ILSI SEAR A’Asia Maternal & Infant Nutrition Australia...
Transcript of ILSI SEAR A’Asia Maternal & Infant Nutrition Australia...
“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.
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
24 months Infant Infant Infant
36 months Infant Infant Infant Infant
Biospecimens
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
24 months 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
6 months 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
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
6 months 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
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
6 months 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
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
6 months 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
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?
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?
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?
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?
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?
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?
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
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.
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).
C. De Filippo et al., Proc Natl Acad Sci U S A 107, 14691 (Aug 17, 2010).
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.
!
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
File: BIS C0191 12MTH FoxP3 MNC.006
Sample ID: Tregs
Patient ID: FOXP3/4/45RA
Tube: Untitled
Acquisition Date: 15-Jun-12
Gate: G3
Gated Events: 7505
Total Events: 22365
X Parameter: FL1-H (Log)
Y Parameter: FL3-H (Log)
Region Events% Gated% Total
Lymphocytes 7505 100.00 33.56
Other lymphocytes 0 0.00 0.00
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
File: BIS C0191 12MTH FoxP3 MNC.006
Sample ID: Tregs
Patient ID: FOXP3/4/45RA
Tube: Untitled
Acquisition Date: 15-Jun-12
Gate: No Gate
Gated Events: 22365
Total Events: 22365
X Parameter: FSC-H (Linear)
Y Parameter: SSC-H (Linear)
Region Events% Gated% Total
Lymphocytes 15133 67.66 67.66
Other lymphocytes 9850 44.04 44.04
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
BIS C0191 12MTH FoxP3 MNC.006
Lymphocytes
100
101
102
103
104
FL3-H
100 101 102 103 104
FL1-H
BIS C0191 12MTH FoxP3 MNC.006
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.
!
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
File: BIS C0191 12MTH FoxP3 MNC.006
Sample ID: Tregs
Patient ID: FOXP3/4/45RA
Tube: Untitled
Acquisition Date: 15-Jun-12
Gate: G3
Gated Events: 7505
Total Events: 22365
X Parameter: FL1-H (Log)
Y Parameter: FL3-H (Log)
Region Events% Gated% Total
Lymphocytes 7505 100.00 33.56
Other lymphocytes 0 0.00 0.00
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
File: BIS C0191 12MTH FoxP3 MNC.006
Sample ID: Tregs
Patient ID: FOXP3/4/45RA
Tube: Untitled
Acquisition Date: 15-Jun-12
Gate: No Gate
Gated Events: 22365
Total Events: 22365
X Parameter: FSC-H (Linear)
Y Parameter: SSC-H (Linear)
Region Events% Gated% Total
Lymphocytes 15133 67.66 67.66
Other lymphocytes 9850 44.04 44.04
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
BIS C0191 12MTH FoxP3 MNC.006
Lymphocytes
100
101
102
103
104
FL3-H
100 101 102 103 104
FL1-H
BIS C0191 12MTH FoxP3 MNC.006
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
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
File: BIS C0191 12MTH FoxP3 MNC.006
Sample ID: Tregs
Patient ID: FOXP3/4/45RA
Tube: Untitled
Acquisition Date: 15-Jun-12
Gate: G3
Gated Events: 7505
Total Events: 22365
X Parameter: FL1-H (Log)
Y Parameter: FL3-H (Log)
Region Events% Gated% Total
Lymphocytes 7505 100.00 33.56
Other lymphocytes 0 0.00 0.00
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
File: BIS C0191 12MTH FoxP3 MNC.006
Sample ID: Tregs
Patient ID: FOXP3/4/45RA
Tube: Untitled
Acquisition Date: 15-Jun-12
Gate: No Gate
Gated Events: 22365
Total Events: 22365
X Parameter: FSC-H (Linear)
Y Parameter: SSC-H (Linear)
Region Events% Gated% Total
Lymphocytes 15133 67.66 67.66
Other lymphocytes 9850 44.04 44.04
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
BIS C0191 12MTH FoxP3 MNC.006
Lymphocytes
100
101
102
103
104
FL3-H
100 101 102 103 104
FL1-H
BIS C0191 12MTH FoxP3 MNC.006
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.
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