NDPIA Network Meeting 160411
The infant gut microbiota and allergy development
Maria Jenmalm
Professor of Experimental Allergology, Div of Neuro & Inflammation Sciences, Dept of Clinical & Experimental Medicine
Atopic dermatitis (IgE-mediated)
Asthma Allergic rhino- conjunctivitis
MJ
The allergic march
M
Decreased microbial stimulation
Delayed immune maturation Impaired immune regulation
0 6 12 18 24
20 40 60 80 100
0
CXCL10/IP-10
(pg/ml)
100 200 300 400 500 600 700
0 CCL22/MDC
(pg/ml)
Th2
Th1
Age (mo)
Th2-skewing early in life
Abrahamsson et al, Clin Exp Allergy 2011; 41: 1729-39
n=107-120
CCL22
Th2
CCR4
Th1
CXCR3
CXCL10
Large, diverse and continuous microbial pressure from the gut microbiota
West CE, Jenmalm MC, Prescott SL.
The gut microbiota and its role in the development of allergic disease:
a wider perspective. Clin Exp Allergy 2015; 45: 43-53
Wold AE. The hygiene hypothesis revised: is the rising frequency of allergy due to changes in the intestinal flora? Allergy 1998; 53: 20-5.
Björkstén B. Effects of intestinal microflora and the environment on the development of asthma and allergy. Springer Semin Immun 2004; 25: 257
West CE, Renz H, Jenmalm MC, Kozyrskyj AL, Allen KJ, Vuillermin P, Prescott SL.
The gut microbiota and inflammatory non-communicable diseases:
associations and potentials for gut microbiota therapies. J Allergy Clin Immunol 2015; 135: 3-13
10 13 - 10 14 organisms 400- 1000 species
1-2 kg (60% of faeces)
Low diversity and stability of the gut microbiota in infants and elderly
Claesson MJ, Jeffery IB, Conde S, Power SE, O'Connor EM, Cusack S, Harris HM, Coakley M, …, Stanton C, Marchesi JR, Fitzgerald AP, Shanahan F, Hill C, Ross RP, O'Toole PW: Gut microbiota composition correlates with diet and health in the elderly. Nature 2012; 488: 178-84
Rodriguez JM , Murphy K, Stanton C, Ross RP, Kober O, Juge N, Avershina A, Rudi K, Narbad A, Jenmalm MC, Marchesi JR, Collado MC: The composition of the gut microbiota throughout life, with an emphasis on early life.
Microbial Ecol Health Dis 2015; 26: 26050
7
Reduced Bacteroidetes diversity in children developing allergic disease
0,00!
0,10!
0,20!
0,30!
0,40!
0,50!
0,60!
1 week! 1 month! 12 months!
Allergic!
Non-allergic!
Shannon diversity
index
*
n=20 n=20
Abrahamsson et al, J Allergy Clin Immunol 2012; 129: 434-40
Wang et al J Allergy Clin Immunol 2008; 121: 129–34 Forno et al Clin Mol Allergy 2008; 6: 11
Bisgaard et al J Allergy Clin Immunol 2011; 128: 646–52 Ismail et al Pediatr Allergy Immunol 2012; 23: 674-81
Barcoded 454 pyrosequencing of the V3 and V4 regions of the 16S rRNA gene
shannon_1w 8
shannon_1w_A shannon_1m
shannon_1m_A shannon_12m
shannon_12m_A 0
1 2 3 4
Shannon Diversity Index
1 week 1 month 12 months
no yes no yes no yes
* **
Age Asthma
doi: 10.1111/cea.12253 Clinical & Experimental Allergy, 44, 842–850
O R I G I N A L A R T I C L E
Clinical Mechanisms in Allergic Disease © 2013 John Wiley & Sons LtdLow gut microbiota diversity in early infancy precedes asthma at school age
T. R. Abrahamsson1, H. E. Jakobsson2, A. F. Andersson3, B. Bj€orkst�en4,5, L. Engstrand2,3and M. C. Jenmalm1,6
O R I G I N A L A R T I C L E
High salivary secretory IgA antibody levels are associated with less late-onset wheezing in IgE-sensitized infants
Anna Sandin1, Bengt Bjo¨rkste´n2, Malin F. Bo¨ttcher3, Erling Englund4, Maria C. Jenmalm3,5and Lennart Bra˚ba¨ck1,6
Pediatric Allergy and Immunology
2011; 22: 477-81
at 12 mo
MJ
No of bifidobacterial species detected by real-time PCR
at 1 mo of age
0-1 2
3-4 0
5 10 15 20 Salivary 25
(
μSIgA g/ml) at 6 mo
ORIGINAL ARTICLE
Influence of early gut microbiota on the maturation of childhood mucosal and systemic immune responses
Gut microbiota and immune responses
Y. M. Sj¨ogren1, S. Tomicic2, A. Lundberg2, M. F. B¨ottcher2, B. Bj¨orkst´en3, E. Sverremark-Ekstr¨om1and M. C. Jenmalm2
Clinical Mechanisms in Allergic Disease
doi: 10.1111/j.1365-2222.2009.03326.x Clinical & Experimental Allergy, 39, 1842–1851
c2009 Blackwell Publishing Ltd
Bifidobacterial diversity correlated also to
house dust endotoxin levels
Center for Advanced Research in Public Health CSISP-FISABIO, Valencia
Alex Mira
Spanish National Research Council IATA-CSIC, Valencia
MCarmen Collado Majda Dzidic V3-V5
Results to be published
Microbiota Antigen Microarray
microarray containing 40 recombinant microbiota antigens seroreactivity to 8 Bacteroides, 24 Firmicute &
8 Proteobacteria antigens
Benjamin S Christmann, Charles O Elson Univ of Alabama at Birmingham, AL, USA
Reduced seroreactivity to microbiota antigens during infancy in allergic children
Christmann et al, J Allergy Clin Immunol 2015; 136:1378-86
rIB2 rIB12
rIB20 EF20
Firmicutes/Bacteroidetes Firmicutes
Proteobacteria Firmicutes
CB 6m 12m 24m 7y CB 6m 12m 24m 7y
CB 6m 12m 24m 7y CB 6m 12m 24m 7y
Sjögren Y et al, Clin Exp Allergy 2009; 39: 518-26
Relative amount of Lactobacilli group I vs allergy up to 5 years of age
allergic, n=14 non-allergic, n=28
L rhamnosus, L paracasei, L casei
* p=0.06
% colonised
The importance of prenatal probiotic supplementation in eczema prevention
Pre- & postnatal supplementation n=2 757
11 studies
(pooled data)
OR 0.89 (95% CI 0.59-1.35) p=0.59 Number needed to treat = 50
OR 0.54 (95% CI 0.50-0.59) p<0.001 Number needed to treat = 12
Abrahamsson et al, L reuteri
J Allergy Clin Immunol 2007; 119: 1174
effect on sensitization, strain dependent?
Only postnatal supplementation n=638
4 studies
(pooled data)
TA
Probio,c treated Placebo treated
The importance of prenatal probiotic supplementation in eczema prevention
Pre- & postnatal supplementation n=2 757
11 studies
(pooled data)
OR 0.89 (95% CI 0.59-1.35) p=0.59 Number needed to treat = 50
OR 0.54 (95% CI 0.50-0.59) p<0.001 Number needed to treat = 12
BUT - not clear preventive effects on respiratory allergies
Only postnatal supplementation n=638
4 studies
(pooled data)
TA
Abrahamsson et al
J Allergy Clin Immunol 2007; 119: 1174 Abrahamsson et al
Pediatr Allergy Immunol 2013; 24: 556-61
% of SPT+ children with allergic symptoms 0-5 y
n 443 445 69 78
Kuitunen et al
J Allergy Clin Immunol 2009; 12: 335
*
Less IgE-associated allergic disease 0-5 years only in Caesarean-delivered children supplemented w probiotics
Mothers: gw 36-delivery Twice daily L rhamnosus GG (ATCC 53103; 5x109 CFU),
L rhamnosus LC705 (DSM 7061; 5x109 CFU), Bifidobacterium breve Bb99 (DSM 13692; 2x108 CFU), Propionibacterium freudenreichii ssp. shermanii JS (DSM 7076; 2x109 CFU
Infants: birth-6 mo The same probiotic capsule opened & mixed w 20 drops of syrup + 0.8 g of galacto-oligosaccharides
ORIGINAL PAPER
Caesarean delivery and risk of atopy and allergic disesase: meta-analyses
P. Bager, J. Wohlfahrt and T. Westergaard
Department of Epidemiology Research, Statens Serum Institut, Artillerivej 5, DK-2300 Copenhagen S, Denmark
Epidemiology of Allergic Disease
doi: 10.1111/j.1365-2222.2008.02939.x Clinical and Experimental Allergy, 38, 634–642
c2008 The Authors Journal compilation c2008 Blackwell Publishing Ltd
Food$aller gy
At opic$e czema
All er gic$rh ini 4s
As thma Hospit
alisa 4on 0.8
1.0 1.2 1.4 1.6
(asthma)
OR
CS, n=9 (6 elective) VD, n=15
Lower diversity of the Bacteroidetes phylum in CS vs VD infants at 1, 3, 12 & 24 months Lower Bacteroides colonization rate in CS vs VD infants at 1 week, 3 and 12 months VD but not CS infants shared more gut microbiota 16S rRNA gene sequences with their own mother than with other mothers during the first 2 years, particularly within the Bacteroidetes and Firmicutes phyla
Jakobsson et al, Gut 2014; 63: 559-66
Delivery mode and
gut microbiota development
The importance of prenatal probiotic supplementation in eczema prevention
Pre- & postnatal supplementation n=2 757
11 studies
(pooled data)
OR 0.89 (95% CI 0.59-1.35) p=0.59 Number needed to treat = 50
OR 0.54 (95% CI 0.50-0.59) p<0.001 Number needed to treat = 12
Only postnatal supplementation n=638
4 studies
(pooled data)
BUT - probiotics generally given from gestational week 36 TA
Ege et al J Allergy Clin Immunol 2006; 117: 817
Maternal farm exposure during pregnancy important for allergy preventive effects
Experimental studies
Maternal TLR signaling is required for prenatal asthma protection by the nonpathogenic microbe
Acinetobacter lwoffii F78
Conrad et al J Exp Med 2009; 206: 2869-77
New study with
probiotic supplementation
already from gestational week 20
started
Infancy Prenatal
placenta maternal microbiota
gut, oral?
Delivery
maternal microbiota gut, vaginal
maternal microbiota
milk, skin gut, oral?
immune imprinting
immune maturation
MJ
Perez PF et al: Bacterial imprinting of the neonatal immune system: lessons from maternal cells? Pediatrics 2007; 119: e724 Rautava S et al: Probiotics modulate host-microbe interaction in the placenta and fetal gut… Neonatology 2012; 102: 178 Funkhouser LJ, Bordenstein SR: Mom knows best: the universality of maternal microbial transmission. PLoS Biol 2013 Aagaard K et al: The placenta harbors a unique microbiome. Sci Transl Med 2014; 6: 237ra65.
Figure from West CE, Jenmalm MC, Kozyrskyj AL, Prescott SL:
Probiotics for treatment and primary prevention of allergic diseases and asthma: looking back and moving forward Esp Rev Clin Immunol; In press.
Abrahamsson TR, Wu RY, Jenmalm MC: Gut microbiota and allergy: the importance of the pregnancy period Pediatr Res 2015; 77: 214-9.
Increased gut microbial translocation during pregnancy?
Prenatal microbial immunomodulatory
factors
Dysregulated infant immunity,
allergy development
Mismatched postnatal environment
B I R T H
Mismatched postnatal environment - maladjusted immune regulation?
Jenmalm & Duchén:
Timing of allergy preventive and immunomodulatory dietary interventions
- are prenatal, perinatal or postnatal strategies optimal?
Clin Exp Allergy 2013; 43: 273-8
Anticipatory
modulation of offspring immunity
via epigenetic mechanisms
Conclusions
Gut microbiota important role in immune and allergy development,
more detailed studies required Further studies required to recommend
probiotics for allergy prevention
Interesting to evaluate maternal probiotic or prebiotic supplementation during longer part of pregnancy,
incl immunomodulation
& epigenetic effects
NDPIA Network Meeting 160411
Thanks!
Parents and children in our studies
Div of Pediatrics, LiU Thomas Abrahamsson Malin Fagerås Böttcher
Karel Duchén Anne-Marie Fornander Karin Fälth-Magnusson
Kicki Helander Ted Jakobsson
Lena Lindell Lennart Nilsson Kristina Warstedt
Div of Inflammation Medicine, LiU Martina Abelius
Judit Arvelund-Svensson Christina Ekerfelt
Jan Ernerudh Anna Forsberg Johanna Huoman Ratnesh Bhai Mehta
Jenny Mjösberg Marie Persson
Div of Obstetrics & Gyn, LiU Göran Berg
Leif Matthiesen
Karolinska Institutet Bengt Björkstén
Lars Engstrand Hedvig Jakobsson
KTH Anders Andersson Div of Pediatrics
Ryhov, Jönköping Göran Oldaeus
Stockholm University Eva Sverremark-Ekström
Ylva Sjögren
Univ of Alabama Ben Christmann Charles O Elson Univ of Western Australia
Susan Prescott
Umeå University Christina West
Tartu Univ Kaja Julge
Tiia Voor CSISP-FISABIO
IATA-CSIC, Valencia MCarmen Collado
Majda Dzidic Alex Mira
