ilsi sear a’asia maternal & infant nutrition australia...

ILSI SEAR A’Asia – Maternal & Infant Nutrition – Australia, August 2014

(www.ilsi.org/SEA_Region)

Bach et al,

NEJM, 2012

“In the absence of urgent action, the rising financial

burden of these [non-communicable] diseases will reach levels that are beyond

the capacity of even the wealthiest countries in the

world to cope”.

Dr Margaret Chan

Director-General of the World Health Organization

Many NCDs (including allergy1, asthma2 and

cardiovascular disease3) have their origins in

early life.

-Developmental Origins of Health and Disease

(DOHaD)

1. Prescott SL. Curr Opin Allergy Clin Immunol 2003;3(2):125-32.

2. Ranganathan S. Eur Respir J 2012;36(4):716-7.

3. Singhal A. Adv Exp Med Biol 2009;646:51-8.

The majority NCDs are characterised by

chronic and abnormal inflammation1.

1. Renz H, et al. Nat Immunol 2011;12(4):273-7.

Prescott, S

JACI, 2013

Epidemiology Basic

science

• Population derived birth

cohort

• (n = 1,069) with antenatal

recruitment

Timepoint Blood Faeces Nasal swab Urine Hair Br. milk Tissue

28/40 Maternal

36/40 Maternal Maternal

Birth Cord blood Infant Infant Cord,

placenta

1 month Infant Infant Infant Mat. & inf. Maternal

3 months

6 months Infant Infant Infant

9 months

12 months Infant Infant Infant Infant


36 months Infant Infant Infant Infant

Biospecimens

Physiological, physical & neurodevelopmental measurements

Timing Lung

function

Aortic

intima-

media

thickness

Eczema Height,

weight, HC

Skin fold

thickness

Blood

pressure

Skin prick

testing

Oral food

challenges

Neuro-

development

al testing

28 wk of

preg.

Maternal

Birth Infant Infant

1 month Infant Infant Infant Mat, Pat,

Infant

Infant Infant


9 months Infant

1 Year Infant Infant Infant Infant Infant

2 Years Infant Infant

4 Years Infant Infant Infant Infant Infant Infant Infant

Domain Anten. Birth 1m 3m 6m 9m 1y 18m 2y 4y

Maternal health/meds + + +

Family medical history +

Demographic & SES + +

Pets/Livestock + + +

Lifestyle + + +

Maternal diet +

Breast feeding + + + + + +

Infant diet + + + + + + +

Infant health & meds + + + + + +

Home environment + + +

Neurodevelopment + + + +

Questionnaire measures

Maternal diet at 28 weeks of pregnancy - Cancer Council Victoria’s Dietary Questionnaire for Epidemiological Studies (DQES)1.

First year of life - modified form of the Phase 3 ISAAC questionnaire2.

18 months and 4 years - Melbourne Infant Feeding and Nutrition Trial questionnaire3.

1. Hodge A, et al. Aust N Z J Public Health 2000;24:576-83.

2. Ellwood P, et al. Of J I Union Tub Lung Dis. 2009;13:1174-82.

3. Campbell K, et al. PEDIATRICS Vol. 131 No. 4 April 1, 2013

pp. 652 -660.

Questionnaire measures

What is the relationship between the ‘Westernised’ gut microbiome and

immune related disease?

What factors lead to abnormal lung development and asthma?

What is the relationship between vitamin D status and allergic disease?

What factors lead to the initiation and potentiation of atherosclerosis during

early life?

What are the levels of specific modern chemicals in Australian women during

pregnancy and do these relate to infant neurodevelopment?

Food allergy

3-fold increase in emergency department presentations due to food allergy anaphylaxis since the late 1990s(1) 10% of one year old infants living in Melbourne have challenge-proven IgE-mediated food allergy(2). 1. W. K. Liew, E. Williamson, M. L. Tang, J Allergy Clin Immunol 123, 434 (Feb, 2009). 2. N. J. Osborne et al., J Allergy Clin Immunol 127, 668 (Mar, 2010).

Elie Metchnikoff, The Nature of

Man, 1903

“…human intestine contains

and enormous range of

bacteria…”

“…is very varied, and contains

and immense number of

different species…about which

little is known”

“it contributes nothing to the

wellbeing of man…”

Bacteria within the human gastrointestinal tract outnumber host cells by 10:1 and host genes by 100:1 1. K. E. Fujimura, N. A. Slusher, M. D. Cabana, S. V. Lynch, Expert

Rev Anti Infect Ther 8, 435 (Apr).

2. J. K. Nicholson et al., Science 336, 1262 (Jun 8).

Number

Function

Farm children: less asthma & atopy

The co-evolution of humans and commensal microbiota has resulted in a symbiotic relationship in which the metabolic products of gut microbiota play a crucial role in maintenance of gut barrier function and immune homeostasis. 1. L. V. Hooper, D. R. Littman, A. J. Macpherson, Science 336, 1268 (Jun 8, 2012).

Substantial inter-individual variation in the microbiome, related to environmental(1) and possibly genetic(2) factors. 1.T. Yatsunenko et al., Nature 486, 222 (Jun 14). 2.S. Z. Josefowicz et al., Nature 482, 395 (Feb 16, 2012).

Germ free mice are unable to develop oral immune tolerance, and their capacity to do so can be restored if the gut microbiota is reconstituted, but only if reconstituted in the immediate postnatal period. N. Sudo et al., J Immunol 159, 1739 (Aug 15, 1997).

Specific gut microbiota signatures can induce food antigen sensitisation and anaphylaxis. M. Noval Rivas et al., J Allergy Clin Immunol 131, 201 (Jan, 2013).

Microbiota diversity and eczema

Wang M, et al. J Allergy Clin Immunol 2008;121(1):129-34. Abrahamsson TR, et al. J Allergy Clin Immunol 2012;129(2):434-40, 440 e1-2. Ismail IH, et al. Pediatr Allergy Immunol 2012;23(7):674-81.

Azad et al, CMAJ, March 2013

A recent study has reported an association between increased faecal microbiota diversity and eczema!!! Nylund et al, BMC Microbiol, Jan 2013

The modern diet is lower in fermentable fibre and higher in fat than 40 to 50 years ago1; Developing countries are moving away from a diet of locally grown fruit and vegetables as they become more Westernised2. 1. K. M. Maslowski, C. R. Mackay, Nat Immunol 12, 5 (Jan, 2011). 2. G. Devereux, Nat Rev Immunol 6, 869 (Nov, 2006).

C. De Filippo et al., Proc Natl Acad Sci U S A 107, 14691 (Aug 17, 2010).

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2930426/


Acetate is the only known ligand for GPR43 Brown. J Biol Chem 2003;278(13):11312-9.

1. Furusawa Y, et al. Nature 2013;504:446-50.

2. Arpaia N, et a. Nature 2013;504:451-5.

3. Trompette A, et al. Nature Medicine 2014.

Thorburn, Immunity, 2014

But what about in humans?

Bottcher et al, Clin Exp Allerg, 2000

!

FoxP3

CD

45R

A

File: BIS C0191 12MTH FoxP3 MNC.006

Log Data Units: Linear Values

Sample ID: Tregs

Patient ID: FOXP3/4/45RA

Tube: Untitled

Acquisition Date: 15-Jun-12

Gate: G1

Gated Events: 15133

Total Events: 22365

X Parameter: FL2-H (Log)

Y Parameter: SSC-H (Linear)

Region Events% Gated% Total

Lymphocytes 15133 100.00 67.66

Other lymphocytes 7605 50.25 34.00

CD4+ Lymphocytes 7505 49.59 33.56

CD45+ve FoxP3 453 2.99 2.03

45RA+ve 9779 64.62 43.72

45RA-ve 2694 17.80 12.05

CD45-ve FoxP3 206 1.36 0.92

FoxP3 high+ve 136 0.90 0.61


Sample ID: Tregs


Tube: Untitled


Gate: G3

Gated Events: 7505

Total Events: 22365


Y Parameter: FL3-H (Log)


Lymphocytes 7505 100.00 33.56


CD4+ Lymphocytes 7505 100.00 33.56

CD45+ve FoxP3 435 5.80 1.95

45RA+ve 4944 65.88 22.11

45RA-ve 1770 23.58 7.91

CD45-ve FoxP3 197 2.62 0.88

FoxP3 high+ve 132 1.76 0.59


Sample ID: Tregs


Tube: Untitled


Gate: No Gate

Gated Events: 22365

Total Events: 22365

X Parameter: FSC-H (Linear)



Lymphocytes 15133 67.66 67.66


CD4+ Lymphocytes 7877 35.22 35.22

CD45+ve FoxP3 907 4.06 4.06

45RA+ve 11002 49.19 49.19

45RA-ve 4325 19.34 19.34

CD45-ve FoxP3 1725 7.71 7.71

FoxP3 high+ve 538 2.41 2.41

0200

400

600

800

1000

SSC-H

100 101 102 103 104

FL2-H

BIS C0191 12MTH FoxP3 MNC.006

Other lymphocytesCD4+ Lymphocytes

0200

400

600

800

1000

SSC-H

00 200 400 600 800 1000FSC-H


Lymphocytes

100

101

102

103

104

FL3-H

100 101 102 103 104

FL1-H


CD45+ve FoxP3

45RA+ve

45RA-veCD45-ve FoxP3

FoxP3 high+ve

Page 1

BIS C0244

12MTH

Naïve CD4+

Memory CD4+

1. Resting Treg

3. FoxP3+ve T cells

2. Activated Treg

Miyara et al, Immunity, 2009.

CD4+/FoxP3low/CD45RA+ rTreg

Birth 6MTH 12MTH

2

3

4

5

6

7

%

Control (n=502, 524 & 468)

Food Allergic (n=24, 27 & 33)

Tolerant (n=20, 22 & 26)

**

**

!

FoxP3

CD

45R

A


Log Data Units: Linear Values

Sample ID: Tregs


Tube: Untitled


Gate: G1

Gated Events: 15133

Total Events: 22365




Lymphocytes 15133 100.00 67.66


CD4+ Lymphocytes 7505 49.59 33.56

CD45+ve FoxP3 453 2.99 2.03

45RA+ve 9779 64.62 43.72

45RA-ve 2694 17.80 12.05

CD45-ve FoxP3 206 1.36 0.92

FoxP3 high+ve 136 0.90 0.61


Sample ID: Tregs


Tube: Untitled


Gate: G3

Gated Events: 7505

Total Events: 22365


Y Parameter: FL3-H (Log)


Lymphocytes 7505 100.00 33.56


CD4+ Lymphocytes 7505 100.00 33.56

CD45+ve FoxP3 435 5.80 1.95

45RA+ve 4944 65.88 22.11

45RA-ve 1770 23.58 7.91

CD45-ve FoxP3 197 2.62 0.88

FoxP3 high+ve 132 1.76 0.59


Sample ID: Tregs


Tube: Untitled


Gate: No Gate

Gated Events: 22365

Total Events: 22365

X Parameter: FSC-H (Linear)



Lymphocytes 15133 67.66 67.66


CD4+ Lymphocytes 7877 35.22 35.22

CD45+ve FoxP3 907 4.06 4.06

45RA+ve 11002 49.19 49.19

45RA-ve 4325 19.34 19.34

CD45-ve FoxP3 1725 7.71 7.71

FoxP3 high+ve 538 2.41 2.41

0200

400

600

800

1000

SSC-H

100 101 102 103 104

FL2-H


Other lymphocytesCD4+ Lymphocytes

0200

400

600

800

1000

SSC-H

00 200 400 600 800 1000FSC-H


Lymphocytes

100

101

102

103

104

FL3-H

100 101 102 103 104

FL1-H


CD45+ve FoxP3

45RA+ve

45RA-veCD45-ve FoxP3

FoxP3 high+ve

Page 1

BIS C0244

12MTH

Naïve CD4+

Memory CD4+

1. Resting Treg

3. FoxP3+ve T cells

2. Activated Treg

Miyara et al, Immunity, 2009.

Epidemiology

hypotheses e.g. dietary

fermentable fibre

Mechanistic

hypotheses e.g. SCFAs & nTregs

C. De Filippo et al., Proc Natl Acad Sci U S A 107, 14691 (Aug 17, 2010).



Our Women’s Our Children’s

Fundraising Committee

The Scobie & Claire

Mackinnon Trust

Investigator Team: Peter Vuillermin, Anne-Louise

Ponsonby, Mimi Tang, Richard Saffery, Katie Allen, John

Carlin, Terry Dwyer, Justine Ellis, Fiona Collier, Anne-

Hotchin, Mike Forrester, Peter Sly, Pat Holt, Sarath

Ranganathan, Colin Robertson, Graham Hall, David

Burgner, Michael Cheung, Jennifer Koplin, David Martino

Collaborators: Leonard Harrison, Yuxia Zhang, David

Topping, Michael Conlon, Michael Skilton, David

Celermajer

Fieldwork Team: Elizabeth Sykes, Melissa Cadwell, Kaye

Hollingworth, Stacey Hayes, Louise King, Natalie Bond,

Catherine Lloyd-Johnsen, Heather Anderson, Kristin

Ferguson, Thomas Battersby, Karen Hosking

Students: John Molloy, Kate McCloskey, Christos

Symeonides, Ranjana Warrier, Luka Campbell, Sabina

Stellmaker, Suzanne Luong, Nahaani Sutton, Ryan Yu Fai

Hon, Nakita Clements

Barwon Biomedical Research Laboratory: Carling Southall

and Danielle Kennedy

Data management and biostatistical team: Luke Stephens,

Kim Jachno, Louise King, Angela Pezic

E-support: Luke Stephens

General support: William Siero, Helen Raschella, Angela

Pezic, Barwon Obstetric and Midwifery teams

The Sheppard Foundation

ilsi sear a’asia maternal & infant nutrition australia...

Documents