Milano - 31 Gennaio 2008
Probiotici e Allergie
Luci e ombre
Paolo M. Matricardi
Klinik für Pädiatrie mit Schwerpunkt
Pneumologie und Immunologie
Charitè Universitätmedizin - Berlin
Probiotici e Allergie
Scienza o Invenzione?
mito
realtà
sommario
1. Origini
2. Il “lancio”: dati, dubbi, reazioni
3. Gli studi successivi: conferme e smentite
4. Il giudizio attuale e le prospettive future
5. Quale pediatria?
sommario
1. Origini
2. Il “lancio”: dati, dubbi, reazioni
3. Gli studi successivi: conferme e smentite
4. Il giudizio attuale e le prospettive future
5. Quale pediatria?
2003
2002
2001
2000
1999
1998
1997
1996
1995
1994
1993
1992
1991
1990
publications on “probiotics” and “allergy”
2003
2002
2001
2000
1999
1998
1997
1996
1995
1994
1993
1992
1991
Tot = 104
Tot Trials
1631
149
254
42
104
13
127
4
100
4
31
2
9
1
41
6
41
6
11
4
7
2
42
6
2
1
“Probiotics” (all)
AND “Diarrhoea”
AND “Allergy”
AND “Cancer”
AND “Inflam. Bowel Dis”
AND “Urinary tract inf.”
AND “Arthritis”
AND “Irritable bowel”
AND “Helicobacter pylori”
AND “cirrhosis”
AND “dental caries”
AND “cholesterol”
AND “respiratory infections”
publications on “probiotics” and “cancer”
“Probiotics”
Tot = 127
2003
2002
2001
2000
1999
1998
1997
1996
1995
1994
1993
1992
=
a “PANACEA” broken out in 1997-1998 ?
1991
40
35
30
25
20
15
10
5
0
Tot = 1631
1990
40
35
30
25
20
15
10
5
0
publications on “probiotics”
1990
450
400
350
300
250
200
150
100
50
0
PROBDEMO
Project Reference:
FAIR961028
Start Date: 1996-09-01
T. Mattila-Sandholm
PROBDEMO
Functional foods incorporating probiotic bacteria with scientifically supported
health claims have great potential for improving the quality of life and already
constitute a rapidly growing EU and export market. The European food industry,
however, is facing an alarmingly growing competition on the European and
International markets from large American and Japanese food producers.
However, considerable confusion and scepticism exists on the side of
consumers, consumer organisations, and scientific community about the
claims associated with probiotic products.
This greatly hampers further exploitation of functional foods from probiotic
bacteria and weakens the market position of European producers in the face of
competition.
To eliminate these hurdles, speed up adaptation of the probiotic food
technology and enhance the attractiveness of new probiotic foods, it is
essential to demonstrate the up-to-date basis for marketable claims by:
From The Cordis website: http://cordis.europa.eu/search/index.cfm „probdemo“
General Information:
- presenting the health and nutritional benefits of probiotic bacteria and foods,
with special emphasis on intestinal integrity and immune modulation;
[…..]
-disseminating the obtained knowledge to the extended audience consisting of
both industries, authorities and consumers.
The project will be divided into four interactive tasks :
[….]
- pilot testing by clinical human trials in children and adults;
[…]
-dissemination of knowledge to extend audiences.
-The clinical trials and novel methods to measure health beneficial claims are essential for
making approval of such claims possible by the authorities and to obtain sound information
for the public consumer.
-The stated objectives will be realised by a consortium of leading European food industries
experienced in the production of probiotic foods and multidisciplinary research groups in the Nordic,
central and southern EU countries, covering expertise in the fields of medicine, microbiology,
immunology and molecular biology. In addition, an industrial and consumer platform including SMEs
will be formed to guarantee the interaction between science and industrial exploitation.
The project is an essential extension of previous R&D programmes of the EU and Nordic countries.
The results are disseminated in demonstration workshops and are expected to convey to the
consumer the credibility of health beneficial claims of functional foods from probiotic
bacteria.
From The Cordis website: http://cordis.europa.eu/search/index.cfm „probdemo“
sommario
1. Origini
2. Il “lancio”: dati, dubbi, reazioni
3. Gli studi successivi: conferme e smentite
4. Il giudizio attuale e le prospettive future
5. Quale pediatria?
Kalliomaki M - Lancet 2001;357:1076-9
ECZEMA ATOPICO
Lactobacillus rhamnosus
Eczema atopico n=15/64 (23.4%)
trattati n=64
nascita
1 mese prima
del parto
6° mese
1 mese prima
del parto
p 0.008
primi 6 mesi di vita
Eczema atopico n=31/68 (45.6%)
PLACEBO n=68
nascita
24° mese
6° mese
primi 6 mesi di vita
24° mese
Kalliomaki M - Lancet 2001;357:1076-9
(1° studio)
N=28 La madre
ECZEMA ATOPICO
N=6/28 (21.4%)
assume LGG
p ???? AEDS
N=29 La madre
assume Placebo
N=???
?
N=57
PLACEBO
N=68
Ecz. At. = 31/68 (45.6)
15/64 (23.4) LGG
N=39 Bambino/a
N=??
assume placebo
p ???? ?AEDS
Bambino/a
N=75
(2° studio)
N=36 assume LGG
birth
6 mesi
?
N=9/36 (25.0%)
2 anni
N=64
Effetto 1
La madre mangia LGG
LGG stimolerebbe il GALT della madre
Il GALT modificherebbe l’immunità nel Latte
LGG
Il latte stimulerebbe il GALT del bambino
gut
AEDS = 21%
AEDS = 25%
gut
il GALT del bambino sopprimerebbe l’eczema
unico effetto, troppi meccanismi ?
LGG
Lactobacilli colonizerebbero l’intestino
del bambino/a
La pelle non svilupperebbe l’eczema
Effetto 2
[….]
sommario
1. Origini
2. Il “lancio”: dati, dubbi, reazioni
3. Gli studi successivi: conferme o smentite?
Lattobacilli e Dermatite Atopica
Trials di prevenzione
Trials di terapia
4. Il giudizio attuale e le prospettive future
5. Quale pediatria?
sommario
1. Origini
2. Il “lancio”: dati, dubbi, reazioni
3. Gli studi successivi: conferme o smentite?
Lattobacilli e Dermatite Atopica
Trials di prevenzione
Trials di terapia
4. Il giudizio attuale e le prospettive future
5. Quale pediatria?
Lactobacilli and Bifidobacteria in allergic and healthy
children during the first 1-2 years of life
Outcome
N/N
(+/-)
Bifidobacteria
Lactobacilli
33
(SWE)
no association
"protective"
29
(EST)
no association
"protective"
no association
no association
"protective"
no association
Bjorksten
CEA 1999
Food All
(SPT+ 2y)
Kalliomaki
JACI 2001
Atopy
(SPT+ 1y)
29
(FIN)
Bjorksten
JACI 2001
AD
(SPT+ 1y)
44
(EST/SWE)
small numbers ; different outcomes; different study design; conflicting results
Allergyflora study design (2001-2004)
infants recruited in Goteborg, in London, in Rome
(n=314)
microbial flora
days
birth
7
3 14
AD
months
28
diary
2
diary
6
diary
12
diary
18
diary
faecal samples
rectal
swab
questionnaires
clinical examination
blood sample
Adlerberth I. et al., JACI 2007
No association of early gut “probiotic” colonization and later atopy
Bifidobacteria
Lactobacilli
Low
High
Low
High
Bifidobacteria col. by total IgE at 18 mo
Lactobacilli col. by total IgE at 18 mo
Neg
Pos
Neg
Pos
Bifidobacteria col. by food specific IgE at 18 mo
Lactobacilli col. by food specific IgE at 18 mo
No association of early “probiotic” gut colonisation with AD
AD
Bifidobacteria
Healthy
AD
Aerobi totali
No effect
E Coli
No effect
Klebsiella
No effect
Enterococci
S. aureus
No effect
CONS
No effect
Anaerobi totali
No effect
Bacteroides
No effect
Bifidobacteria
No effect
Clostridia
No effect
Lactobacilli
No effect
No effect
Lactobacilli
AD
Healthy
sommario
1. Origini
2. Il “lancio”: dati, dubbi, reazioni
3. Gli studi successivi: conferme o smentite?
Lattobacilli e Dermatite Atopica
Trials di prevenzione
Trials di terapia
4. Il giudizio attuale e le prospettive future
5. Quale pediatria?
Perth probiotics study for
allergy prevention




230 high risk infants (maternal allergy)
Lactobacillus acidophilus 3x109 or placebo
From birth for 6 months
Given directly to infants regardless of feeding
methods
 Outcomes:
 Effects on immune development
 Effects on early disease and sensitisation
(1 year, 2.5 years and 5 years)
Summary of immune outcomes
118 had blood samples at 6 months
Comparison of infants on Probiotics (n=58) vs placebo (n=60)
 No effects on innate (TLR) immune
function
 No effects on APC function
 No effects on allergen Th1/ Th2 responses
 No effects on allergen-induced FOXP3
Summary of 1 year clinical outcomes
179 completed supplementation & reviewed at 12
months
Comparison of infants on Probiotics (n=89) vs placebo (n=88)
Children on probiotic:
 No difference in risk of atopic dermatitis (AD)
 No difference on risk of clinical food allergy
 More likely to have sensitisation (SPT+) p=0.03
 More likely to have SPT+ atopic dermatitis
p=0.045
Probiotic associated with more atopy and SPT+ AD
Risk (odds ratio, 95%CI) of early allergic outcomes
in children on probiotics relative to the placebo group
Atopic Dermatitis (AD)
Any AD
SCORAD > 25
AD & sensitisation
*
Symptomatic food allergy
Sensitisation (SPT+)
*
Any SPT+
Any food
Egg
Peanut
Cows milk
HDM
Cat
Grass
0.1
1
10
Favours probiotic
Favours placebo
supplementation
supplementation
(OR)
sommario
1. Origini
2. Il “lancio”: dati, dubbi, reazioni
3. Gli studi successivi: conferme o smentite?
Lattobacilli e Dermatite Atopica
Trials di prevenzione
Trials di terapia
4. Il giudizio attuale e le prospettive future
5. Quale pediatria?
Lactobacillus GG (LGG)
Viljanen M - Allergy 2005;60:494-500
230 patients with AEDS; age 1-11 months;
randomized, open, 3 groups; LGG (80), mix (76), placebo (74)
LGG/mix
plus CM elimination diet and topical skin treatment
no differences in the following
outcome variables:
• SCORAD (end of the study period)
• SCORAD decrease (children w AEDS)
• SCORAD decrease (children w CMA)
differences where seen only with post-hoc
subclassification of the patients on the basis
of a positive RAST/SPT
No differences between treatment
groups 4 weeks after treatment. No
differences in children with CMA
Author’s conclusions
Treatment with LGG may alleviate AEDS
symptoms in IgE-sensitized infants but
not in non-IgE-sensitized infants
Lactobacillus GG (LGG)
Gruber C et al. - JACI 2006;112:S239
LGG (5x109 CFU) = 54
weeks
12
0
Placebo = 48
102 patients with mild to moderate AD; age 3-12 months ;
SCORAD >15 or <40; no probiotic food; randomized, DBPC;
LGG, n=54
Placebo, n=48
40
Symptom load (mean, SD)
35
30
25
20
15
10
5
0
Baseline
4 weeks
8 weeks
12 weeks
Conclusions
This placebo-controlled trial showed no
therapeutic effect of LGG against
mild-to-moderate atopic dermatitis
in infancy
sommario
1. Origini
2. Il “lancio”: dati, dubbi, reazioni
3. Gli studi successivi: conferme e smentite
4. Il giudizio attuale e le prospettive future
5. Quale pediatria?
Allergy 2003; 58: 461-471
“….. their use should be considered as
experimental.
..... the number and quality of clinical studies are
insufficient
…. no level of evidence can be ascribed
…. performance of studies fulfilling the criteria of
evidence based medicine should be strongly
encouraged.
….
GINA, 2002; p. 99
“... all these strategies currently remain in the realm of hypothesis and require
appropriate investigation.”
EAACI-TF7 – Allergy 2003
“…, clinical studies are not conclusive yet. More studies are therefore essential.
Muraro A. et al. EAACI - Pediatr Allergy Immunol 2004;15:291-307
PP: Dietary prevention of allergic diseases.
“This theory (intestinal microbial flora) needs confirmatory evidence”.
Flohr C, Pascoe D, Williams HC - Br J Dermatol. 2005;152:202-16.
Larger well-designed pragmatic trials on probiotics and the
prevention and treatment of AD are now needed to inform
whether such interventions should be used in routine clinical
practice.
Hywel Williams
Cochrane Database of Systematic Reviews 2007 Issue 4 (Status: New)
Copyright © 2007 The Cochrane Collaboration. This version first
published online: 17 October 2007 in Issue 4, 2007
[….]
JACI 2007;119:746-7
JACI 2007;119:746-7
Probiotici e Allergie
Scienza o Invenzione?
mito
realtà
JACI 2007;119:1019-21
BETA
Patent Search
Edizione 2002
Atti:
Annals of Allergy, Asthma and Immunology
2002, vol. 89, no. 6, sup. 1, pp. 75 - 82
Inventing probiotic functional foods
for patients with allergic disease
Kirsi Laiho; Arthur Ouwehand; Seppo Salminen; Erika Isolauri
sommario
1. Origini
2. Il “lancio”: dati, dubbi, reazioni
3. Gli studi successivi: conferme e smentite
4. Il giudizio attuale e le prospettive future
5. Quale pediatria?
aufwiedersehen