NEW AREAS OF NUTRITION
RESEARCH
Dr. SESIKERAN, MD, FAMS
Director
National Institute of Nutrition
(Indian Council of Medical Research)
Hyderabad – 500 007
1
New Areas of Nutrition Research
Micronutrient Research
Focus: Iron, Zinc, Vitamin A, Folic acid, Vitamin B12
Center of excellence in micronutrient
research
 Basic research
 Clinical research
 Programme research
 Policy research
2
CEMR
Basic research
Clinical Research
Programme research
Policy research

Biomarkers of micronutrient status

Currently available biomarkers represent steps too far along
the disease process
 Proteomics, Nutritional genomics to identify subclinical
indicator levels
 What are the cellular and molecular events leading to the
interventional effects? Hepcidin/Zinc transporters
 Functional indicators

Field friendly methods
Simultaneous determination of multiple micronutrient status
– DBS method
3
CEMR
Basic research
Clinical Research
Programme research
Policy research
 Updating of RDA requires establishing accurate methods.

Bioavailability of high priority micronutrients
This would allow us to establish the RDA for the
vulnerable
segments
of
the
population;
children, adolescent girls, pregnant and lactating and
non lactating women
 National data base on bioavailability of high priority
nutrients using the state- of- the art method of stable
isotopic method.
4
CEMR
Basic research
Clinical Research
Programme research
Policy research

The new and emerging nanotechnology

Discovery,
development,
and
delivery
micronutrient intervention strategies

Sensitive biomarkers of micronutrient status
of
5
CEMR





Basic research
Clinical Research
Programme research
Policy research
Bioavailability trials
Efficacy trials- RCT/Cohort studies
Evidence- based micronutrient supplementation models
for its replication.
Relationships between disease of stomach & intestine
such as helicobacter pylori and other infections and
micronutrients
Research
leads
from
multiple
micronutrient
supplementation study – implications in stress, attention
concentration and reduced duration of illness, increases
height, weight, bone area, fat-free mass,
6
CEMR
Basic research
Clinical Research
Programme research
Policy research
Translational research-food fortification
Large scale epidemiological data
Country investment
Public private partnerships
Programme monitoring and evaluation

Intervention trials in an integrated manner

Dietary diversification infrastructure to test regional diets for
its health benefits

Biofortification:
Conventional
plant
breeding
and
micronutrient dense plants holds promise for enhancing the
nutrient content of staple foods.
7
CEMR

Basic research
Clinical Research
Programme research
Policy research
Strategies: Innovative strategies–single vs multiple:
ideal
combinations of micronutrients for anemia
prevention and

control
Guidelines: Country and region specific (type and level
of nutrient)

Economic analysis

Review National Nutrition Policy with regards to
micronutrients
8
New Areas of Nutrition Research:
Nutrition and Food Safety
I.
Molecular strategies to Reduce foodborne diseases to
improve nutritional status:
i)
Development of molecular detection methodologies:
-
Development of advanced techniques such as
molecular
fingerprinting
of
disease
causing/toxigenic fungal/bacterial strains and
formation of a database.
-
Establishing molecular epidemiology approaches
for investigation of foodborne diseases/outbreaks
(development of biomarkers).
9
Evolving Risk Assessment Strategies for
Toxins/contaminants Derived from
Processing
Eg:
Acrylamide, melamine.
Research for reducing levels of such
contaminants formed during processing
10
Addressing New food safety concerns:
Salt reduction and food safety

Studies on microbial safety of processed foods
with reduced sodium (sodium replacement food
preservatives: chloride salts of other ions such
as KCl, CaCl)

(Implications of Salt and Sodium Reduction on
Microbial Food Safety

Peter J. Taormina Critical Reviews in Food
Science and Nutrition 2010: 50: 3, C209 — 227)
11
Nutrition and food safety research (Contd…)
Enhance Research on food safety assessment techniques:
i)
Enhancement of safety assessment techniques for foods derived
from modern technological methods of food production (rDNA
technology/biotechnology):
ii)
Development of profiling techniques (microarrays, proteomics,
chemical fingerprinting with Nuclear Magnetic Resonance
techniques) for testing /understanding compositional changes in the
food modified to express various quality traits such as enhanced
nutritive value.
iii)
Enhancement of in silico approaches (bioinformatics) for assessing
specific properties such as allergenicity potential.
iv)
Evolving safety assessment techniques for foods expressing
pharmaceuticals (focus on toxicity, allergenicity, level of exposure).
12
Nutrigenetics: Nutrient-gene interactions /
lipidomics / genomics / proteomics

Understanding the nutrient-gene interactions in amelioration of
chronic diseases, insulin resistance, obesity and cardiovascular
diseases

by studying i) the enzymes, genes including their polymorphism of
lipid and lipoprotein metabolism and ii) the impact of various dietary
factors in the amelioration process of these conditions is an
important area.

Gene polymorphism is considered to be one of the important
components, which influences the individual responsiveness to the
environmental factors including diet.

Study the basic gene polymorphism of candidate genes involved in
lipid and lipoprotein metabolism namely apo AI, apo E, PPAR,
PPAR, PPAR, paraoxonase 1 and fatty acid binding protein in
experimental models of obesity and obese humans.

Dietary response of the individuals with these polymorphisms to the
supplementation of PUFA, forms the basis for studying nutrient
gene interactions/lipodomics/proteomics etc.
13
Fatty Acid Metabolism..

Scavenger receptor class BI is 82 KDa protein with 509 amino acids
and member of CD-36 super family of proteins. They are widely
expressed in the liver and other steroidogenic organs like adrenals
and gonads and bring about selective uptake of cholesteryl esters
from HDL particles.

SR-B1 is shown to be involved in the regulation of plasma HDL-C
levels and reverse cholesterol transport, cardio-protection,
steroidogenesis and reproduction (SR-BI).

Current research showed the role of SR-BI in cholesterol efflux
and/or influx, estrogen and vitamin E delivery.

Lower expression of SR-BI is also reported in adipose tissue and
skeletal muscle. However, its function in these tissues is not known
and no studies have revealed their functions beyond RCT,
vasodilatation and steroidogenesis
14
Fatty Acid Metabolism

It is possible that SR-BI functions as a membrane-fatty acid
transporter, especially in adipose tissue and skeletal
muscle.

Similarly even in humans, the role of CD 36, in fatty acid
translocation in adipose tissue and skeletal muscle has
been suggested.

The presence of high levels of soluble CD36 in plasma is
also considered as a marker for liver injury in conditions of
glucose intolerance.

Nutrients like vitamin A & E, PUFA up-regulate the
expression of SR-B1 and possibly CD 36 family of proteins.
Therefore, the role of these nutrients in ameliorating
dyslipidemia, insulin resistance and liver injury is an
important research area
15
Endoplasmic Reticular Stress (ER)

ER stress is an important event in the development of disease
processes like obesity, insulin resistance and associated hepatic
steatosis (Non alcoholic fatty liver disease NAFLD).

Cellular stress conditions lead to ER stress and result in the
accumulation of unfolded or misfolded protein (UPR & MPR) .

UPR pathway is considered as an important target for the treatment
of fatty liver disease which results in fibrosis.

Potential of certain compounds like PBA (Phenyl butyric acid)
TODCA (Taurodeoxy cholic acid) or over expression of molecular
chaperones (BUP/GRP 78) in ameliorating hepatic steatosis should
be tested.

Besides UPR pathway, polymorphism of ABCC2, which determines
the susceptibility to hepatic steatosis should also be considered.
16
Peri-natal Nutrition
Folic acid and Vitamin B 12
 Other than known neural tube defects with folic
acid deficiency the current research focuses on
role of FA and B12 in the causation of obesity
and chronic diseases.
 Role of prenatal Iron deficiency in
Behavioural & Cognitive development
CNS,
17
Peri-natal and early life Nutrition
Vitamin D

Some studies ( Lucknow & NIN) have shown maternal
Vitamin D status related to birth weight

In early infancy role of vitamin
D deficiency in
immune status , infections apart from growth is being
investigated.

Role of Essential fatty acids in pre and post natal
development

Identification Markers for identification of zinc
deficiency which exists even in developed countries
18
Research Agenda on Behavioral Change

To improve infant and young child feeding practices.
- Generalised formula
- Region specific formula

To help in proper adolescent growth – arrest the NCD
epidemic

To modify nutritional KAP of families as a unit

To care givers in the health and nutrition of elderly

Determinants of regulator of appetite – Behavioral or
neurochemical or both.
19
OMEGA-3 FATTY ACID (DHA) ASSOCIATED WITH
WORKING MEMORY, AMONG HEALTHY BOYS.

Preclinical and clinical imaging studies that suggest that dietary DHA
intake is a robust modulator of functional cortical activity”

It is unknown how DHA suppl may affect functional cortical activity in
humans. McNamara et al recruited 33 health boys aged 8-10 yr
randomly assigning them to one of two doses of DHA (400 or 1200 mg
per day, Martek Biosciences) or placebo for 8 wk.

The “main finding” from the fMRI data indicated significant increases
in the activation of the dorsolateral prefrontal cortex part of the brain in
the DHA groups – an area of the brain associated with working
memory. Changes in other parts of the brain, including the occipital
cortex (the visual processing centre) and the cerebellar cortex (plays a
role in motor control) were observed.

“These findings suggest that this imaging paradigm could be useful for
elucidating neurobiological mechanisms underlying deficits in cortical
activity in psychiatric disorders associated with DHA deficiencies,
including ADHD and major depression
20
Increased intakes of DHA may improve
mental function in middle age people

Increased blood levels of DHA were associated with improved
nonverbal reasoning and working memory in people between 35 and
54, but intakes of ALA and EPA were not.

The findings of a study (Muldoon et al, University of Pittsburgh)
suggested that DHA is related to brain health throughout the
lifespan and may have implications for clinical trials of
neuropsychiatric disorders. “Higher DHA was related to better
performance on tests of nonverbal reasoning and mental flexibility,
working memory, and vocabulary”. “Among the 3 key omega-3
PUFA, only DHA was associated with major aspects of cognitive
performance in non-patient adults younger than 55 yr”

The potential brain boosting benefits of omega-3 have been reported
by numerous studies, most recently at the Alzheimer's Association
2009 International Conference on Alzheimer's Disease (ICAD 2009)
in Vienna
21
Application of Metabolomics in Nutrition Research

Metabolomic approach led to identification of new
metabolites of phytochemicals, which can be used to
distinguish individuals fed different phytochemicalcontaining foods.

Nutritional metabolomics in the in vivo setting to
characterize responses to different diets in the context of
molecular pathways, physiology and health status.

Lankinen and colleagues studied the effect of
carbohydrate modification on serum metabolic profiles in
subjects with the metabolic syndrome
Nutrition , Metabolism & Cardiovascular Diseases (2009) 19, 816-824
22
Application of Metabolomics in Nutrition Research

Dietary carbohydrate modification may alter the
concentrations of proinflammatory lipids.

Metabolomics is a powerful tool for the study of
metabolic and lipid related disorders.

Human metabolome has been shown to be
sensitive to age, gut microbial composition and
personal health status.
Nutrition , Metabolism & Cardiovascular Diseases (2009) 19, 816-824
23
Anti-oxidant Research

Observational
evidence
is
strongly
suggestive
of
substantial evidence that eating plenty of antioxidant-rich
fruit and vegetables is associated with reduced risk of
chronic disease.

Observational
evidence
to
suggest
that
intake
of
individual antioxidants whether in food or spontaneous
use of supplements is associated with reduced risk of
chronic diseases.

There is very little direct experimental evidence that taking
extra antioxidants as supplements will yield long-term
holistic health benefits.
Journal compilation © 2009 British Nutrition Foundation Nutrition Bulletin, 34, 309-315
24
Non-Nutritional Component of Indian Plant Food

Reverse Pharmacology

Active
principles
Vs
combined
effect
of
components

Active principles or markers for standardization

Efficacy and Effectiveness Trails
25
Rank Prize Lecture – 2008
Global Nutrition Challenges for Optimal Health and Well-being
Ricardo Uauy, Camila Corvalan and Alan D. Dangour
 Major nutrition challenges faced today include:
a)
Addressing the pending burden of under nutrition (low
birth
weight,
severe
wasting,
stunting
and
Zn, retinol, Fe, iodine and folic acid deficits) affecting
those individuals living in conditions of poverty and
deprivation;
b)
Preventing nutrition-related chronic diseases (obesity,
diabetes,
CVD, some forms of
cancer and
osteoporosis) that, except in subSaharan Africa, are
the main causes of death and disability globally.
c)
Delaying or avoiding, via appropriate nutrition and
physical activity interventions, the functional
declines
associated with advancing age.
Proceedings of the Nutrition Society (2009), 68, 34-32.
26
Agricultural Technology for Better Nutrition

GM Crops for nutrition and food security

Marker assisted breeding to identify traits in lesser known
food
crops
and
selective
breeding
to
address
micronutrient inadequacies.

New Technologies like ultra rice, Soya based dhal
analogues - large scale effectiveness trials.
27
Epigenetics – Heritable changes in gene
expression that operate outside of DNA

Epigenetics - genes beyond the DNA

Switches - that turn genes on or off

Nutrition, stress, infection, inflammation? - control these
switches

Heritable effects in humans.
DNA methylation
Histone acetylation
Histone deacetylation
National Institute of Nutrition, Indian Council of Medical
Research, Department of Health Research (MHFW)
28
Vitamins/minerals/amino acids- affect DNA methylation
Choline
Methionine
Ch.dehydrogenose
Betaine
Vit B12 & Folic Acid
M.Synthase
Homocysteine
Methionine
Methionine
MAT
MAT
SAM
S-Adenosyl Methionine
Methyl transferase
Methyl group donor + Homocysteine
SAM regulates
IGF 2 methylation
fetal growth
Methionine
MAT
29
Ornithine
Arginine
NO
polyamines
SAM
Regulates IGF2
Placental angiogenesis & growth
Placental fetal blood flow
Improved fetal
growth &
development
Nutritional & O2 supply from mother to fetus
Improved fetal growth & development
30
Methyl Donor Supplementation Prevents
Transgenerational Amplification of Obesity
1.
The genetic tendency for obesity in Avy mice was
progressively exacerbated
2.
This transgenerational amplification of body weight was
prevented by a promethylation dietary supplement.
3.
Any relevance to human transgenerational obesity?
4.
Smoking in grand parents predicts asthma in grand child
5.
Effect of maternal food restriction or maternal exercise
on birth weight - last for more than one generation.
Int J Obes (Lond). 2008 October 28RA Waterland
31
Bacterial Infection causes DNA
(IGF2) hypermethylation
Overall 10.3% increase in CpG methylation within Igf2 promoter
region in placental DNA from infected intra-uterine growth restricted
placentas.
A 27% reduction in weight in infected mice

2.3-fold decrease in IGF2 mRNA levels in placentas from intrauterine growth restricted fetuses.

In humans with intra-uterine growth restriction, placental
tissues displayed a 2.6- fold decrease in the expression of IGF2,
(McMinn and colleagues)

Any role for infection on methylation?
Bobetsis et al.
32
Nutrition / Hypoxia / Infection
IUGR and associated complications
INFLAMMATION
Epigenetic Alterations

Nutrition (methyl donors) - induce epigenetic alterations

Infections – induce epigenetic alterations – IUGR

Role of methyl donors on IUGR ?

Hypoxia or Inflammation or both alter epigenetics?
33
Altered Inflammatory Response in IDA & PEM Children
1600
1400
pg/ 10 6cells
1200
1000
800
400
200
0
IL2
IL4
IL5
IL10
IDA children
PEM children
Normal children
34
Nutrients Modulates Inflammation
Effect of vitamin A (2 lakhs IU orally), on IL2 response from PHA stimulated
Peripheral Blood Mononuclear Cells (PBMC) of 10 normal children. IL2 response after
15 days of vitamin A was significantly decreased (p<0.05; Paired t-test) compared to
baseline response.
R.Hemalatha et al, 2007
35
Increased Inflammatory Response in
Women at Term
 29 % of women we studied had chorioamnionitis
(CHA) marker of intrauterine infection
 15% prevalence of BV in women at term
 The mean concentration of IL8 was > 2000pg –
indicative of inflammation
 30% prevalence of BV in women of reproductive
age group
R.Hemalatha et al,Res J Obstet Gynecol.,1:18-24,2008
36
IUGR more prevalent in women with Chorioamnionitis
2700
2600
BW in gm
2500
*
2400
2300
2200
2100
2000
Body weight
with out chorioamnionitis
with chorioamnionitis
* P<0.02
R.Hemalatha et al,Res J Obstet Gynecol.,1:18-24,2008
37
Linear growth and head circumeferance
- in Chorioamnionitis
50
- chorioamnionitis
+chorioamnionitis
45
*
35
▲
30
25
H
C
gt
h
20
Le
n
Cm
40
* p<0.02
▲p=0.09
R.Hemalatha et al,Res J Obstet Gynecol.,1:18-24,2008
38
IUGR more prevent in women with Inflammation(IL- 8)
2600
BW in gms
2500
2400
2300
2200
2100
2000
IL-8<Median(71)
IL-8>Median(72)
R.Hemalatha et al,Res J Obstet Gynecol.,1:18-24,2008
39
New born Length,HC,ABC and Intrauterine
Inflammation
50
IL-8 <Median(71)
IL-8>Median(72)
45
Cm
40
35
30
25
20
Length
HC
ABC
R.Hemalatha et al,Res J Obstet Gynecol.,1:18-24,2008
40
Intrauterine Inflammation predicts Symmetrical
Growth retardation
45
40
Symmetrical grow th retardation
Asymmetrical grow th retardation
39.3
Normal
% prevalence of HCA
35
30
28.3
25
25
20
15
10
5
0
Hemalatha R et al, Res J Obstet Gynecol., 1: 18-24, 2008
National Institute of Nutrition, Indian Council of Medical Research,
Department of Health Research (MHFW)
41
FUTURE OBJECTIVES

To control obesity and related risk factors
through
epigenetic
alterations
by
dietary
manipulation

To improve birth weight through epigenetic
alterations by dietary manipulation

Dietary manipulation to reduce Inflammation
and epigenetic alteration
42
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