Short Curriculum Vitae

• Nama : Prof. Dr. Agus Firmansyah, Sp.A(K)

• Tgl. lahir : Jakarta, 7 Agustus 1952
• Jabatan : Ketua Divisi Gastrohepatologi IKA FKUI-RSCM, Jakarta
• Pendidikan : Pediatric Gastroenterology & Nutrition, SUNY, New York, USA.
• Organisasi : Ketua Dewan Etika IDAI
• Publikasi : 58 buah publikasi internasional
• Promotor : 32 Doktor
• Penghargaan : Penghargaan Dokter Puskesmas Teladan, Mes.Kes RI, 1979.
Penghargaan Peneliti Terbaik, FKUI, 1989.
Penghargaan Peneliti Terbaik, Universitas Indonesia, 1989.
Penghargaan M. Kodiyat, IDI, 1998.
Penghargaan Sudjono Poesponegoro, IDI, 2002.
Penghargaan Dokter Terpuji, IDI, 2012.
Penghargaan Penetiti Produktif, FKUI, 2013.
Penghargaan Lifetime Achievement in Research, FKUI, 2014.
Penghargaan AH Markum, IDAI, 2017
Probiotics, Prebiotics or
Synbiotics: which one?

Agus Firmansyah
Dept. of Child Health, Faculty of Medicine
Universitas Indonesia, Jakarta
Probiotics Prebiotics Synbiotics

Lacto- FOS +
bacillus
Inulin Bifidobacterium

Bifido- FOS +
FOS Lactobacillus
bacterium

GOS +
Others GOS Lactobacillus +
Bifidobacterium
Clinical

Evidence of

Probiotics
Probiotics on Acute Diarrhea
Treatment: Metaanalysis
1. Van Niel at al, Pediatrics 2002;109:1-13
2. Huang et al, Dis Dis Sci 2002;47:2625-34.
3. Sazawal et al, Lancet Infect Dis 2006;6:374-82.
4. McFarland et al, Int J Prob Preb 2006;1:63-76.
5. Alen et al, The Cochran Library, 2009.
6. Salari er al. Inflamm Allergy Drug Targets 2012:11-3-14
7. Applegate et al, BMP Public Health 2013;13:1-8
8. Wanke & Szajewska, Pediatr Polska 2014;89:6-16
→ Lactobacillus, Saccharomyces, Bifidobacterium
Probiotics Treatment for Acute Diarrhea in Indonesia

Author Strain Dose Result

Manoppo, 2010 S thermophillus, B lactis, L acidophilus 1010 cfu, Shorten duration of diarrhea
Manado Reduce severity of diarrhea
Shinta et al, 2011 L reuteri 1010, 5 days Shorten duration of diarrhea
Semarang L GG 109, 5 days Shorten duration of diarrhea
Agustina et al, 2007 L rhamnosus, Inuln, Fiber, Zn, Fe 5 x 108 cfu Shorten duration of diarrhea
Jakarta
Simadibrata et al, 2013 L rhamnosus, L acidophilus 2 x 109 cfu Shorten duration of diarrhea
Jakarta
Sudarmo SM et al B bfidum 108 cfu, 7 days Decrease stool frequency
Surabaya
Hegar et al, 2014 L rhamnosus, L acidophilus 109 cfu, 7 days No difference
Jakarta
Putra et el, 2007 L acidophilus, B longum, S thermophilus 107 cfu, 5 days Shorten duration of diarrhea
Bali
Akasiry et al, L acidophilus, B longum, S thermophilus 107 cfu, 5 days Shorten duration of diarrhea
Makassar
 Evidence:
Certain Probiotics
shorten duration of
diarrhea
 Gut Flora and Diarrhea

• 29 healthy Indian infants

• 49 children with acute diarrhea (<2 yr)
• Bifidobacteria ↑ in healthy infants
• Enterobacteria ↑ nin diarrheal infants
• Changes in gut microbiota composition
• Do not know for how long !!

Albert MJ et al, 1977

Dysbiosis
Need to recover dysbiosis
after diarrhea in children
 Diarrhea due to E. Histolitica
occured in children with dysbiosis
 Probiotics Treatment for Acute
Diarrhea

Probiotics treatment for diarrhea

in children
is to normalized the changes in
microbiota composition (dysbiosis) after
diarrhea to prevent
the later bad effects on health
 Gut Microbiota
Early Life Dysbiosis

Later adult health

(Obesity, IBD, IBS, Allergic Diseases, DM, CVD,
Colorectal Cancer)
Arrieta et al, Frontier in Immunology, 2014
Probiotics for Prevention of AAD:
Metaanalysis
1. D’souza et al, BMJ, 2002
2. Szajewska et al, J Pediatr, 2006
3. Suzawal et al, Lancet Infect Dis, 2006
4. Mc Farland, Anaerobe, 2009
5. Hempel et al, JAMA , 2012
6. Videlock er al, Aliment Pharmacol Ther, 2012
7. Pattani er al, Open Medicine, 2013
8. Goldenbberg et al, Cochranem 2013
→ Saccharomyses, Lactobacillus, Bifidobactderium
 Probiotics in the treatment of AAD

Authors Probiotics N Result

Siitonen (1990) LGG 16 +

Buts (1993) SB 19 +

Mc Farland (1994) SB 124 +

Surawics (2000) SB 32 +

Pochapin (2000) LGG 25 +

 Evidence:
Certain Probiotics can
prevent and treat
antibiotics-associated
diarrhea
Other indication of
using probiotics in
children ?
Probiotics Effect on Constipation

• RCT, 85/761 (11.2%) functional constipation, 4-10 years,

Jakarta
• L acidophillus, B longum, S thermophillus; 109 cfu, 2 times a
day for 2 weeks vs placebo
• Improvement of stool consistency (27/39 vs 17/39; p=0.022)
• Imrovement in painful defecation (31/39 vs 20/39; p=0.009)
• Overall improvement (31/39 vs 18/39; p=0.002)

Permatasari & Firmansyah, 2009

Probiotics Effect on Lactose Intolerance

Arifin et al, Paediatr Indones, 2006

• 42 children, 10-12 years, prevalence 63,6 %, Jakarta
• Two weeks administration of probiotics (L acidophyllus, B
longum, S faecium; 2 x 109 cfu) could relieve lactose intolerance
symptoms in children consumed full-cream milk.

Rampengan et al, South Asian J Trop Med Public Health, 2010

• 86 children, 10-12 years, prevalence 66,5%, Manado
• Treatment with probiotics (L helveticus + L rhamnosus; 4 x 109
cfu) for 2 weeks can reduce clinical symptoms and BHT H2 level
in children aged 10-12 years with lactose intolerance.
Probiotics Effect on H. pylori infection

• RCT in Jakarta
• Standard treatment: Omeprazole, Clarithromycin, Amoxyllin
• Standard treatment + probiotics vs standard treatment
• L acidophillus, B longum, S thermophillus; 109 cfu, 2 times a
day for 2 weeks vs placebo
• Reduced side effects
• Similar eradication rate
Aryani et al, 2010
Probiotics Effect on Immune response

• RCT, 15-45 months old children

• To investigate the effect of E faecium in milk on
humoral immune respoonse and body weight
• Probiotics vs placebo
• Total salivary sIg A level and bodyweight significantly
increased in probiotics groups compared to the placebo
• Changes in total salivary IgA levels were significantly
higher in underweight children supplemented with
probiotics

Surono et al, 2011

Probiotics Effect on Stool Mucosal
Morphology

• Anmal study, Wistar rats, starved rats (3 days only

water)
• Refeeding with chow for 6 days
• L acidophilus + L rhamnosus (2 x 109 cfu) vs placebo
• Probiotics given during reffeding period in starved rats
exert positive effect on:
Number of villi
Mucosal thickness
Villi height
Mucosal damage score
Maulidiyan et al, 2013
 Antagonism Modification
of pH

Restore of Anti-secretory
permeability effect
Probiotics

Balance of intestinal Mucin

microbiota up-regulation

Immune effects Interaction with

enterocytes

Mechanism of action of probiotics in the gut, Salvatore & Vandenplas, 2010.

Clinical

Evidence of

Prebiotics
Effect of Prebiotic on Calcium
Absorption
Ref Subject N Prebiotic Study Design Result

1 9-13 yr 100 Inulin/FOS 1 year Calcium absorption

supplement to greater. Bone mineral
diet density higher
2 Man 9 Inulin Latin square Significant increase in
feeding study Ca absorption
2 Woman 15 FOS RCT crossover Ca absorption
increased

1. Abrams et al, 2005 : 2. Coudray et al, 1997 ; 3. van de Heuvel et al, 2000.
 Effect of Prebiotics on Immune
Parameters in Infants
Study design, Study group
Ref Prebiotic used duration, subject (age) Outcome
number
1 FOS/inulin RCT, DB, 10 wk, 7-9 mo Higher blood IgG levels
n=55 after measles vaccination
2 FOS RCT, DB, 4 mo, 4d Higher anti-polio IgA
n=61
3 Gos/FOS RCT, DB, 32 wk, n- 4 d Higher fecal sIgA levels
57
4 GOS’FOS RCT, DB, 26 wk, Term infants Higher fecal sIgA levels
n=187

1. Saavedra et al, 2002; 2. Paineau et al, 2014;

3. Bakker-Zzierikzee et al, 2006; 4. Scholtens et al, 2008.
Effect of Prebiotic on Infection in Infants
Ref Prebiotic Study design,
used duration, Target group Outcome
subject number
1 GOS/FOS RCT, 6 mo, Infants at risk for Less incidence of
n=206 atopy and infection respiratory infections,
reduction in number of
infection period
2 GOS/FOS RCT, 12 mo, Infants (average Lower incidence of acute
n=342 age 53 d) diarrhea, less multiple
antibiotic treatment per
year, less respiratory
infection
3 GOS/FOS RCT, 4 wk, Preterm infants Lower incidence of
n=113 serious infectious
morbidity

1. Arslanogu et al, 2007; 2. Bruzzese et al, 2009; 3. Westerbeek et al, 2010.

 Effect of Prebiotic on Fecal
Microbiota Composition in
Children
Ref Subjects Inulin or OF Study Results
Inulin OF (g/d) Incorpor Design Length Bifido Other
N= Age (mo) (g/d] ated in (d) bacter bacteria
ium
1 67 4 1.7 Formula RCT DB 84 ↑
2 140 12-24 2.3 Formula RCT DB 21 ↑
3 56 0-2 wk 4 g/l Formula RCT DB 14 ↑ E coli ↓
4 14 1 wk 1.5 Formula RCT DB 21 ↑ Lacto ↑

1. Brunser et al, 2006; 2. Brunser et al, 2006; 3. Kapiki et al, 2007; 4. Kim et al; 2007.
 Effect of Mixture GOS/FOS (9:1) on
Fecal Microbiota Composition in
Children
Ref Subjects Inulin or OF Study Results
GOS/FOS Incorporated Design Length Bifido Other
N= Age (mo) in (d) bacter bacteria
ium
1 90 6d 4 or 8 g/l Formula RCT DB 28 ↑ Lacto ↑
2 57 1-4 8 g/l Formula RCT DB 21 ↑ Lacto ↑
3 15 4-6 4.5 g/l Formula RCT DB 42 ↑ Lacto ↑
4 19 0-4 6 g/l Formula RCT DB 120 NS

1. Moro et al, 2002; 2. knol et al, 2005; 3. scholtens et al, 2006; 4. Baker-ierkzee et al; 2005.
 Increased
absorption of
calcium

Increased fecal Increased fecal

concentration of concentration
Bifidobacteria and of sIgA
Lactobacilli
PREBIOTICS

Reduction of Production of
Clostridium spp SCFA

Decreased
consistency of
stool

Prebiotics and the gut proven effects in children, Salvatore & Vandenplas, 2010.
Mechanism of
Prebiotic
Physiological effects In diet
of prebiotics
(Fos et al, 2007)
Gut microbiota

Growth of Fermentation Fermentation product

probiotics of prebiotic SCFA, lactate, gas

Altered composition Altered metabolite

of gut microbiota profile
Inhibition of growth and
adhesion of pathogens
Immune
modulation Improved
Physiolgical effects in the host defecation
Effect on pattern
diseases
Effect of prebiotics Prebiotic
in the intestinal tract Inulin, FOS, GOS, Lactulose

Not digested or absorbed

in stomach & small intestine

Colonic microflora
Fecal bulking and
imunnomodulation Bifidobacteria ↑
Increasing fecal output
Lactobacilli ↑

Microbial fermentation
Energy source for
Antimicrobial effect of prebiotic to SCFA and
colonocyte
lactic acid

Reduced pH

Enhance absorption Sherman et al, 2009

of calcium
 Evidence:
Prebiotics can prevent
infections and stimulate
immune response and a
good gut microbiota
composition
Clinical

Evidence of

Synbiotics
Synbiotics Effect on Growth

• RCT, Healthy children aged 12 months, Jakarta

• Milk containing synbiotics: B longum, L rhamnosus, Inulin,
FOS
• 199 synbiotics vs 194 control
• 12 months follow-up
• No difference in antibody response to Measles and Hepatitis
A vaccine
• No difference in mental and motor development
• Significant increase in Lactobacilli
• Weight gain was greater in the synbiotic group

Firmansyah et al, 2011

 Nutrition Journal 2012;11:1-32

2007-2011
Syn : 3 studies, 475 infants
Pro : 10 studies, 933 infants
Pre : 12 studies, 1563 infants
Growth, morbidity, immunologis, feses

There is no data available to established if synbiotics

are superior to prebiotics or prebiotics
Although synbiotic preparations are increasingly used,
the potential benefits to gut health may be limited
as only specific combinations may enhance
probiotic survival and growth
PRO PRE SYN
Exogenous Specific synergies
Proliferation of
between pro and pre
strain endogenous strain
in GI tract

Known health Effects on the

microbiota’s Controlled site specific
properties metabolic activity release of probiotics in the
GI tract
Immuno-
modulation Specificity?
potential Larger more solely
fermentable prebiotics
Relatively rapid with SCFA production
Specificity to more distally in the
individual host? fermentation in
the proximal colon
colon
Colonization?

Bandyopadhyay & Mandal, 2014

Contain probiotics & prebiotics

Synergism, prebiotics compound selectively favors probiotics

compound

FOS + Bifidobacterium is synbiotics

FOS + Lactobacillus casei is not synbiotics

Other argument: synergism is ingestion of Lactobacillus in one hand

and promotion of indigenous Bifidobacterium in the other hand

Schrezenmeir and de Vrese, 2001

Treatment Prevention

Keep
Restoring gut
balancing gut
microbiota
microbiota

Treatment of Prevention of
diseases diseases
 Summary
• Probiotics is used especially for
treatment, except for Antibiotics
Associated Diarrhea
• Prebiotics is used especially for
prevention and stimulation
• Synbiotics ??? For prevention but
depend on composition of
probiotics and prebiotics.
Which probiotics ?
Which Probiotics are good ?

Probiotic should be live

until gut with adequate
amount

Dual Coated
Probiotic should be strong
enough from any kind of
spicy food we eat

Probiotic should be proven

by a variety of studies Local RCTs
 External protection : consisting of
a peptide/protein matrix. Against
moisture, temperature, and mechanical
pressure during production, and
transportation.

Probiotics Dual Coating Technology

Internal protection : consisting of a hydro –

colloidal polysacharide matrix. Against gastric
acid and bile salt in the digestive tract in order
for the bacteria to reach the intestines alive in
good condition to colonize and proliferate.
How to keep
Dual-coated probiotics 4th Generation
Probiotics alive until
gut with adequate Cell Biotech, Korea
amount ? Patented in
Korea, Japan,
Europe
Micro-capsulated probiotics 3rd Generation

A Japanese company

2nd Generation Enteric-coated probiotics

Some American Companies

1st Generation Non-coated probiotics

Most conventional manufacturer
Survivality of Dual Coated Probiotic
VS Non Coated Probiotics
 Diarrhea
Consipation
Sanjaya et al, 2007
Permatasari et al, 2009
Alasiry et al, 2007

RCT in Indonesia
Combination of
La, Bl, St

Helicobacter pylori Lactose Intolerance

Aryani et al, 2010 Arifin et al, 2006
 Zinc
or/and
Probiotics
For diarrhea ?
Zinc, Probiotic, Free Lactose
• RCT, acute diarrhea, 1-28 months, Turkey
• Prospective experimental, n = 60 each group
1. Probiotics
2. Zinc
3. Free lactose (FL) Group 2,4 > 1,3,5,6,7,8
4. Probiotics + Zinc Group 4 > Group 2
5. Probiotics + FL
6. Zinc + FL
7. Probiotic + Zinc + FL
8. ORS or IVR Dalgic et al, 2011
 Zn vs Zn plus Probiotics
• RCT, Moewardi Hospital, Surakarta
• Children aged 6 mo – 2 yr with acute diarrhea
• 32 subject each group (Zn vs Zn + Pro)
• Zn 20mg/day for 10 days
• Probiotics 2 x 109 cfu for 10 days.
Duration of diarrhea in combination Zn and
Probiotics group is significantly shorter than
Zn only group (p <0.001; 2 days)
Kusumoindiah, 2009
Use of probiotics in
Immuno-
compromised
children ???
 39 RCT comprising 9402 subjects
No or mild adverse effect were reported
Should reassure clinicians
Probiotics are safe when used in
children with HIV/AIDS
 11 studies involving 1557 patients
Reduced severity and frequency of diarrhea
5 cases with bacteremia
 5529 infants
Reduced incidence of severe NEC
RR 0.43 (CI 0.33-0.56)
Reduced mortality
RR 0.65 (CI 0.52-0.81
Why I give probiotics ?

• Probiotics is a enterocyte protector

• Shorten duration of diarrhea for one day
• Normalize dysbiosis after acute diarrhea
• Dysbiosis early in life have association with
morbidity in later adulthood
• Probiotics maintain gut health and save to be
supplemented to healthy children
• Use probiotics which have been proven in
Indonesia
Indications for Giving Probiotics

Acute Diarrhea
Prevention of AAD
Persistent Diarrhea
Malnutrition
Helicobacter pylori
Lactose intolerance
Functional constipation
Supplement for Gut Health
 Reduce incidence and
shorten duration of diarrhea
 Bifidobacteria significantly ↑ in probiotics infants
Enterobacteriacea significantly ↑ in placebo infants
Gut Health Better in Probiotics Infants
 Breastmilk Protection

Suspect Sepsis Suspect Sepsis No Sepsis

Full-term Full-term Full-term Healthy
Formula feeding Breastfeeding Breastfeeding
Antibiotics Antibiotics No Antibiotics

GUT Microbiota (PCR)

Bifidobacteria ↓ Bifidobacteria ↑ Bifidobacteria ↑

Lactobacillus ↓ Lactobacillus ↑ Lactobacillus ↑
Enterobactericeae ↑ Enterobactericeae ↓ Enterobactericeae ↓

Dysbiosis Similar
Christy Manoppo, Disertation. 2014
Synbiotics

• HMO
• Bifidobacteria
• Lactobacillus
 Harmfull
Beneficial
Comensal
SUMMARY Opportunistic
Bacteria
Bacteria
Beneficial
Harmfull
Comensal
Opportunistic
Bacteria
Bacteria

Antibiotics Gut microbial

Ballance gut
Diarrhea dysbiosis
microbiota Malnutrition

Permeability N Permeability ↑
Toxemia/Sepsis ↓ Nutrition Toxemia/Sepsis ↑
Gut fucntions ↑ Lifestyle Gut fucntions ↓
Probiotics
Prebiotics

Importance of balanced nutrition and gut microbiota and

consequences of gut dysbiosis
Ingin Sehat, Makan Probiotik
Thank You