Associate Professor MarkVickersLiggins Institute

The University of Auckland

18:10 - 18:30 Early Life Nutritional Programming - Can We Change Our

Children's Futures?

Associate Professor Mark Vickers,Liggins Institute, University of Auckland, New Zealand.GP CME Rotorua June 10th, 2016

Early Life Nutritional Programming -Can we change our children's futures?

Introductiono obesity and related metabolic disorders

such as type 2 diabetes have reached epidemic levels

o these increases are largely attributed to lifestyle factors such as poor diet and the decline in physical activity

o now well-established that alterations in early life nutrition (ELN) can increase riskfor obesity and metabolic disorders in offspring

Developmental Programming

The First 1000 Days- much of a child’s future is determined by the quality of

nutrition in the first 1000 days

- initial focus was undernutrition but effects of maternal overweight and obesity are leading to a double burden of disease at both ends of the nutritional spectrum

Preconception +

Better understanding of ELN offers avenuesfor prevention rather than treatment

Early life food activity

What determines our health potential?

Disease risk

Developmental

Plasticity

Critical windows of opportunity ?

B ir th w e ig h t (k g )

Imp

air

ed

Glu

co

se

To

lera

nc

e (

%)

0

1 0

2 0

3 0

4 0

< 2 .5 > 4 .5

The “Barker” Hypothesis- Programming of Type 2 Diabetes andimpaired glucose tolerance in adultmen based on birthweight

- Similar data for blood pressure,heart disease, stroke etc….

- Early emphasis was on low birthweight

Margaret Burnside

Lady Inspector of Midwives, 1905-

Records enabled tracing of 16000 men and women born in Hertfordshire between 1911-1930

The Dutch Famine 1944-1945- daily intake reduced from 1800

calories to 400-800 calories

- exposure to maternal malnutrition was associated with 2-fold risk of childhood obesity

- 3-fold increase in cardiovasculardisease and atherogenic lipid profiles

- marked increase in risk of breast cancer

- transmission to 2nd generation

From Godfrey et al., TEM, 2010

- The earlier the intervention the bigger the effect on later risk reduction

The importance of the early life period

What can be programmed ?Cardiovascular system

Respiratory system

Immune system

Endocrine system

Reproductive system

CNS

Skeletal Muscle

Bone

Liver

Kidney

Ageing

CHD, blood pressure

lung volume

stress axis

puberty, PCOS

depression

allergies, asthma

insulin resistance

bone density

cholesterol

renal function

lifespan

Appetite, adipocytes obesity

Transgenerational Effects

F0 (mother)

F1 (fetus)

Germ cells

F2 generation

Environmental effectse.g. maternal obesity, stress

The effects of a single environmental exposure can be transmittedtransgenerationally. An adverse maternal environment (F0) effects not only thedevelopment of the fetus (F1) but can also affect the germ cells which form the F2

generation.

Not just maternal nutrition !- increasing evidence for the role

of paternal factors in health and well-being of offspring

- Weight loss in males prior to conception can improve health outcomes for the child

- Shared parental responsibility

Pre-clinical models are a key tool for the investigation of mechanisms underlying the early life development of obesity and related metabolic disorders

Programming of Disease:Evidence from pre-clinical models

Control UN Mother

Maternal Undernutrition

Balanced Diet from Birth

Control UN

Vickers et al., Am J Physiol. 2000

Maternal Undernutrition Model

Blood pressure Insulin Leptin Fat Pad (%)

Intake C-Peptide Activity R. Temp

Control UN90

100

110

120

130

140

150

*

Systo

lic B

P (

mm

Hg

)

Control UN0.0

0.5

1.0

1.5

2.0

2.5

3.0

*

ng

/ml

Control UN0

5

10

15

20

25

30

*

ng

/ml

Control UN0

1

2

3

4

5

6 *

%B

W

Control UN

0.15

0.20

0.25

0.30

*

kcal/g

BW

Control UN

2500

3000

3500

4000

4500

*

Dis

tan

ce t

ravelle

d (

cm

)

Control UN0

500

1000

1500

2000

*

pM

Control UN

35.0

35.5

36.0

36.5

37.0

37.5

*

C

* p< 0.05 for maternal diet effect

+ learning, stress reactivity and………..

Maternal Obesity

- over 60% of women of reproductive age are overweight- obesity “epidemic” in pregnant women- leads to increased complications of pregnancy including

miscarriage, hypertension, gestation diabetes

- maternal obesity leads to increased risk of obesity and metabolic disease in offspring

B o d y fa t

C o n tro l M a te rn a l H F C o n tro l M a te rn a l H F

0

1 0

2 0

3 0

4 0

**

M a le s F e m a le s

% B

od

y F

at

- maternal high fat nutrition induces significant obesity in offspring,independent of the level of postnatal diet

Maternal Obesity Chow fed offspring of mothers fed a HF diet

Howie et al, J Physiol, 2009

Control MHF

Maternal Sugar Intake

C o n t ro l F ru c to s e

0

1

2

3

4

P la s m a le p tin , b ir th

*

ng

/ml

Maternal fructose intakeresults in increases in obesity-related hormonesin offspring at birth

Vickers et al., Endocrinology 2011

Can programming be prevented via early life modifications?

What interventions ?• Dietary

• Lipids/fatty acids, pre-/probiotics, taurine, polyphenols, vitamins, methyl donors etc…

• Pharmacologic• Leptin, growth hormone, insulin sensitizers

(GLP-1 analogs etc)

• Behavioral/lifestyle• Exercise, counselling etc…

When to intervene ?• Pre-conception, pregnancy, lactation,

early infancy/childhood

Maternal Effects

0 .0

0 .2

0 .4

0 .6

HO

MA

IR

Ma

tern

al

+

*H F : N S

C L A : P < 0 .0 5

In te ra c t io n : N S

C O N C L A H F H F C L A

• A maternal high fat diet significantly impairs insulin sensitivity in both mother and offspring and is normalised with CLA

*HF vs CON; +HFCLA vs HF, n=6 litters/group

Maternal lipid supplementationConjugated linoleic acid (c9, t11-CLA )

0 .0

0 .1

0 .2

0 .3

HO

MA

IR

We

an

lin

g M

ale

*

C O N C L A H F H F C L A

H F : N S

C L A : P < 0 .0 1

In te ra c t io n : p < 0 .0 5

O ffs p r in g e f fe c ts

Folic acid1

Glycine2

Choline3

Mixed supplements4

Maternal supplementationimproves metabolic and cardiovascular outcomesin offspring following both undernutrition andmaternal obesity

1. Torrens et al., (2006) 2. Jackson et al., (2002)3. Vickers et al., (2012) 3. Carlin et al., (2013)

Epigenetics & Dietarymethyl donors

- change in gene function without a change in gene sequence

- the gut microbial community has been called a “forgotten organ”

- manipulation of the flora to enhance the beneficial components represents a promising therapeutic strategy for a range of disorders

- supplementation of infant formula with oligosaccharides may compensate for the lack of some of the complex moleculesnaturally present in human milk?

Role of the gut microbiota

0.8g/100ml

(n=27)

0g/100ml

(n=33)

0.4g/100ml

(n=30)

log

10

of

CF

U/g

we

t fa

ec

es

(m

ed

ian

, IQ

R)

2

3

4

5

6

7

8

9

10

11

12

Reference range (IQR) of breastfed infants (n=15)

Bifidobacteria

Group difference according to Mann-Whitney U-test: * p<0.05 vs. 0.0, # vs. 0.4

**#

Breast-fed scGOS/lcFOS Standard Formula formula

Specific mixture of oligosaccharides – impact on the intestinal microbiota development

Moro et al, 2002

Oligosaccharide supplementation to infant formula can change the microbiota profile to that similar of a breastfed infant

Prebiotics offer protection against infection in formula fed infants

After 6 months After 24 months

Arslanoglu S, Moro GE, Boehm G. J. Nutr.; 2007 137(11): 2420-4 Arslanoglu S, Moro GE, Schmitt J, Boehm G.,

J. Nutr. 2008; 138: 1091–1095.

Cu

mu

ltiv

e I

nc

ide

nc

e (

%)

0

5

1 0

1 5

2 0

2 5

3 0

A n y

in f e c t io n

A n y r e c u r r e n t

in f e c t io n

R e c u r r e n t

U R T I

*

**

P la c e b o

s c G O S /lc F O S

Infe

ctio

us

ep

iso

de

s p

er

in

fa

nt

0

1

2

3

4

5

6

O v e r a l l

e p is o d e s

F e v e r

e p is o d e s

A n t ib io t ic

p r e s c r ip t io n s

*

**

P la c e b o

s c G O S /lc F O S

*p<0.05 from placebo

- Early dietary intervention with probiotic oligosaccharides haslasting effects on reducing infection rates

Protection Against Allergy in Formula Fed Infants: Atopic DermatitisAfter 6 months After 24 months

Arslanoglu S, Moro GE, Schmitt J, Boehm G.,

J. Nutr. 2008; 138: 1091–1095.

Moro GE, Arslanoglu S, Stahl B, Jelinek J, Wahn U, Boehm G. Arch Dis Childhood 2006 ; 10: 814-19.

Cu

mu

lati

ve

in

cid

en

ce

of

ato

pic

de

rma

titi

s (

%)

C o n t ro l s c G O S / lc F O S

0

5

1 0

1 5

2 0

2 5

(n = 1 0 4 ) (n = 1 0 2 )

**

2 3 .1 %

9 .8 %

Cu

mu

lati

ve

in

cid

en

ce

of

ato

pic

de

rma

titi

s (

%)

C o n t ro l s c G O S / lc F O S

0

1 0

2 0

3 0

(n = 6 8 ) (n = 6 6 )

*

2 7 .9 %

1 3 .6 %

scGOS- short chain galacto-oligosaccharidesLc-FOS – long chain fructo-oligosaccharides

Early prebiotic oligosaccharide supplementation: Reduced prevalence of allergic manifestations at 5y follow-up

Arslanoglu S. et al. 2012. J. Biol. Reg. & Homeo. Ag.

scGOS – short chain galacto-oligosaccharideslc-FOS: long chain fructo-oligosaccharides

Pre

va

len

ce

(%

)

0

5

1 0

1 5

2 0

2 5

3 0

A n y

a lle rg y

A n y p e rs is te n t

a lle rg y

P e rs is te n t

a to p ic

d e rm a titis

P e rs is te n t

w h e e z in g

R h in o c o n ju n c tiv it is

* *p = 0 .0 9

*

P la c e b o

s c G O S /lc F O S

Why is the ELN messagenot on the “health radar” ?

- impact of ELN on programming of disease has been well known for decades

- offers knowledge for prevention rather than treatment

- has the message been poorly communicated ?

Long time-frame to consider:

Pre-conception until 3 years of age

Consistency to avoid confusion

An example…….

“Most mothers-to-be agreed that the structure ofprenatal visits are not responsive to their individualneeds, so they turned to technology to fill theirknowledge gaps."

"They would rather watch videos and use social mediaand pregnancy-tracking apps and websites in order toget the information they need.”

- Important to get the right informationacross based on practical, evidence-basedrecommendations

Getting the right information

Kraschnewski JL et all.; J Med Internet Res. 2014 ;16(6):e147.

Practical Guidelines for Positive Action

- Most dietary advice is offered withthe aim of avoiding health issues during pregnancy and minimising risk

- The ELN booklet was different and aimed to provide nutritional guidanceto help optimise the long term futurehealth of the baby

www.earlylifenutrition.org

Aim of the ELN Report

- To provide a current overview of early life nutrition research

- Provide practical, evidence based recommendations to maximisenutritional status before and during pregnancy, as well as infancy and early childhood, when the foundations of futurehealth are created.

- Feedback demonstrated that there was a need for clear, evidence-basedguidelines

What are the key messages ?Pre-conception

What are the key messages ?Pregnancy

What are the key messages ?

0-12 months

1-3 years

Effective translation of research knowledge

Control IUGRControl IUGR

- Potential that interventions in setting of “intact” systems may lead to adverse outcomes

- how best to identify those “at risk” of programmed disorders ? – tailored approach, metabolic markers ?

- the first 1,000 days of life represents a vulnerable period for programming of NCD risk, and is an important target for prevention of later disease.

- the right nutrition during this developmental window can have a profound impact on a child’s later life disease risk and behavioural and cognitive development

- given the transgenerational impacts, it can also shape a society’slong-term health

- the ELN message has been poorly communicated in the past and there is a need to provide clear evidence-based recommendations to provide nutritional guidance to help optimise the long term future health of both mother and child

Discussion

AcknowledgementsThe Developmental Programming Group,Liggins Institute, University of Auckland

Marsden Fund Royal Society of New Zealand

Health Research Council of New Zealand

Gravida: National Centre for Growth and Development

AcknowledgementsELN Experts Panel

Professor Peter SW Davies, Queensland Children’s Medical Research Institute,University of Queensland, Australia.

Professor John Funder,Prince Henry’s Institute, Melbourne, Australia.

A/Professor Debbie Palmer,University of Western Australia, Australia.

A/Professor John Sinn,University of Sydney, Australia.

A/Professor Clare Wall,University of Auckland, New Zealand

Danone Nutricia provided funding to support the production of the ELN report but had no input into the content or recommendations therein

- change in gene function without achange in gene sequence

- epigenetic gene promoter methylation at birth is associatedwith child's later adiposity (Godfrey et al., Diabetes, 2011)

- maternal supplementation withω-3 PUFA during pregnancy maymodulate global methylation levels(Lee et al, Am J Nutr., June,2013

- epigenetic mechanisms could provide attractive targets for prenatal modulationof obesity risk

Epigenetics