Corporate research

1
Improving the quality of food and health for
people all over the world
Peter Olesen, PhD, CSOForskningsdirektørChr.
Hansen A/S
Do Bioactive Compounds in Food Have Disease
Reduction Potentials?
Plant Biotech Denmark Annual Mtg 2008 Life-KU,
Copenhagen - Jan 30, 2008
2
Weight management is a 7 bn world market
Source Behavioral Risk Factor Surveillance
System, CDC.
Prevalence 1986
1996
2006

• Trends
• The target population increasingly comprises
  children as well as adults
• Do-it-yourself options (e.g. meal
  replacements, OTC diet pills) are booming
• Satiety is the fastest growing segment
• Products are still based on emerging technologies

3
WHO Forecast
In 2020 70 of all diseases will be related to
lifestyle
The science behind the folds
6.5 bio people 1 bio overweight 300 mio obese
(min.)
4
Adverse metabolic effects of western diet and
lifestyle
THE METABOLIC SYNDROME
STRESS
Obesity
Inflammatory (chronic) changes Pro-inflammatory
cytokines

• Cancer
• oesophageal
• colorectal

Insulin resistance
Diabetes
Cardiovascular
5
Prof. Bob Grimble, Univ. Southampton, UK
The nutrition challenges of the 21st century
will need to focus on the advantages and
disadvantages of having an immune system
Thank you - for inviting me

peter.olesen_at_dk.chr-hansen.com tlf. 45 45747330
/ 22495210
6
The human gut layers of complexity
Gut epithelium (mucosa)
Gut lumen
Submucosal layers
Commensal bacteria (microbiota)
7
FOCUS epithelial barrier immune response
GUT LUMEN

• Infection
• High fat diet
• Env./stress

Dendritic cells sensing luminal factors
(cells,bioactives)

• Gut microbiome
• Probiotics
• Prebiotics

• Other bioactives

MUCOSAL /SUBMUCOSAL LAYERS
BARRIER FUNCTION

• connective tissue
• immune cells macrophages, DCs, Treg, Thelp
  etc.
• nerve cells
• vascular

FOOD

• metabolism
• fermentation
• bioconversion
• uptake/signalling nutrients bioactives

NF-kBTLRs
8
FOCUS epithelial barrier immune response

• Gut microbiome
• Probiotics
• Prebiotics

• Infection
• High fat diet
• Env./stress

• Other bioactives

Immune/inflammatory response
Defence
BARRIER FUNCTION
Imbalance
IBS,IBD,CD etc.
NF-kBTLRs
9
FOCUS epithelial barrier immune response

• Gut microbiome
• Probiotics
• Prebiotics

• Infection
• High fat diet
• Env./stress

Adipo-cytes
Fatty liver

• Other bioactives

Systemic inflammation MS
Immune/inflammatory response
Ins.res.T2DM
Athero-sclerosis
Defence
BARRIER FUNCTION
Imbalance
CVD etc
IBS,IBD,CD etc.
NF-kBTLRs
LPS/endotoxaemia?
10
Probiotic focus generic catalogue
functions / selling
points

• Well-being
• Stability / constipation / transit time
• Improving/maintaining gut health
• Competitive exclusion
• Colonisation
• Formation of antimicrobial substances
• Improving bodys natural defenses
• Immune stimulation
• Lowering blood cholesterol
• Poorly documented area

recentYoplait launch Essence IMMUNITYBOOST
NOT JUST YOGHURT US sales of probiotic
refrigerated milk rose to 55 mio 2006-07 - up
from 38 mio (45)
11
Dr. Hans van NoortTNO, NL
Human DCs show differential in vitro responses
to different probiotic bacteria

• activation of pattern-recognition receptors on
  DCs incl. TLRs
• powerful induction of DC maturation
• early cytokine chemokine responses are often
  similar, indicating common activation of
  NF-?B
• other cytokine responses are quantitatively very
  different
• late DC responses diverge and indicate
  differential induction by bacteria of many
  growth and differentiation factors

LPSL. acidophilus NCFM L. acidophilus La-5B.
lactis Bb-12 B. lactis BI-07
The in vitro response of human DCs to probiotics
involve secretion of several immune regulatory
and/or health-promoting factors
12
Can Bifidobacteria help prevent development of
metabolic syndrome?
Significant correlations Bifido endotox
pos Other bact endotox neg Bifido
glucose toler. pos Bifido insulin secr.
pos Bifido normalisedinflammatory tone
pos
High fat diet oligofructose
High fat diet
Endotoxaemia(plasma LPS
Endotoxaemia(plasma LPS
Caecal counts- Gram positives- Bifidobacteria
Caecal counts- Gram positives- Bifidobacteria
Selective Increases of Bifidobacteria in Gut
Microflora Improve High-Fat-Diet-Induced Diabetes
in Mice Through a Mechanism Associated with
EndotoxaemiaCani PD et al. 2007, Diabetologia,
in press
Modifying the gut microbiota in favour of
Bifidobacteria may prevent deleterious effects of
high-fat-diet-induced metabolic diseases
13
The Cardi-04 technology
Fermented dairy products
specific yoghurt bacteria (proteolytic)
Effect of Cardi-04 on systolic and diastolic
blood pressure in spontaneously hypertensive
rats, measured by telemetry - (in press)
milk proteins
enzymes
Systolic 176(9) -gt 169(9) mmHg Diastolic
131(5) -gt 123(5) mmHg (p lt o.o5)
Cardiologists OK!
peptides
ACE-inhibitors

• significantly lovered BP and normalized HR
  in hypertensive rats
• receptor binding and cholesterol HDL/LDL data
  in vitro
• animal tests ? first human
• 2 full human clinical trials running, 1st
  launch 2007/08
• 6 patent filings

14
Dr. Joseph A. BaurHarvard Med. School
Resveratrol a plant polyphenol and
anti-oxidant is anti-inflammatory
Effect of resveratrol on obese mice

• Decrease in
• Inflammation
• Fat accumulation
• Diabetes development
• Liver damageIncrease in
• Endurance

15
Links between type of caloric intake (food
components), oxidative inflammatory stress and
metabolic syndrome
Diabetes is associated with increased ROS
generation, oxidative injury (lipids, proteins,
DNA) and obesity
Dr. Paresh DandonaUniversity New York
Glucose challenge stimulates ROS generation by
plasma leucocytes (PMNLs and MNCs)
GREAT FUTURE FOR ANTI-OXIDATIVE
ANTI-INFLAMMATORY PLANT BIOACTIVES?
Increased ROS generation (oxidation) and lipid
peroxidation are key events in atherogenesis
(arterial plaque formation)
J Clin Endocrin Met. 2000, 85 2970-72 Am J
Clin Nutr 2002, 75 767-72 Am J Clin Nutr 2004,
79 682-90 Am J Clin Nutr 2004, 80
51-57 Diabetes careMarch 2007
Lipid and protein intake stimulates increased
generation of ROS in plasma leucocytes
Glucose intake stimulates an increase in NF-?B
and two other pro-inflammatory transcription
factors
Caloric intake in the form of orange juice and
fructose does not induce either oxidative or
inflammatory stress
16
Clinical efficacy a major shortcome
Probiotics Prebiotics
(Fermented) Milk Peptides
Resveratrol a.o. Plant Phenolics

• GI stability
• Inflammatory gut diseases
• Anti-inflammatory
• Anti-infective
• Immune stimulating
• Anti-allergic

• Anti-hypertensive
• Anti-arrhythmic
• Anti-cholesterolaemic
• Anti-atherosclerotic
• Anti-inflammatory
• Satiating (anti-obesigenic)

• Anti-oxidant
• Anti-inflammatory
• Anti-diabetic
• Anti-obesigenic
• Liver protecting
• Energy (endurance)

COMMON FEATURES small, additive,
multiple/multifactorial effectsCOMMON CHALLENGE
impressive laboratory and pre-clinical data
BUT human
clinical trials often inconclusive
17
Probiotics/bioactives in the FoodDrug interphase
Targeted
Build-microflora-immunity
Acute (drug)-specific-advanced
Prevent-biomarkers of complications-e.g.,
cholesterol, hypertension
Balance-protect-maitain
Life-time
Risk reduction
Prevention
Treatment
18
Probiotics/bioactives in the FoodDrug interphase
SPECIAL NUTRITION-compromised-genetic, etc.
Targeted
Build-microflora-immunity
Acute (drug)-specific-advanced
Specific-needs-pre/post natal
Prevent-biomarkers of complications-e.g.,
cholesterol, hypertension
Balance-protect-maintain
Life-time
General-anti-inflammation-anti-oxidation
Risk reduction
Prevention
Treatment
NORMALHEALTHYFOOD
19
Probiotics/bioactives in the FoodDrug interphase
SPECIAL NUTRITION-compromised-genetic, etc.
Targeted
Build-microflora-immunity
Acute (drug)-specific-advanced
Specific-needs-pre/post natal
Prevent-biomarkers of complications-e.g.,
cholesterol, hypertension
Balance-protect-maintain
Life-time
General-anti-inflammation-anti-oxidation
Risk reduction
Prevention
Treatment
HUMAN CLINICAL- single compound- single
effects- high efficacy- ST intervention
NEW PARADIGM- population of actives- multiple
effects- low efficacy- LT additive
NORMALHEALTHYFOOD
20
EU health claims classification and burden of
proof
Regulation (EC) No 1924/2006 on Nutrition and
Health Claims made on food
Commission/ Member States
Applicant
Nutrition claims
Health claims
Function claims

• Nutrient content
• Comparative
• Other substance

Reduction of disease riskchildren claims
Based on generally accepted scientific data
Based on newly developed or proprietary data
Art. 13.1
Art. 13.5
Art. 14
Annex
Positivelist
Fast trackEFSAProcedure
CommitteeEFSAProcedure
21
Regulatory challenges Nutrition and Health claims
FOSHU, Japan(1991-2001-2005) - Standardised-
Qualified- Dis. risk reduction
New EFSA decision tree, QPS(Qualified
Presumption of Safety) EU Novel Foods regulation
safety evaluation of ingredients and products
not in use before 1997.
In the future The Name of the Game is Claim
EFSA, EU
FDA, USA

• In legal/regulatory terms, functional foods
  do not constitute a specific category of
  food.
• Basically, health claim regulations apply
  to any kind of food.
• But clearly different categories of health
  claims can be approved.

S. America
FSANZ, Aust-NZ)
SE. Asia
22
Regulatory challenges Nutrition and Health claims
FOSHU, Japan(1991-2001-2005) - Standardised-
Qualified- Dis. risk reduction
New EFSA decision tree, QPS(Qualified
Presumption of Safety) EU Novel Foods regulation
safety evaluation of strains not in use before
1997. L. helveticus used as dairy starter/adjunct
cultures, has some probiotic functionality
EFSA, EU
FDA, USA

• In legal/regulatory terms, functional foods
  do not constitute a specific category of
  food.
• Basically, health claim regulations apply
  to any kind of food.
• But clearly different categories of health
  claims can be approved.

S. America
FSANZ, Aust-NZ)
SE. Asia
23
Improving the quality of food and health for
people all over the world
Peter Olesen, PhD, CSOForskningsdirektørChr.
Hansen A/S
Do Bioactive Compounds in Food Have Disease
Reduction Potentials?
YES but its very difficult to prove within the
clinical dogma!
Plant Biotech Denmark Annual Mtg 2008 Life-KU,
Copenhagen - Jan 30, 2008
24
and theres enough for everybody!
Dr. Keith GrimaldiSciona
25
Thank you - for inviting me
dkpeo_at_chr-hansen.com tlf. 45 45747330 /
22495210