degradation products that humans cannot digest (e.g.,
cellulose or oligosaccharides)can be fermented into short-chain
fatty acids by enteric organisms, where they may be used as an
energy source or have other beneficial effects

Ecology of Gut Microbiata (2)
 At birth in a vaginally delivered infant, the gut becomes
colonized with organisms similar to his/her motherʼs vaginal
flora and that promotes the development of innate and
adaptive immunity
 In contrast, infants delivered by Cesarean section harbor
bacterial communities that resemble those of the skin such
as Staphylococcus, Corynebacterium, and
Propionibacterium species.

Ecology of Gut Microbiata (3)
 Beneficial bacteria such as Bifidobacterium are also transferred
to the infant from the mother during breast-feeding and serve to
colonize the infant gut. During the first few years of life, diversity
of the gut microbiome increases rapidly in response to diet and
illness.
 Administration of antibiotics in infants appears to diminish the
diversity of gut flora that in turn could have negative effects on
long-term health such as increasing the risk of developing
asthma, allergy, and obesity

Rationale for the use of probiotics
in diarrheal diseases
 Modify the composition of the colonic microflora and act against
enteric pathogens
 Synthesis of antimicrobial substances (e.g. Lactobacillus GG and L.
acidophilus strain LB have been shown to produce substances that
inhibit Gram-positive and Gram-negative pathogens) Silva M, Antimicrobial
substance from a human Lactobacillus strain. Antimicrob Agents Chemother 1987;31:1231-3.
 Competition for nutrients required for growth of pathogens Wilson KH,
Role of competition for nutrients in suppression of Clostridium difficile by the colonic microflora. Infect Immunol
1988;56:2610-4.
 Competitive inhibition of adhesion of pathogens Michail S, Lactobacillus
plantarum reduces the in vitro secretory respone of intestinal epithelial cells to enteropathogenic
Escherichia coli infection. J Pediatr Gastroenterol Nutr 2002;35: 350-5.
 Modification of toxins or toxin receptors Czrucka Saccharomyces boulardii inhibits
secretagogue-mediated adenosine 3’,5’-cyclic monophosphate induction in intestinal cells.
Gastroenterology 1994;106:65-72.

o Certain probiotics increase the number of circulating
lymphocytes, induce lymphocytic proliferation, increase specific
antibody responses to Rotavirus vaccine and cytokine secretion,
including interferon-γ (IFN-γ), and stimulate phagocytosis
Aattour N, et al. Oral ingestion of lactic-acid bacteria by rats increases lymphocyte proliferation and interferon-
gamma production. Br J Nutr 2002; 87: 367–73.
o Mack et al. showed that some lactobacilli species (L. rhamnosus
strain GG and L. plantarum strain 299v) inhibit, in a dose-
dependent manner, binding of E. coli strains to intestine-derived
epithelial cells grown in tissue culture
Mack DR, et al. Probiotics inhibit enteropathogenic E. coli adherence in vitro by inducing intestinal mucin gene
expression. Am J Physiol 1999;276:G941-950.

o Probiotics also enhance mucosal immune defenses and protect
against structural and functional damage in the brush border of
enterocytes often promoted by enterovirulent pathogens.
o Probiotics appear to interfere with the cross-talk between pathogens
and host cells (i.e. inhibit pathogen-induced cell signaling)
Lievin-Lactobacillus acidophilus (strain LB) from the resident adult human gastrointestinal microflora exerts
activity against brush border damage promoted by a diarrhoeagenic Escherichia coli in human enterocyte-like
cells. Gut 2002;50:803-11.
 Commensal flora appear to be necessary for the induction of
tolerance to non bacterial dietary antigens. The normal tolerance to
ovalbumin is lost in animals kept in a germ-free environment but can
be regained once a normal gut flora is introduced
Sudo N., The requirement of intestinal bacterial flora for the development of an IgE production system fully susceptible to oral
tolerance inductionJ Immunol 1997;159: 1739-45.

PROBIOTICS
FOR THE TREATMENT AND PREVENTION
OF
ACUTE DIARRHEA IN CHILDREN

Probiotics in the treatment of acute
infectious diarrhea
 RCTs comparing probiotics versus placebo in children
aged 1 to 48 months with acute infectious diarrhea
were identified (Inpatients, in developed countries)
 The meta-analysis revealed that probiotics (L. GG, L.
reuteri and S. boulardii ) compared with placebo
significantly reduced the risk of gastroenteritis lasting
≥3 days (relative risk [RR]: 0.40; 95% confidence interval
(CI): 0.28-0.57)
Szajewska H, et al. Probiotics in the treatment and prevention of acute infectious diarrhea in infants and
children: a systematic review of published randomized, double-blind, placebo controlled trials. J Pediatr
Gastroenterol Nutr 2001;33:S17-25.

Efficacy of probiotics in the treatment of acute diarrhea
measured as reduction in risk of diarrhea lasting
≥3 days in children 1-48 months-old with acute gastroenteritis
Szajewska H, et al. Probiotics in the treatment and prevention of acute infectious diarrhea in infants and
children: a systematic review of published randomized, double-blind, placebo controlled trials. J Pediatr
Gastroenterol Nutr 2001;33:S17-25.

Probiotics for treatment of acute diarrhea in children:
randomised clinical trial of five different preparations
Roberto Berni Canani et al. doi:10.1136/BMJ, 2007

Allen SJ et al. Probiotics for treating acute infectious diarrhea.
Cochrane Database Syst Rev.2010:CD003048
 The Cochrane systematic review by Allen et al. included 63 studies,
56 of which corresponded to a total of 6,489 pediatric patients.
 A single organism was evaluated in 46 of the studies and
combinations of 2 to 8 organisms were evaluated in 17 studies.
 L. casei GG was the organism that was studied the most (13
studies), followed by S. boulardii (10 studies). The doses and
treatment durations varied widely.
 Fifteen studies utilized high doses of the organisms (≥ 109CFU/day)
and 26 studies used low doses (≤ 109CFU/day).
 The results showed that probiotics reduced the mean duration of
diarrhea by 24.76 h as well as the frequency of bowel movements
on day 2 after the intervention

Szajewska H, Meta analysis : Saccharomyces boulardii for
treating acute diarrhea in children.
Aliment Pharmacol Ther. 2007;25:257---64
 The meta-analysis by Szajewska et al. included 5
RCTs conducted on a total of 619 healthy children
between the ages of 2 months and 12 years that
received S. boulardii in doses of 250-750 mg daily
for 5-6 days.
 The results showed diarrhea was reduced by 1.1
days in 4 studies (standardized mean difference
[SMD] = -1.1; 95% CI: -1.3 to -0.83)

Applegate JA et al.
Systematic review of probiotics for the treatment of community-
acquired acute diarrhea in children.
BMC Public Health. 2013;13 Suppl 3:S16.39
 Eight RCTs were evaluated in the systematic review by Applegate et al.
 The studies utilized different combination of probiotics:
a) L. bulgaricus with S. thermophilus;
b) L. acidophilus, L. bulgaricus, S. thermophilus, and Bifi-dobacterium bifidum
c) L. acidophilus and Bifidobacterium infantis
d) Lactobacillus GG, L. acidophilus, L. casei, L. plantarum, and B. infantis
The Lactobacillus GG, S. boulardii, L. acidophilus, Bacillus clausii, and
Enterococcus faecium strains were used individually
 The results showed a 14% reduction in the mean duration of diarrhea
and a 13.1% reduction in the frequency of bowel movements on day
2 of treatment with Lactobacillus GG and with some of the probiotic
combinations

Szajewska et al. Use of probiotics for management of acute gastroenteritis:
A position paper by the ESPGHAN Working Group for Probiotics and Prebiotics.
J Pediatr Gastroenterol Nutr. 2014;58:531---9
 A review by the European Society for Pediatric Gastroenterology,
Hepatology and Nutrition (ESPGHAN) was published in 2014 on the
use of probiotics in acute gastroenteritis, reporting that they were
able to reduce the duration of diarrhea by approximately one day.
 The efficacy and safety of probiotics depend on the strain employed
and the dose at which they are administered.
 The probiotics with the higher level of evidence and greater
recommendation grade are Lactobacillus GG and S. boulardii.
 L. reuteri DSM 17938 and L. acidophilus LB have a lower
recommendation grade due to scant evidence. The rest of the
probiotics cannot be recommended.

Lactobacillus acidophilus Mixture in Treatment of
Children Hospitalized With Acute Diarrhea
Jamie M. Pinto et al. Clinical Pediatrics 2016, Vol. 55(13) 1202–1209
 Is the duration of hospitalization of young children with acute
diarrhea associated with the use of a probiotic mixture that contains
80% L acidophilus?
 They found that the LOS of children with acute diarrhea was not
affected by the administration of L acidophilus mixture, independent
of patients’ age, duration of diarrhea prior to admission, prior use of
antibacterial therapy, and duration of treatment with IVF
 The use of L acidophilus mixture as adjuvant therapy is not beneficial
for young children hospitalized with acute diarrhea.

Probiotics in Pediatrics
Meenakshi Bothra
Indian J Pediatr (May 2015) 82(5):399–400
 Data need to be interpreted with caution as most of the
studies were not from low middle income countries and there
was marked variability across the studies, such as use of
different strains, variable doses, and different breast feeding
and dietary practices.
 The only large RCT evaluating the effect of probiotics on
prevention of diarrhea in India was in an urban slum that
found a protective efficacy of 14% (95% CI 4–23%) in 3758
children, followed for a period of 24 wk. However, one must
note that the 95 % CI was very wide

Johnston BC, et al.
Probiotics for the prevention of pediatric antibiotic-associated
diarrhea.
Cochrane Database Syst Rev. 2011:CD004827.
 In a meta-analysis of 15 randomized controlled trials that
included 2,874 children
 Johnston et al. showed that the incidence of AAD in the
group of children treated with probiotics was 9%,
compared with 18% in the control group (RR = 0.52; 95%
CI: 0.38-0.72; I2= 56%)

Szajewska H. et al.
Probiotics in the prevention of antibiotic-associated diarrhea in
children:
A meta-analysis of randomized controlled trials.
J Pediatr.2006;149:367---72.
 The meta-analysis by Szajewska et al. evaluated 6
randomized controlled trials on 766 children.
 The authors concluded that treatment with probiotics,
compared with placebo, reduced the risk for AAD in 28.5%
to 11.9% (RR = 0.44).
 A sub-group analysis showed that the reduction in the risk
for AAD was associated with the use of S. boulardii and
LGG.

Probiotics are effective at preventing Clostridium difficile-
associated diarrhea: a systematic review and meta-analysis
Christine SM Lau et al, International Journal of General Medicine 2016:9 27–37

Summary of randomized controlled trials on efficacy
of probiotics in the prevention of nosocomial
diarrhea in infants and toddlers.
Szajewska H, et al. Lactobacillus GG in prevention of diarrhea in hospitalized children. J Pediatr
2001;138: 361-5.

Probiotics and Child Care: Absence Due to
Infections: A Randomized Controlled Trial
 A total of 290 infants were randomly allocated to receive a placebo
or a combination of Bifidobacterium lactis and Lactobacillus
rhamnosus in a dose of 109 colony forming units of each daily for a
6-month intervention period
 RESULTS: Median absence from child care was 11 days. Intention to
treat analysis showed no difference between the probiotics and
placebo groups (P = .19).
 Additionally, there was no difference in any of the secondary
outcomes between groups; the number of children with doctor-
diagnosed upper or lower respiratory tract infections, the number
of doctor visits, antibiotic treatments, occurrence and duration of
diarrhea, and days with common cold symptoms, fever, vomiting,
or caregivers’ absence from work.
Rikke P. Laursen et al. DOI: https:// doi. org/ 10. 1542/ peds. 2017- 0735

Fermental Infloran Biogaia Enterogermina Ultrabiotic Ultralevure
Lactobacillus
Rhamnosus GG
Saccharomyces
Boulardi
Lactobacilus
Clausii
Bifidobacterium
Bifidum
Lactobacillus
Acidophillus
Lactobacillus
Bulgaricus
Lactobacilus
Reuteri
Streptococcus
Thermophilus

Myths and Facts
 A quarter of the bacteria in many Probiotic will be dead by the time you
take them
 Half will not survive through the stomach because of gastric acid
 3% of Saccharomyces Boulardii may be recovered from the stools of the
recipient
 You can tell if a probiotic is freeze-dried or lyophilized because the label
will tell you to refrigerate the bottle or the number of bacteria will
diminish dramatically. I used to think that probiotics that required
refrigeration were the highest quality, but the opposite is true.
 One study analyzed 18 commercially available probiotic products available
in the United States and found that 7 (39%) had differences between the
stated and actual concentrations of bacteria
 1 billion (109) CFU among 100 Trillion (1012) CFU in the gut is like One
person in a stadium that has 100,000 people
Katz JA, et al. Commercially available probiotic preparations: are you getting what you pay
for? Gastroenterology. 2002

Fermental Infloran Biogaia Enterogermina Ultrabiotic Ultralevure
Lactobacillus
Rhamnosus GG
2.109 6.109
Saccharomyces
Boulardi
100 mg
Lactobacilus
Clausii
2.109
Bifidobacterium
Bifidum
1.109
Lactobacillus
Acidophillus
1.109
Lactobacillus
Bulgaricus
Lactobacilus
Reuteri
105
5Drops
Streptococcus
Thermophilus

Why do we need so many treatments for
a self limited disease?
 Patient well being (maintaining or restoring health)
 Client satisfaction
 1 Physician < 300 citizens
 500 annual graduates from national medical faculties
 There are 6 requests for licensure of 6 new medical
faculties pending in the ministry of higher education
 The financial profit is huge : 25,2% of the Lebanese
population is < 14 years of age. If we consider 2
prescriptions/child/year that would sum up to > 2 million
prescriptions/year.

Conclusions
1. The beneficial effects of probiotics against acute diarrhea in
children seems to be moderate, strain- and dose dependent
and significant in watery diarrhea caused by some viruses.
2. Probiotics appear ineffective against invasive, bacterial
diarrhea.
3. The beneficial effects are more evident when treatment with
probiotics is initiated early in the course of disease.
4. The 2 probiotics recommended by ESPEGHAN are
Lactobacillus Rhamnosus GG and Saccharomyces Boulardii
5. Probiotics are generally safe, however, they should not be
used in healthy kids and in critically ill or immune-
compromised patients.

Thank you for your attention
QUESTIONS

Which probiotic for acute diarrheea in children

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