EAACI Allergy School 2018-03-16

Genome, methylation and allergic diseaseMaria Jenmalm

Professor of Experimental Allergology,Div of Neuro & Inflammation Sciences,

Dept of Clinical & Experimental Medicine

EAACIdedicatedtoAllergyScience,committedtoyourHealth 2

Disclosure

Inrelationtothispresentation,Ideclarethefollowing,realorperceivedconflictsofinterest:

Aconflictofinterestisanysituationinwhichaspeakerorimmediatefamilymembershaveinterests,andthosemaycauseaconflictwiththecurrentpresentation.Conflictsofinterestdonotprecludethedeliveryofthetalk,butshouldbeexplicitlydeclared.Thesemayincludefinancialinterests(e.g.owningstocksofarelatedcompany,havingreceivedhonoraria,consultancyfees),researchinterests(researchsupportbygrantsorotherwise),organisationalinterestsandgifts.

IhavereceivedfundingforaclinicaltrialandhonorariaforlecturesfromBioGaiaAB,aswellasconsultantfees,honorariaforlecturesandtravelsupportfromNutricia/Danone.

Atopicdermatitis

(IgE-mediated)

AsthmaAllergic rhino-conjunctivitis

MJ

The allergic march

MJ

Time and dose ofallergen exposure

Genotype

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Images: aaaai.orgastmaoallergiforbundet.seclipartconnection.comfoodallergens.infoornl.gov/hgmis

Epigenetics

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20

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100

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100

200

300

400

500

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Abrahamsson et al, Clin Exp Allergy 2011; 41: 1729-39

n=107-120

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MJ

Immune deviation during pregnancy

IL-4 IL-10

via e g progesterone

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Th2 skewing in newborns-

epigenetic regulation

8

Different epigenetic mechanisms

Chromatine structure

Waddington1957

One genome – many cell types

Epigenetic regulation allows cells to maintain their ‘state’

10

DNA methylation

• Covalent modification of DNA

• Primarily at cytosines

• Affects the binding of proteins that regulate the activity of genes

TF

CGC CGA TGA GCT ATG CAT AGC TCA TCG GCGDNMT3

CH3 CH3

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DenovoDNAmethylation

Epigenetic inheritance

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Epigenetic inheritance

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CH3CH3

CGC CGA TGA GCT ATG

CH3 CH3

CAT AGC TCA TCG GCG

CGC CGA TGA GCT ATG

DNMT1 CH3

DNAmethyltransferase1

DNA methylation patterns can be inherited

Maintenance of DNA methylation patterns during cell division

DenovoDNAmethylation

MaintenanceDNAmethylation

14

DNA methylation allows Th cell differentiation & contributes to flexibility

Suarez-Alvarez et al: DNA methylation: a promising landscape for immune system-related diseases 2012; 28: 506-514

2018; 45: 48–56

reprogrammingplasticity CH2OH

CH3

16

Dysregulation of DNA methylation at MAPK signaling-associated genes during early CD4+ T-cell development may contribute to suboptimal T-lymphocyte responses in early childhood associated with the development of food allergy

Prescott & Saffery: The role of epigenetic dysregulation in the epidemic of allergic disease. Clin Epigenetics 2011; 2: 223-32

18

Barker’s hypothesis of fetal originsof adult disease: IUGR, low birth weight, and premature birth have a causal relationship to the origins of hypertension, coronary heart diseaseand non-insulin-dependent diabetes

Thrifty phenotype: adaptive response for deprived prenatal environment maladaptive for postnatal environment

Developmental Origins of Health and Disease (DOHaD) hypothesis:early nutrition and growth affects long-term health

A

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BCCL22

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Cord blood Th2- and Th1-associated chemokinesvs sensitisation development to 6 years of age

Abelius et al: High cord blood levels of the Th2-associated chemokines CCL17 and CCL22 precede allergy development during the first 6 years of lifePediatr Res 2011; 70: 495-500

Abelius et al: Th2-like chemokine levels are increased in allergic children and influenced by maternal immunity during pregnancyPediatr Allergy Immunol 2014; 25: 387-93

Major changes in microbial exposure to children in westernized countries and increasing prevalence of allergic diseases

- epigenetic effects?

Abrahamsson TR, Wu RY, Jenmalm MC: Gut microbiota and allergy: the importance of the pregnancy period. Pediatr Res 2015; 77: 214-219

MJ

Decreased microbial stimulation

Delayed immune maturationImpaired immune regulation

Large, diverse and continuous microbialpressure from the gut microbiota

1013-1014 organisms

400-1000 species(many unknown)

1-2 kg (60% of faeces)

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

Björkstén B. Effects of intestinal microflora and the environment on thedevelopment 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

Commensals

TregTGF-βIL-10

Gut mucosal environment normally tolerance promoting

eg butyrate

epigenetic effectsHDAC inhibition

GPR43

GPR109a

Modified from Ohland CL, Jobin C: Microbial activities and intestinal homeostasis: A delicate balance between health and disease. Cell Mol Gastroenterol Hepatol 2015; 1: 28-40

SCFA mediated immunomodulatory effects

29/09/2014

3

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Low diversity and stability of the gut microbiotain 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

26

Reduced Bacteroidetes diversity in children developing allergic disease

0,00!

0,10!

0,20!

0,30!

0,40!

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doi: 10.1111/cea.12253 Clinical & Experimental Allergy, 44, 842–850

ORIGINAL ARTICLE Clinical Mechanisms in Allergic Disease© 2013 John Wiley & Sons Ltd

Low gut microbiota diversity in early infancy precedes asthma at schoolageT. R. Abrahamsson1, H. E. Jakobsson2, A. F. Andersson3, B. Bj€orkst"en4,5, L. Engstrand2,3 and M. C. Jenmalm1,6

1Division of Pediatrics, Department of Clinical and Experimental Medicine, Link€oping University, Link€oping, Sweden, 2Department of Microbiology, Tumorand Cell Biology, Karolinska Institutet, Stockholm, Sweden, 3Division of Gene Technology, Science for Life Laboratory, School of Biotechnology, KTH RoyalInstitute of Technology, Stockholm, Sweden, 4Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden, 5School of Health andMedical Sciences, €Orebro University, €Orebro, Sweden and 6Unit of Autoimmunity and Immune Regulation, Division of Clinical Immunology, Department ofClinical and Experimental Medicine, Link€oping University, Link€oping, Sweden

Clinical&

ExperimentalAllergy

Correspondence:Thomas Abrahamsson, Division of

Paediatrics, Link€oping UniversityHospital, SE-581 85 Link€oping,Sweden.E-mail: thoab@telia.com

Cite this as: T. R. Abrahamsson, H. E.Jakobsson, A. F. Andersson, B.Bj€orkst"en, L. Engstrand and M. C.

Jenmalm, Clinical & ExperimentalAllergy, 2014 (44) 842–850.

SummaryBackground Low total diversity of the gut microbiota during the first year of life is asso-ciated with allergic diseases in infancy, but little is known how early microbial diversityis related to allergic disease later in school age.Objective To assess microbial diversity and characterize the dominant bacteria in stoolduring the first year of life in relation to the prevalence of different allergic diseases inschool age, such as asthma, allergic rhinoconjunctivitis (ARC) and eczema.Methods The microbial diversity and composition was analysed with barcoded 16S rDNA454 pyrosequencing in stool samples at 1 week, 1 month and 12 months of age in 47infants which were subsequently assessed for allergic disease and skin prick test reactivityat 7 years of age (ClinicalTrials.gov ID NCT01285830).Results Children developing asthma (n = 8) had a lower diversity of the total microbiotathan non-asthmatic children at 1 week (P = 0.04) and 1 month (P = 0.003) of age,whereas allergic rhinoconjunctivitis (n = 13), eczema (n = 12) and positive skin prickreactivity (n = 14) at 7 years of age did not associate with the gut microbiota diversity.Neither was asthma associated with the microbiota composition later in infancy (at12 months). Children having IgE-associated eczema in infancy and subsequently develop-ing asthma had lower microbial diversity than those that did not. There were no signifi-cant differences, however, in relative abundance of bacterial phyla and genera betweenchildren with or without allergic disease.Conclusion and Clinical Relevance Low total diversity of the gut microbiota during thefirst month of life was associated with asthma but not ARC in children at 7 years of age.Measures affecting microbial colonization of the infant during the first month of life mayimpact asthma development in childhood.

Keywords asthma, allergic rhinoconjunctivitis, birth, children, diversity, hygiene hypothe-sis, microbiota, molecular microbiologySubmitted 15 September 2013; revised 2 November 2013; accepted 4 December 2013

Introduction

A limited microbial exposure may underlie the increasein allergic diseases in affluent countries [1]. Recentreports indicate that a high diversity of the gut microbi-ota in infancy may be more important than the preva-lence of specific bacterial taxa [2–4]. The suggestedunderlying rationale is that the gut immune systemreacts to exposure to new bacterial antigens andrepeated exposure would enhance the development of

immune regulation. Although sharing several commonfeatures, the phenotype and the mechanisms underlyingthe different allergic diseases such as asthma, eczemaand allergic rhinoconjunctivitis (ARC) are heteroge-neous [5–7]. Also, the importance of and relationshipwith the intestinal microbiota may differ between thedifferent diseases. Previously, low gut microbial diver-sity during the first month of life has been associatedwith subsequent eczema [2, 8–10] and sensitization [2,3, 8], but still there are no studies reporting low gut

• Antigen transmission• Tolerogenic immune mediators

• TGF-β, IL-10, IgA, IgG• Human milk microbiota• Microbiota modulating factor

Prenatal period Postnatal periodOral intake of pro- and prebiotics

The newborn acquires the maternal vaginal and gut microbiome (Lactobacillae, Bifidobacterium, Bacteroides etc.), favoring further commensal colonization.

Microbial transmission through vaginal birth

Oral intake ofpro- and prebiotics

Intestinal colonization by symbiotic bacteria

Transfer of tolerogenic mediators to the baby

Breastfeeding:

ORAL TOLERANCE

Intestinal colonization by symbiotic bacteria

• IgA ↑• Treg ↑• IL-22 ↑• Enhanced epithelial barrier integrity

May support and benefit a homeostatic microbial colonization of the infant´s gut.

epigenetic effects

The importance of prenatal probiotic supplementation in eczema prevention

Pre- & postnatal supplementationn=2 75711 studies(pooled data)

OR 0.89 (95% CI 0.59-1.35) p=0.59Number needed to treat = 50

OR 0.54 (95% CI 0.50-0.59) p<0.001Number needed to treat = 12

Only postnatal supplementationn=6384 studies(pooled data)

Abrahamsson et al J Allergy Clin Immunol 2007; 119: 1174

BUT - not clear preventive effects on respiratory allergies

Abrahamsson et al Pediatr Allergy Immunol 2013; 24: 556-61

Forsberg A, West CE, Prescott SL, Jenmalm MC: Pre- and probiotics for allergy prevention: time to revisit recommendations? Clin Exp Allergy 2016; 46: 1506-1521

Abrahamsson et al J Allergy Clin Immunol 2007; 119: 1174tydligast effekt på sensibilisering

POSITION ARTICLE AND GUIDELINES Open Access

World Allergy Organization-McMaster UniversityGuidelines for Allergic Disease Prevention(GLAD-P): ProbioticsAlessandro Fiocchi1†, Ruby Pawankar2†, Carlos Cuello-Garcia3,4, Kangmo Ahn5, Suleiman Al-Hammadi6,Arnav Agarwal3,7, Kirsten Beyer8, Wesley Burks9, Giorgio W Canonica10, Motohiro Ebisawa11, Shreyas Gandhi3,7,Rose Kamenwa12, Bee Wah Lee13, Haiqi Li14, Susan Prescott15, John J Riva16, Lanny Rosenwasser17,Hugh Sampson18, Michael Spigler19, Luigi Terracciano20, Andrea Vereda-Ortiz22, Susan Waserman21,Juan José Yepes-Nuñez3, Jan L Brożek3,21* and Holger J Schünemann3,21

Abstract

Background: Prevalence of allergic diseases in infants, whose parents and siblings do not have allergy, isapproximately 10% and reaches 20–30% in those with an allergic first-degree relative. Intestinal microbiota maymodulate immunologic and inflammatory systemic responses and, thus, influence development of sensitization andallergy. Probiotics have been reported to modulate immune responses and their supplementation has beenproposed as a preventive intervention.

Objective: The World Allergy Organization (WAO) convened a guideline panel to develop evidence-basedrecommendations about the use of probiotics in the prevention of allergy.

Methods: We identified the most relevant clinical questions and performed a systematic review of randomizedcontrolled trials of probiotics for the prevention of allergy. We followed the Grading of RecommendationsAssessment, Development and Evaluation (GRADE) approach to develop recommendations. We searched for andreviewed the evidence about health effects, patient values and preferences, and resource use (up to November2014). We followed the GRADE evidence-to-decision framework to develop recommendations.

Results: Currently available evidence does not indicate that probiotic supplementation reduces the risk ofdeveloping allergy in children. However, considering all critical outcomes in this context, the WAO guideline paneldetermined that there is a likely net benefit from using probiotics resulting primarily from prevention of eczema.The WAO guideline panel suggests: a) using probiotics in pregnant women at high risk for having an allergic child;b) using probiotics in women who breastfeed infants at high risk of developing allergy; and c) using probiotics ininfants at high risk of developing allergy. All recommendations are conditional and supported by very lowquality evidence.

Conclusions: WAO recommendations about probiotic supplementation for prevention of allergy are intended tosupport parents, clinicians and other health care professionals in their decisions whether to use probiotics in pregnancyand during breastfeeding, and whether to give them to infants.

Keywords: Allergy, Prevention, Probiotics, Practice guidelines, GRADE

* Correspondence: brozekj@mcmaster.ca†Equal contributors3Department of Clinical Epidemiology and Biostatistics, McMaster UniversityHealth Sciences Centre, Room 2C19, 1200 Main Street West, Hamilton, ONL8N 3Z5, Canada21Department of Medicine, McMaster University, Hamilton, ON, CanadaFull list of author information is available at the end of the article

journal

© 2015 Fiocchi et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the CreativeCommons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly credited. The Creative Commons Public DomainDedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article,unless otherwise stated.

Fiocchi et al. World Allergy Organization Journal (2015) 8:4 DOI 10.1186/s40413-015-0055-2

+ Cabana et al Pediatrics 2017; in press.n=184, no effect on eczema

% 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-analysesP. Bager, J. Wohlfahrt and T. WestergaardDepartment of Epidemiology Research, Statens Serum Institut, Artillerivej 5, DK-2300 Copenhagen S, Denmark

Clinical andExperimental

Allergy

Correspondence:Peter Bager, Department ofEpidemiology Research, Statens SerumInstitut, Artillerivej 5, DK-2300Copenhagen S, Denmark.E-mail: pbg@ssi.dk

Summary

Background Studies of delivery by caesarean section (c-section) and the offspring’s risk ofallergic diseases are of current interest due to concerns about the increased use of c-section inmany countries. However, previous studies have reported inconsistent findings.Objective We investigated whether delivery by c-section is associated with an increased risk ofatopy and allergic disease by reviewing the literature, performing a meta-analysis, andassessing publication bias.Methods We used a systematic literature search of MEDLINE (1966 to May 2007). Six commonallergic outcomes were included: food allergy/food atopy, inhalant atopy, eczema/atopicdermatitis, allergic rhinitis, asthma, and hospitalization for asthma. For each outcome a meta-analysis was performed, where a summary odds ratio (OR) was calculated taking into accountheterogeneity between the study-specific relative risks. Publication bias was assessed usingthe funnel plot method.Results We identified 26 studies on delivery by c-section and one or more of the six allergicoutcomes. C-section was associated with an increased summary OR of food allergy/food atopy(OR 1.32, 95% CI 1.12–1.55; six studies), allergic rhinitis (OR 1.23, 95% CI 1.12–1.35; sevenstudies), asthma (OR 1.18, 95% CI 1.05–1.32; 13 studies), and hospitalization for asthma (OR1.21, 95% CI 1.12–1.31; seven studies), whereas there was no association with inhalant atopy(OR 1.06, 95% CI 0.82–1.38; four studies) and eczema/atopic dermatitis (OR 1.03, 95% CI0.98–1.09; six studies). Funnel plots indicated that the association with food allergy/foodatopy could be difficult to interpret due to publication bias. For each significant associationwith an allergic outcome, only 1–4% of cases were attributable to c-section.Conclusion Delivery by c-section is associated with a moderate risk increase for allergicrhinitis, asthma, hospitalization for asthma, and perhaps food allergy/food atopy, but not withinhalant atopy or atopic dermatitis. The increased use of c-section during the last decades isunlikely to have contributed much to the allergy epidemic observed during the same period.

Keywords allergic disease, caesarean section, epidemiology, mode of delivery, risk factorsSubmitted 9 October 2006; revised 13 November 2007; accepted 27 November 2007

Introduction

Reports on the offspring’s risk of developing allergicdisease following delivery by caesarean section (c-section) [1–26] are of current interest due to the increaseduse of c-section in many countries. The proportion ofc-sections has increased up to 30% of all deliveries, whilein the 1970s, it was generally below 15%, as recom-mended by the World Health Organization [27, 28]. Sofar, the epidemiological association between c-sectionand risk of allergic outcomes has been inconsistent, andto the best of our knowledge, neither a review of studiesnor a meta-analysis of the reported risk estimates has beenpublished. The suspicion of an association has been raised

Epidemiology of Allergic Disease

because c-section babies have a different gut flora[29–33], which has been suggested to prolong immuno-logical immaturity and thereby increase the risk of laterdevelopment of allergic disease [34, 35]. In addition,delivery by c-section is a well-recognized cause ofneonatal respiratory morbidity, in specific transient ta-chypnea of the newborn (TTN) and respiratory distresssyndrome (RDS) [36–39]. A number of studies suggestthat TTN and RDS are associated with an increased risk oflater asthma [21, 23, 40–42].

We aimed to provide a review and meta-analyses ofepidemiological studies of delivery by c-section and riskof allergic outcomes, and evaluate publication bias. Inaddition, we investigated whether reported risk estimates

doi: 10.1111/j.1365-2222.2008.02939.x Clinical and Experimental Allergy, 38, 634–642

!c 2008 The Authors

Journal compilation !c 2008 Blackwell Publishing Ltd

Food$allergy

Atopic$eczema

Allergic$rhini4s

Asthma

Hospitalisa4on

0.8

1.0

1.2

1.4

1.6

(asth

ma)

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

VD

CS+

vaginalseeding CS

The importance of prenatal probiotic supplementation in eczema prevention

Pre- & postnatal supplementationn=2 75711 studies(pooled data)

OR 0.89 (95% CI 0.59-1.35) p=0.59Number needed to treat = 50

OR 0.54 (95% CI 0.50-0.59) p<0.001Number needed to treat = 12

Only postnatal supplementationn=6384 studies(pooled data)

TABUT - probiotics generally given from gestational week 36Forsberg A, West CE, Prescott SL, Jenmalm MC: Pre- and probiotics for allergy prevention: time to revisit recommendations? Clin Exp Allergy 2016; 46: 1506-1521

+ Cabana et al Pediatrics 2017; in press.n=184, no effect on eczema

BUT - not clear preventive effects on respiratory allergies

Ege et al J Allergy Clin Immunol 2006; 117: 817

Maternal farm exposure during pregnancy important for allergy preventive effects

Experimental studiesMaternal TLR signaling is required for prenatal asthma protection by the nonpathogenic microbe Acinetobacter

lwoffii F78Conrad et al J Exp Med 2009; 206: 2869-77

New study withprobiotic

supplementation already from

gestational week 20 started

Abrahamsson TR, Wu RY, Jenmalm MC: Gut microbiota and allergy: the importance of the pregnancy period. Pediatr Res 2015; 77: 214-9.

Jenmalm MC: The mother-offspring dyad: microbial transmission, immune interactions and allergy development. J Intern Med 2017; 82: 484-95.

Brand et al: Epigenetic regulation in murine offspring as a novel mechanism for transmaternal asthma protection induced by microbes. J Allergy Clin Immunol 2011; 128: 618–25

Schaub et al: Maternal farm exposure modulates neonatal immune mechanisms through regulatory T cells. J Allergy Clin Immunol 2009;123: 774–82 (hypometylation Foxp3 locus)

Infancy

placenta

maternalmicrobiotagut, oral?

maternalmicrobiotamilk, skingut, oral?

immuneimprinting

immunematuration

maternalIgG

antibodies maternalIgA

antibodies

Delivery

maternalmicrobiotagut, vaginal

infant intestinal IgA responses

Serie2

Serie1infant intestinalT cells

Prenatal

Serie2

Serie1

Figure from Jenmalm MC, Prescott SL: The intestinal microbiota and the child’s immune system.In: Browne PD, Claassen E, Cabana MD: Microbiota in health and disease: from pregnancy to childhood. Wageningen Academic Publishers; 2017.

via epigenetic mechanisms?

Prenatal microbial

immunomodulatoryfactors

Dysregulatedinfant immunity,

allergydevelopment

Mismatchedpostnatal

environment

BIRTH

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

Anticipatorymodulation of

offspring immunity via epigenetic

mechanisms

Conclusions

Gut microbiota important rolein immune and allergy development,

potentially via epigenetic mechanisms, more detailed studies required

Further studies required to recommendprobiotics for allergy prevention

Interesting to evaluate maternal probiotic or prebiotic supplementation during longer part of pregnancy,incl immunomodulation

& epigenetic effects

EAACI Allergy School 2018-03-16

Thanks!Parents and children

in our studiesDiv of Pediatrics, LiUThomas AbrahamssonMalin Fagerås Böttcher

Karel DuchénAnne-Marie FornanderKarin Fälth-Magnusson

Kicki HelanderTed JakobssonLena Lindell

Lennart NilssonKristina Warstedt

Div of Inflammation Medicine, LiUMartina Abelius

Judit Arvelund-SvenssonChristina Ekerfelt

Jan ErnerudhAnna Forsberg

Dhanapal GovindarajJohanna HuomanCamilla Janefjord

Ratnesh Bhai MehtaJenny Mjösberg

Georgia Papapavlou Marie Persson

Lina Tingö

Div of Obstetrics & Gyn, LiUGöran Berg

Leif Matthiesen

Karolinska InstitutetBengt BjörksténLars Engstrand

Hedvig Jakobsson

KTHAnders Andersson

Div of PediatricsRyhov, Jönköping

Göran Oldaeus

Stockholm UniversityEva Sverremark-Ekström

Ylva Sjögren

Univ of AlabamaBen ChristmannCharles O Elson

Univ of Western AustraliaSusan Prescott

Umeå UniversityChristina West

Tartu UnivKaja JulgeTiia Voor

CSISP-FISABIO IATA-CSIC, Valencia

MCarmen ColladoMajda Dzidic

Alex Mira

EAACI Allergy School 2018-03-16