Probiotics for Preventing Allergy

in Infants
Seppo Salminen
University of Turku
Functional Foods Forum
Turku, Finland
Universität Bodenkultur, Vienna, Austria

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 Definition of a probiotic

Probiotic:
...a living microbial preparation, which
beneficially influences human health, when
given in the right dose

WHO 2002

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 Probiotics and allergy...

…Hygiene hypothesis – less exposure to microbes

...Nutrition hypothesis – altered nutrition/microbiota

…Environmental changes

…Increasing c-section, decreasing breast-feeding

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 Microbiota Acquisition
• Mother’s microbiota
800-1200 species
• Infant’s microbiota at birth
1-15 species
• Interaction continues
during breast-feeding

• Probiotic basis
• Hygiene and Nutrition
hypothesis

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 Intestinal Microbiota
Acquisition

Copyright Erika Isolauri &

Seppo Salminen, 2008,
Walkers’ Pediatric
Gastroenterology
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 Breastmilk Microbiota

Bacteria in Breast Milk

-Bacteria from skin, breastmilk, infant

mouth and gut

-Partly responsible for breastmilk

protective effects

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 Breast Milk Bacteria in 7 countries (urban)
70

60

50

40 Bifidobacteria
30
Lactic Acid
20 Bacteria

10
Sinkiewicz and
0 Sweden Israel South Africa Japan Peru South Korea Denmark Nordström 2005

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 Bifidobacterium levels in breast-milk

5,00

4,50

4,00

3,50

3,00 2,78 ± 1,12

Log cells/mL

2,50

2,00

1,50

1,00

0,50

0,00
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284
Sample
Gueimonde et al 2007
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 Bifidobacterium Species Composition in
Breast Milk
100 %

90 %

80 %

70 %

60 %

% of ocurrence 50 %

40 %

30 %

20 %

10 %

0%
B. longum group B. catenulatum B. bifidum B. breve B. lactis group B. adolescentis
group
Species-groups

Gueimonde et al 2007
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 Breast Milk Bacteria: Probiotic effect?
• Breast milk always contains bacteria
• Key factors for infant gut microbiota
development

• Health promoting
• Positive impact of microbiota
succession
• Breast-feeding and disease
protection?
– Diarrhea, atopic diseases, overweight
– natural probiotic action?

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 Disturbed Microbiota during Early Life:
Hygiene and Nutrition Hypothesis

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 Microbiota aberrancies in Infants
 Diarrhea
 Risk of diarrhea
 Allergy
 Risk of atopic diseases
 Stress
 Obesity
 Autism?
 Hepatic encephalopathy

 QUESTION 1: can the

aberrancies be prevented or
reversed by specific probiotics?
 QUESTION 2: how to select
probiotics for specific targets?

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 Aberrant Microbiota
 Allergic infants and children have
significantly different microbiota
 Composition and activity different
 Akkermansia muciniphila; role in mucus
 Deviations in microbiota precede atopic
eczema development
 Bifidobacterium deficiency, altered
Bifidobacterium/Clostridium ratio
Akkermansia
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 Differences in Microbiota Composition Preceding
Allergy
HITChip

* p-value 0.025 # p-value

0.001

Children developing atopy: less Bacteroidetes

and Clostridium cluster IX bacteria at 18 mo

** ##

qPCR of Bifidobacterium spp: children developing atopy have significantly less B.

longum/infantis at the age of 6 mo (Nylund et al. 2013 BMC Microbiology)
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 HEALTH PROMOTING DIVERSITY OF EARLY
MICROBIOTA?

• Children developing allergic disease

have higher diversity in microbiota at 6
• Less diverse – similar to microbiota of
healthy breast-fed infants
• Bifidobacteria often dominate in
breastfed infants

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 Probiotics in primary prevention of atopic disease:
a randomised placebo-controlled trial
Kalliomäki et al. 2001, 2003, 2007

• 159 pregnant women; infants at high risk of atopic disease

• comparable family history and birth characteristics

• Lactobacillus GG (ATCC 53103) / placebo 2-4 weeks before

delivery
– until 6 months of age
– lactating mother / infant

• Primary endpoint: atopic eczema in the infant

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 Prevention?: The effect of pre-& postnatal
Lactobacillus GG on the frequency of atopic eczema

50
45
40
35
30
25
20 nnt 4.5
15 (95% CI 2.6-15.6)
10
5
0
Placebo Probiotic

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Lactobacillus rhamnosus GG
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 TGF-ß IN BREASTMILK AT 3
MONTHS (PG/ML)

TGF-
in breastmilk:
protection
against atopic
eczema

Rautava et al.2002
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 Cumulative incidence of eczema
during the first 7 years of life

log-rank p=0.008

p=0.008
p=0.03
p=0.027

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 Effect of probiotics during pregnancy and
breastfeeding on eczema risk in the infant
Rautava et al. JACI 2002

%
50

45
placebo n=32
40

35 LGG n=30

30

25 NS

20
p=0.0098
15

10

0
Seppo Salminen
chronic eczema SPT
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PROBIOTICS & ALLERGY PREVENTION?
• Several successful interventions
• Kalliomäki et al 2001, 2003, 2007; Kukkonen
et al 2007; Abrahamsson et al. 2008, Wickens
et al 2008, Kim et al 2009, Niers et al. 2009

• No clinical effect
• Taylor et al 2007, Kopp et al 2008, Soh et al
2009

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 PROBIOTICS & ALLERGY PREVENTION?

• Successful interventions with L rhamnosus

• Kalliomäki et al 2001, 2003, 2007; Huurre et al 2008
• Lactobacillus rhamnosus and
Bifidobacterium lactis (HN001/HN009)
Wickens et al 2008 (L rhamnosus effective)
• L acidophilus (previously uncharacterized
strain) no clinical effect (Taylor et al 2007)

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 Isolauri, Rautava & Salminen. Gastro Clin N Am 2012
Seppo Salminen
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 Isolauri, Rautava & Salminen. Gastro Clin N Am 2012
Seppo Salminen
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 Isolauri, Rautava & Salminen. Gastro Clin N Am 2012
Seppo Salminen
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 Isolauri, Rautava & Salminen. Gastro Clin N Am 2012
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 DIFFERENCES IN INTERVENTION

Kopp et al. 2008 Kalliomäki et al 2001,2003

• No difference in eczema • Deacreased risk of eczema

• Mean duration of • Mean duration of
breastfeeding 9.2 breasfeeding 6.5 months
months
• Probiotic supplier • Probiotic supplier Valio
Infectopharm
• Study population in • Study population in
Germany Finland
(antroposophic?)
• Follow-up • Follow-up
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 Effect of maternal perinatal probiotics on
eczema risk in the infant
Rautava et al. JACI 2012

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 Effect of maternal perinatal probiotics on
eczema risk in the infant at 2 years of age
Rautava et al. JACI 2012
%
80

70
placebo

60 LPR+BL999

50 ST11+BL99
9

40 p<0.001
p<0.001
30 NS NS

20 p=0.016

10
p=0.003

0
Seppo Salminen eczema chronic eczema SPT
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Seppo Salminen
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 Genome of Probiotics:
infant probiotics
 Several genomes available publicly
 Some infant ones (eg. B lactis, LGG,
several others) known
 Viability, metabolic state, stability (also
genetic)
 Differences due to manufacture and
processing

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 +
Antigen load

Gut barrier
Inflammation

Growth
dysfunction

Symptoms
ABERRANT
Microbiota

Specific Probiotic
BALANCED
Nutrition
Microbiota
Environment

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 Why Probiotic Effects Differ?
Probiotic Genome
Strains vary
Production methods vary
Dose/administration time
Viability usually poorly assessed
Gene expression

Host/Mother/Infant Environment
Genetics, Microbiome Mode of delivery
Diet/Geographical location Transfer of microbiota
Type of microbiota & health Feeding regimens
Duration of breastfeeding Antibiotics
Colonization process Toxins
Compliance/adherence
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 Specific Probiotic Effects
 Stabilize gut barrier and inflammation to control
epithelial barrier

 Maintain or restore normal commensal

microbiota to improve barrier

 Express dedicated effectors that modulate

inflammation predisposition, activity and
promote normal microbiota and epitelial function

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 Future?

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 FUTURE

Information, guidance

Personalised nutrition,

Specific probiotics for

infants and children for allergy

prevention

Seppo Salminen
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 Thank you

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 Safety of Probiotics in Infants
 Premature infants 12 years LGG
(FI)
 Perinatal administration follow-up
up to 15 years LGG and 7 years
Bb12

 US FDA:
-Bifidobacterium lactis and S
thermophilus GRAS for infant
foods
- Lactobacillus rhamnosus GG
GRAS for infant foods

 EFSA QPS: Current probiotics

including LGG and B lactis Bb12
fulfill QPS criteria

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