The impact of long chain polyunsaturated fatty acids on food allergy and cardiovascular disease

240 Pages·2013·12.85 MB·English

The impact of long chain polyunsaturated fatty acids
on food allergy and cardiovascular disease
Fish and no chips?
ISBN/EAN: 978-90-6464-695-9
COVER DESIGN
Roquefort ontwerpers, Utrecht, The Netherlands
LAYOUT
Ferdinand van Nispen, Citroenvlinder-DTP.nl, Bilthoven, The Netherlands
PRINTING
GVO drukkers & vormgevers B.V. | Ponsen & Looijen, Ede, The Netherlands
THE WORK IN THIS THESIS WAS FUNDED BY
Nutricia Research Foundation
© 2013 LIEKE VAN DEN ELSEN, UTRECHT, THE NETHERLANDS
All rights reserved. No part of this thesis may be reproduced or transmitted in any form,
by any means, electronic or mechanical, without prior written permission of the author.
The impact of long chain polyunsaturated fatty acids
on food allergy and cardiovascular disease
Fish and no chips?
De invloed van lange keten meervoudig onverzadigde vetzuren
op voedselallergie en cardiovasculaire ziekten
(met een samenvatting in het Nederlands)
Proefschrift
ter verkrijging van de graad van doctor aan de Universiteit Utrecht
op gezag van de rector magnificus, prof. dr. G.J. van der Zwaan,
ingevolge het besluit van het college voor promoties
in het openbaar te verdedigen op
dinsdag 24 september 2013 des middag te 4.15 uur
door
Lieke Wilhelmina Johanna van den Elsen
geboren op 6 januari 1985 te Best
Promotor Prof. dr. J. Garssen
Co-promotor Dr. L.E.M. Willemsen
Printing of this thesis was financially supported by
Danone Research – Centre for Specialised Nutrition
Bioriginal, Research Diet Services BV, eBioscience, Plexx B.V., Infection & Immunity Center Utrecht
CONTENTS
CHAPTER ONE General Introduction 7
CHAPTER TWO Long chain n-3 polyunsaturated fatty acids in the
prevention of allergic and cardiovascular disease 25
CHAPTER THREE Increased intake of vegetable oil high in n-6 PUFA
enhances allergic symptoms to cow’s milk protein
and prevents oral tolerance induction by partial
whey hydrolysate in mice 65
CHAPTER FOUR N-3 LCPUFA reduce allergy-related mediator release
by human mast cells in vitro via inhibition of
reactive oxygen species 81
CHAPTER FIVE Dietary long chain n-3 polyunsaturated fatty acids
prevent allergic sensitization to cow’s milk protein in mice 103
CHAPTER SIX CD25+ Regulatory T-cells transfer n-3 LCPUFA
induced tolerance in cow’s milk allergic mice 127
CHAPTER SEVEN Dietary DHA is more effective than EPA in suppressing
allergic symptoms in whey or peanut allergic mice 143
CHAPTER EIGHT Dietary fish oil improves endothelial function and
lowers blood pressure via suppression of sphingolipid-
mediated contractions in spontaneously hypertensive rats 161
CHAPTER NINE Salmon consumption by pregnant woman reduces
ex vivo umbilical cord endothelial cell activation 181
CHAPTER TEN Summarizing discussion 199
Nederlandse samenvatting 223
Curriculum Vitae 231
List of publications 231
Acknowledgements 237

CHAPTER
ONE
General introduction
Over the last years scientists have focused more and more on the relation between
lifestyle, health and disease. Several food components are associated with beneficial
health effects, while other dietary habits are associated with diseases such as allergies
and cardiovascular disease (CVD). While conventional drugs act via the ‘one target-one
drug’ concept, nutrition exerts smaller effects at multiple sites (1). Amongst others, poly-
unsaturated fatty acids (PUFA) are extensively studied in relation to health and disease.
The human diet contains a broad variety of fatty acids differing in chain length and
amount of double bonds. PUFA contain two or more double bonds and are categorized in
n-6 and n-3 PUFA according to the position of the first double bond near the methyl end
(see review Chapter Two). The recommended daily consumption of fat is 30% of total cal-
orie intake (approximately 65 g). The European Food Safety Authority (EFSA) recommends
that 4.5% of total daily energy intake is derived from n-6 PUFA and 1% from n-3 PUFA (2).
The last decades have seen a fall in the consumption of saturated fatty acids, whereas
the intake of PUFA has increased. This shift in fatty acid intake mainly involved the in-
creased use of vegetable oils and products such as margarine that are rich in n-6 PUFA,
predominantly linoleic acid (LA; 18:2n-6) «Table 1». On the other hand the consumption
of long chain n-3 PUFA (LCPUFA) from oily fish, such as eicosapentaenoic acid (EPA; 20:5n-
3) and docosahexaenoic acid (DHA; 22:6n-3) consisting of 20 or more carbon atoms, has
gradually decreased «Table 2» (3, 4). Humans evolved on a diet with a 1:1 ratio of n-6:n-3
PUFA. Nowadays this ratio is approaching 10-25:1 in westernized countries (4, 5).
Table 1 Typical fatty acid composition of vegetable oils (% of total fatty acids) (6)
SFA MUFA PUFA
LA ALA
Canola oil 6 62 22 10
Corn oil 13 28 58 1
Olive oil 17 72 10 1
Soybean oil 15 24 54 7
Sunflower oil 12 19 68 1
SFA: saturated fatty acids; MUFA: monounsaturated fatty acids; PUFA: polyunsaturated fatty acids;
LA: linoleic acid; ALA: α-linolenic acid
The clinical health benefits from the use of n-3 LCPUFA from oily fish in the (secondary)
prevention of CVD have been demonstrated clearly (see Chapter Two). A large part of
the Western population has a high risk of developing CVD and it is one of the most im-
portant causes of death in developed countries (7, 8). N-3 LCPUFA research in CVD was
inspired by the very low cardiovascular mortality rate among the Greenland Inuit (10-30%
lower than in Denmark) which was associated with their diet (9, 10). Inuit consume large
amounts of oily fish containing a high content of n-3 LCPUFA and therefore have high
8
e
n
o
r
e
t
p
a
h
plasma levels of EPA and DHA and low levels of n-6 PUFA (11, 12). Besides the low preva- C
lence of CVD, Inuit also have a low prevalence of allergic diseases. 15-30% Of the Western
population is affected by allergic disease. Atopic disease prevalence is low when a high
n-3 LCPUFA content is found in sera (13, 14). Furthermore, a high intake of n-6 PUFA,
especially LA, is associated with allergic sensitization and eczema (15, 16). However, it
remains to be elucidated whether n-3 LCPUFA are capable of reducing the susceptibility
to develop allergic disease.
Table 2 Typical fatty acid composition in selected fish (per 100 g edible portion, raw) (4)
Total fat SFA MUFA PUFA
Total EPA DHA
Anchovy 4.8 1.3 1.2 1.6 0.5 0.9
Cod 0.7 0.1 0.1 0.3 0.1 0.2
Haddock 0.7 0.1 0.1 0.2 0.1 0.1
Halibut 13.8 2.4 8.4 1.4 0.5 0.4
Herring (Pacific) 13.9 3.3 6.9 2.4 1.0 0.7
Mackerel 13.0 2.5 5.9 3.2 1.0 1.2
Salmon (Chinook) 10.4 2.5 4.5 2.1 0.8 0.6
Trout 3.4 0.6 1.0 1.2 0.1 0.4
Tuna (albacore) 4.9 1.2 1.2 1.8 0.3 1.0
SFA: saturated fatty acids; MUFA: monounsaturated fatty acids; PUFA: polyunsaturated fatty acids;
EPA: eicosapentaenoic acid; DHA: docosahexaenoic acid
FOOd allErgy
With an estimated prevalence of 30% in children in Western societies, atopic disorders
are an important public health problem (17). Atopic dermatitis and food allergy readily
develop in the first year of life and in 30% of children with atopic dermatitis food allergy
is the underlying cause (18, 19). Food allergy affects about 6% of young children (20) and
the major food allergens are milk, egg, peanut, three nuts, shellfish, fish, wheat and soy
(21). Symptoms include atopic dermatitis, gastro-intestinal and pulmonary distress and
sometimes anaphylaxis. Children are more prone to develop an allergic reaction to food
proteins, since their mucosal barrier and immune system is not yet fully developed and
therefore less efficient (22).
Although also non-IgE mediated food allergic responses exist, often an IgE dependent
type I hypersensitivity reaction is induced. This is characterized by T helper 2 (Th2)
polarization of the immune response and results in acute (<1h) symptoms due to mast
cell activation (see Chapter Two). The underlying etiology is still largely unclear. While
there is a strong genetic factor contributing to food allergy, environmental factors may
9
contribute to the increased prevalence of allergic disease. This includes the hygiene hy-
pothesis and dietary alterations (23). Besides a decline in breast-feeding and the early
introduction of solid foods, major alterations in the diet have paralleled the increase in
allergic disease (24-26). The latter includes, amongst others, the reduced consumption of
n-3 LCPUFA as discussed above.
O
O
O
O
P
glycerol phospholipid O O O R
O-
OH O
P
O O N+
O-
NH
O
sphingophospholipid
Figure 1 Lipid bilayer of the cell membrane containing phospholipids. Glycerol phospholipids con-
sist of two hydrophobic fatty acid chains with varying chain length, double bond number and
position and a polar phosphate-containing head group. The sphingophospholipid sphingomyelin
is composed of a sphingoid base (indicated by dotted line), linked to a saturated or monounsatu-
rated fatty acid and phosphocholine head group.
PUFa metabolites and allergy
PUFA are thought to function via several mechanisms (27). Dietary lipids incorporate in
the phospholipids of the cell membrane «Figure 1» and thus can alter membrane fluidity
and lipid raft composition of a large variety of cell types (28). Furthermore, PUFA may
act on intra- and extracellular receptors and transcription factors including peroxisome
proliferator-activated receptors (29), mitogen-activated protein kinases (30), Toll-like re-
ceptors (31) and G protein-coupled receptors (32). In addition, alterations in eicosanoid
production may underlie the effects of PUFA. In contrast to n-3 LCPUFA, n-6 PUFA intake
has increased during the last decennia. LA is a precursor for arachidonic acid (AA), which
can be metabolized by cyclooxygenases and lipoxygenases into a range of eicosanoids
«Figure 2». The AA metabolite prostaglandin (PG)E may promote allergic sensitization by
2
inhibiting the production of interferon γ but not interleukin (IL)-4, subsequently stimulat-
ing IgE synthesis (33, 34). The type of fatty acids consumed can influence the amount
and type of eicosanoids produced. Dietary n-3 PUFA competitively replace AA in the cell
membranes, therefore inhibiting AA conversion to PG and thromboxanes (TX) of the 2-
and 4-series. While excessive availability of substrate for the generation of AA-derived
10