1

Dr. SESIKERAN, MD, FAMS

DirectorNational Institute of Nutrition(Indian Council of Medical Research)

Hyderabad – 500 007

NEW AREAS OF NUTRITION RESEARCH

2

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

3

CEMR Basic researchClinical ResearchProgramme 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 methodsSimultaneous determination of multiple micronutrient status – DBS method

4

CEMR Basic researchClinical ResearchProgramme 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.

5

CEMR Basic researchClinical ResearchProgramme research Policy research

The new and emerging nanotechnology

Discovery, development, and delivery of

micronutrient intervention strategies

Sensitive biomarkers of micronutrient status

6

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,

CEMR Basic researchClinical ResearchProgramme research Policy research

7

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.

CEMR Basic research

Clinical Research

Programme research

Policy research

8

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

CEMR Basic research

Clinical Research

Programme research

Policy research

9

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).

10

Evolving Risk Assessment Strategies for Toxins/contaminants Derived from

Processing

Eg: Acrylamide, melamine.

Research for reducing levels of such

contaminants formed during processing

11

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)

12

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).

13

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.

14

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

15

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

16

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.

17

Peri-natal NutritionFolic 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 CNS, BehaviouralBehavioural & Cognitive developmentognitive development

18

Peri-natal and early life NutritionVitamin 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

19

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.

20

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

21

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

22

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 phytochemical-containing 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

23

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

24

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

Anti-oxidant Research

25

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

26

Rank Prize Lecture – 2008Global 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 sub- Saharan 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.

27

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.

28

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)

29

Vitamins/minerals/amino acids- affect DNA methylation

Choline Methionine Vit B12 & Folic Acid

Betaine Methionine Methionine

Ch.dehydrogenose M.Synthase Homocysteine

SAMS-Adenosyl Methionine

Methyl group donor Homocysteine

Methionine

+

Methyl transferase

MAT

MAT

MAT

SAM regulates IGF 2 methylation

fetal growth

30

NO SAM

OrnithineArginine

polyamines

Placental angiogenesis & growth

Placental fetal blood flow

Nutritional & O2 supply from mother to fetus

Improved fetal growth & development

Regulates IGF2

Improved fetal growth &

development

31

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

32

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 intra-uterine 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.

33

Nutrition / Hypoxia / Infection INFLAMMATION

IUGR and associated complications 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?

34

IL2 IL4 IL5 IL10

pg

/ 10

6 cel

ls

0

200

400

800

1000

1200

1400

1600

IDA children PEM children

Normal children

Altered Inflammatory Response in IDA & PEM Children

35

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

Nutrients Modulates Inflammation

36

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

37

IUGR more prevalent in women with Chorioamnionitis

Body weight

BW

in

gm

2000

2100

2200

2300

2400

2500

2600

2700

with out chorioamnionitis with chorioamnionitis

*

* P<0.02

R.Hemalatha et al,Res J Obstet Gynecol.,1:18-24,2008

38

Linear growth and head circumeferance - in Chorioamnionitis

Cm

20

25

30

35

40

45

50

- chorioamnionitis +chorioamnionitis

*

▲

* p<0.02

▲p=0.09

R.Hemalatha et al,Res J Obstet Gynecol.,1:18-24,2008

39

IUGR more prevent in women with Inflammation(IL- 8) B

W i

n g

ms

2000

2100

2200

2300

2400

2500

2600

IL-8<Median(71) IL-8>Median(72)

R.Hemalatha et al,Res J Obstet Gynecol.,1:18-24,2008

40

New born Length,HC,ABC and Intrauterine Inflammation

Length HC ABC

Cm

20

25

30

35

40

45

50

IL-8 <Median(71) IL-8>Median(72)

R.Hemalatha et al,Res J Obstet Gynecol.,1:18-24,2008

41

39.3

28.3

25

0

5

10

15

20

25

30

35

40

45

% p

reva

len

ce o

f H

CA

Symmetrical grow th retardation

Asymmetrical grow th retardation

Normal

Intrauterine Inflammation predicts Symmetrical Growth retardation

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)

42

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

43