Significance of olive oil in the host immune resistance to infection

Abstract

The effects exerted by polyunsaturated fatty acids (PUFA) on immune system functions have been investigated in recent years. These studies have reported the important role that n-3 PUFA play in the diminution of incidence and severity of inflammatory disorders. Nevertheless, less attention has been paid to the action of monounsaturated fatty acids (MUFA) upon the immune system. The administration of a diet containing a high amount of olive oil in experimental animals produces a suppression of lymphocyte proliferation, an inhibition of cytokine production and a reduction in natural killer (NK) cell activity. Despite these alterations in immune functions, it has been reported that olive oil-rich diets are not as immunosuppressive as fish oil diets. An important aspect in immunonutrition is focused on the relationship between fats, the immune system and host resistance to infection, particularly when these nutrients are supplied to patients at risk of sepsis. Different studies have determined that olive oil-rich diets do not impair the host resistance to infection. Therefore, olive oil constitutes a suitable fat that may be applied in clinical nutrition and administered to critically ill patients. In the present review, we summarize the current knowledge on olive oil and immune system functions, the biological consequences derived from the administration of diets containing olive oil and the impact of olive oil on immune defence.

Full text

Significance of olive oil in the host immune resistance to infection
Marı
´
a A. Puertollano
1,2
, Elena Puertollano
1
, Gerardo A
´
lvarez de Cienfuegos
1
and Manuel A. de Pablo
1
*
1
Unit of Microbiology, Department of Health Sciences, Faculty of Experimental Sciences, University of Jae
´
n, 23071, Jae
´
n (Spain)
2
Department of Metabolism and Nutrition, Consejo Superior de Investigaciones Cientı
´
ficas (CSIC), 28040 Madrid (Spain)
The effects exerted by polyunsaturated fatty acids (PUFA) on immune system functions have been investigated in recent years. These studies have
reported the important role that n-3 PUFA play in the diminution of incidence and severity of inflammatory disorders. Nevertheless, less attention
has been paid to the action of monounsaturated fatty acids (MUFA) upon the immune system. The administration of a diet containing a high
amount of olive oil in experimental animals produces a suppression of lymphocyte proliferation, an inhibition of cytokine production and a
reduction in natural killer (NK) cell activity. Despite these alterations in immune functions, it has been reported that olive oil-rich diets are
not as immunosuppressive as fish oil diets. An important aspect in immunonutrition is focused on the relationship between fats, the immune
system and host resistance to infection, particularly when these nutrients are supplied to patients at risk of sepsis. Different studies have determined
that olive oil-rich diets do not impair the host resistance to infection. Therefore, olive oil constitutes a suitable fat that may be applied in clinical
nutrition and administered to critically ill patients. In the present review, we summarize the current knowledge on olive oil and immune system
functions, the biological consequences derived from the administration of diets containing olive oil and the impact of olive oil on immune defence.
Olive oil: Immune system: Host resistance
Epidemiological studies supported by experimental data from
both animals and humans, have made a significant contri-
bution to increasing knowledge of the relationship between
diet and the immune system, considering nutrient intake as a
critical determinant of immunocompetence
1
. This association
was confirmed after the recognition of long chain n-3 polyun-
saturated fatty acids (PUFA) as nutrients that participate in the
regulation of immune system functions
2
. Olive oil, a funda-
mental constituent of the Mediterranean diet, is also able to
modulate the immune system, since it contains numerous com-
ponents that possess some biological activities. Olive oil has
been associated with the suppression of different immune
functions, although less attention has been paid to the effects
of monounsaturated fatty acids (MUFA), compared with
PUFA, upon the immune system. Classically, MUFA have
been considered as neutral fatty acids and have often been
applied as placebo in studies investigating the anti-inflamma-
tory properties of other fatty acids
3
. Overall, the action of
MUFA on the human immune system has allowed their appli-
cation in the resolution or attenuation of diseases characterized
by inflammatory disorders
4,5
, in the reduction of cancer risk
6
and in clinical nutrition
7
. This article will summarize the cur-
rent state of knowledge concerning the effects and interactions
of olive oil on immune system functions, as well as the action
of this fat in the preservation of host immune defence.
Immunomodulation by fatty acids
Since the 1970s, a number of epidemiological studies
have suggested that certain dietary fatty acids (particularly
long-chain n-3 PUFA contained in oily fish and fish oils)
affect the immune response in both animals and humans.
Early studies in Greenland Eskimos indicated the low preva-
lence of inflammatory disorders in this population
8
, and the
reduction of death from ischemic heart disease, in spite of
the consumption of diets high in fat and cholesterol
9
,or
the low incidence of cancer
10
. Despite their beneficial
effects in the reduction of inflammatory disease prevalence,
other studies have demonstrated that the administration of
diets containing long-chain n-3 PUFA may contribute, at
least in part, to the reduction of host resistance against
infectious agents. Indeed, epidemiological investigations
described a high incidence of tuberculosis in native Eski-
mos
11
, who consume a great amount of n-3 PUFA. These
data are illustrative of the potential action of certain fatty
acids, and of the consequences derived from an excessive
immunosuppression. Nevertheless, this aspect requires more
detailed investigation, because several studies have also
shown that the administration of diets containing fish oil
improves immune defence against infectious microorgan-
isms
12
. It is possible that differences in experimental
design may explain the disparities between studies.
Olive oil: a fat involved in the modulation of immune system
functions
Olive oil is mainly composed of oleic acid, plus additional
different chemical components such as sterols, alcohols, anti-
oxidants, and other fatty acids (apart from oleic acid) of minor
relevance. An interesting study examined the biological
constituents of olive oil responsible for the modulation of
the immune functions and revealed that the immunosuppres-
sive effects attributed to olive oil are likely due to oleic acid
rather than to other minor components of this fat
13
. However,
* Corresponding author: Dr Manuel Antonio de Pablo Martı
´
nez, fax þ 34 953 212 943, email mapablo@ujaen.es

a recent study has demonstrated that the polyphenolic
substances contained in olive oil possess anti-inflammatory
properties
14
.
Different studies investigating the effects of fatty acids on
the immune system have demonstrated that a diet containing
olive oil administered to animals is able to promote a signifi-
cant reduction of lymphocyte proliferation in response to the
mitogen concanavalin A (Con A)
15.
In contrast, human studies
have produced conflicting results, where for example, the
administration of a diet containing an increased amount of
olive oil did not affect proliferation of mitogen-stimulated
lymphocytes
16
. It is possible that the observed differences
between animal and human studies may be attributed in part
to the amount of MUFA administered. Thus, MUFA contrib-
uted approximately 25 to 30 % of total energy in the animal
studies, whereas diets constituted by MUFA supplied approxi-
mately 18 % of total energy in human studies
17
. Although
some animal investigations have reported a reduction of lym-
phocyte proliferation in response to Con A, we did not find a
significant effect of olive oil on the proliferation of murine
lymphocytes stimulated with either Con A or lipopolysacchar-
ide (LPS)
18
. The specific factors that contribute to the contra-
dictory results observed in both mice and humans should be
elucidated in further research, which will help to explain the
discrepancies in the findings published to date. However, it
is important to note that other factors different from the
amount of olive oil in the diet, such as ingestion of other
types of nutrients, could undoubtedly be involved in the differ-
ent experimental results observed between humans and
animals.
Cytokine production is reduced after the administration of
certain dietary lipids. These proteins regulate the growth and
differentiation of different lymphocyte subsets and they acti-
vate and regulate cells that participate in the inflammatory
response. Interleukin-2 (IL-2) is an important cytokine respon-
sible for the proliferation of T-lymphocytes. Administration of
diets containing olive oil for 8 or 12 weeks produced an
increase in IL-2 production in mice
19,20
. IL-4 production, a
cytokine with anti-inflammatory functions was increased in
mice after the administration of a diet containing olive oil
for 4 weeks
21
. In contrast, the production of IL-10, a cytokine
with similar functions to IL-4, was decreased after the admin-
istration of a diet containing olive oil, although the production
of IL-10 was not different from that seen after feeding mice a
low fat diet
15
. Finally, the concentration of IL-12, a cytokine
that participates as a pro-inflammatory protein, was reduced in
mice fed with diets containing olive oil
21
. Other cytokines are
produced mainly by monocytes/macrophages. The synthesis of
these proteins is also modulated by the administration of a diet
containing olive oil. Thus, IL-1 production was diminished,
whereas TNF-a or IL-6 production were increased or not
modified in mice
22,23
. Overall, diets containing olive oil are
also related to the suppression of cytokine production, but
this effect is not as severe as that produced by the adminis-
tration of a fish oil-rich diet.
Natural killer (NK) cell activity is modulated by the action
of certain dietary lipids. NK cells constitute a central lympho-
cyte subset found in blood and spleen that destroy virus-
invaded cells or transformed cells. In animal studies, the
administration of an olive oil diet reduced NK cell activity
24
.
Comparison of data among animals fed different amounts of
oleic acid showed a linear negative relationship, indicating
that oleic acid is responsible for a reduction of NK cell
activity in rats
25
. In fact, this activity is significantly reduced
in mice fed with an olive oil diet after receiving LSTRA
tumor transplantation (an ascitic Moloney virus-induced lym-
phoma), although the greatest suppression was observed in
mice fed with a fish oil diet
26
. Once again, human studies
have not confirmed the animal results; the measurement of
NK cell activity after the administration for one or two
months of a diet containing olive oil did not show significant
differences from the control group, although the activity
of these cells declined after two months of consuming of
this diet
16
.
Consequences derived from the administration of a diet
containing olive oil in the modulation of the immune
system
Resistance to infectious agents
Several lines of evidence have demonstrated that the suppres-
sion of immune system functions exerted by certain dietary
lipids may cause a reduction of host resistance to infection
27 – 30
.
Obviously, available data only refer to experimental animals,
and the effect of dietary lipids that may specifically modulate
host defence to infectious pathogens in healthy humans has
not been clearly established (see Tables 1 and 2). As previously
described, early epidemiological studies reveal that the con-
sumption of diets containing very high amounts of long chain
n-3 PUFA increases the risk of infection and the incidence of
tuberculosis in native Eskimos
11
, despite the beneficial effects
in the reduction of inflammatory disorders
4,8
. Subsequently,
experimental studies have demonstrated a significant reduction
Table 1. Summary of human studies examining the effects of olive oil on immune system function
Study characteristics Findings of the study References
Administration of a diet containing olive oil (18·4 % of
energy) to healthy middle-aged men for 2 months
Unmodified PBMC proliferative response. Suppressed NK
cell activity. Reduced ICAM-1 expression.
16
Risk factors for rheumatoid arthritis in elderly subjects Risk decreased by high consumption of olive oil 5
Administration of olive oil (6·8 g oleic acid/d) to patients
suffering from rheumatoid arthritis
Altered in immune function associated with beneficial
effects on the progression of rheumatoid arthritis
4
Administration of extra virgin olive oil to healthy subjects Decreased markers of oxidative stress 39
In vitro exposure of PBMC to an olive oil-based lipid emulsion Decreased production of pro-inflammatory cytokines 34
In vitro exposure of PBMC to an olive oil-based lipid emulsion Maintenance of immunity and reduced inflammatory response 38
Abbreviation: PBMC, peripheral blood mononuclear cells; ICAM-1, intercellular adhesion molecule-1.

of survival percentage as well as an increase of viable bacteria
in the spleen
31
or liver
32
after the administration of diets
containing long chain n-3 PUFA to mice experimentally
infected with a virulent pathogen. These data indicate that the
suppression of the immune system caused by these fatty acids
leads to a reduction of host resistance against infectious micro-
organisms
27 – 30
. Although the mechanism by which some
dietary lipids affect host resistance to infection are not
clearly defined, changes in pro-inflammatory eicosanoid and
cytokine production may be particularly involved in these
processes.
Numerous investigations have reported the involvement of
long-chain n-3 PUFA in the modulation of natural resistance
against Salmonella typhimurium serovar Typhimurium, Myco-
bacterium tuberculosis, Listeria monocytogenes, influenza
virus or parasites
29,30
. Currently, the information on the effects
of olive oil on host resistance is very poor, but the results
obtained have indicated that the administration of diets con-
taining MUFA are able to reduce infection severity and to pro-
long survival in murine models after the challenge with
L. monocytogenes. In addition, the recovery of viable bacteria
from spleen
31
of mice is reduced at an early stage of infection.
Finally, bactericidal activity of peritoneal cells from mice fed
a diet containing olive oil is more efficient than that from mice
fed a diet containing fish oil
33
. In contrast, the number of
adhering bacteria as well as the number of invading bacteria
is substantially larger in the group fed a diet containing
olive oil
18
.
An important cytokine involved in the activation of Th1
response is IL-12, which plays a relevant role in the elimin-
ation of intracellular bacteria. Thus, IL-12 production is not
initially reduced in mice fed a diet containing olive oil,
although the production of other pro-inflammatory cytokines
such as IL-1, IL-6 and TNF-a was modified after L. monocy-
togenes infection, especially at 24 h of challenge (Fig. 1).
The administration of a diet containing olive oil in mice
infected with L. monocytogenes and intraperitoneally treated
with cyclophosphamide, an immunosuppressive agent, does
not have an effect as great as a fish oil diet on the survival
of mice after infection, or on the recovery of viable bacteria
from mice spleen and liver. It is possible that the immunosup-
pression exerted by diets containing fish oil is aggravated in
this model, whereas in our experience an olive oil diet moder-
ately reduces host resistance to infection (unpublished results).
Olive oil in clinical nutrition
Lipid emulsions constitute an essential component of total par-
enteral nutrition, which represents an indispensable strategy to
improve nutritional status of critically ill patients. The inter-
action between fatty acids and the immune system has
increased the interest in the manipulation of fatty acid compo-
sition in lipid emulsions, which have widely been used in
clinical practice for over 30 years. The administration of an
olive oil-containing emulsion (ClinOleic or SMOFLipid)
appears to be more beneficial to immune system functions
than soybean oil-based emulsions, because it does not alter
inflammatory cytokine production. This property constitutes
an important factor that allows the administration of this
lipid emulsion in patients for whom a reduction of immune
resistance constitutes a drastic event, because they are at a
high risk of infection
34
. In fact, with the purpose of finding
a lipid emulsion capable of protecting mononuclear phagocyte
system functions, a study revealed that the administration of a
lipid emulsion enriched with olive oil to rats infected with
Escherichia coli is efficient and may be used in the preser-
vation of mononuclear phagocyte system functions
35
.
The lipid emulsions most commonly applied as nutritional
therapy support contain n-6 PUFA such as safflower oil or
soybean oil, but they may be involved in adverse effects on
the immune system, especially when are administered in
high doses over a short time period. In fact, an excess of
n-6 PUFA and the low amount of n-3 PUFA are related to
adverse effects on immunological functions
7
. ClinOleic
offers clinical advantages in severally burned patients, with
improved liver functions after administration
36
. Therefore,
emulsions containing olive oil are an important alternative
to soybean oil in parenteral nutrition, because an olive oil-
based lipid emulsion offers better maintenance of immunity
and reduces the inflammatory response
37,38
.
Table 2. Summary of animal studies examining the effects of olive oil on immune system function
Study characteristics Findings of the study References
Rats fed a diet containing 200 g/kg of olive oil for 10 weeks Decreased spleen and lymph node proliferation 15
Rats fed a diet containing 200 g/kg of olive oil for 10 weeks Decreased spleen NK cell activity 24
Mice fed a diet containing 150 g/kg of olive oil for 12 weeks Increased IL-2 and TNF-a production compared with a low fat diet 23
Mice fed a diet containing 200 g/kg of olive oil for four
weeks and challenged with Listeria monocytogenes
Higher survival rates and decreased recovery of viable bacteria from
spleen compared with a fish oil diet
31
Rats fed diets containing 200 g/kg olive oil, sunflower oil or
high oleic sunflower oil for 6 weeks
The immunosuppressive effects attributed to an olive oil diet are mainly
due to oleic acid
13
Balb/c mice fed diets containing 200 g/kg olive oil, fish oil or
hydrogenated coconut oil for 4 weeks and infected
with L. monocytogenes
Increased invasion and adherence of L. monocytogenes to splenic cells 18
Balb/c mice fed diets containing 200 g/kg olive oil, fish oil or
hydrogenated coconut oil for 4 weeks and
subsequently infected with L. monocytogenes
Production of IL-12 is not modified, but increased IL-4 production
after L. monocytogenes infection
21
C57B1/6 J mice fed a diet containing 7 % (w/w) olive oil
diet for 6 weeks and injected with LPS
Decreased inflammatory response and improved survival 40
Rats received an olive oil-based lipid emulsion in a model
of Escherichia coli bacteraemia
Preserved mononuclear phagocyte system, although mortality
is unaffected
35
Rats received an olive oil-based lipid emulsion for 4 weeks Increased expression of the IL-2 receptor (CD25) 37
Abbreviations: NK, natural killer; LPS, lipopolysaccharide; IL, interleukin; TNF, tumor necrosis factor.

Concluding remarks
Diets containing olive oil may exert beneficial effects when
they have been applied in the resolution of inflammatory dis-
orders. Experimental studies have indicated that the immuno-
modulatory action of olive oil is due to oleic acid, but recent
investigations have suggested that anti-inflammatory proper-
ties are also attributed to phenolic compounds. The immuno-
suppressive effects related to olive oil diet administration in
animals are not as great as those produced by long chain n-3
PUFA, which are considered as the most immunosuppressive
fatty acids. The biological properties exhibited by MUFA
may result in a moderate reduction of host defence to patho-
gens. Therefore, it is important to determine the effects pro-
duced by olive oil in patients at risk of sepsis, to ensure that
olive oil does not impair host immune resistance against
infectious microorganisms.
Conflict of interest statement
MAP owned a research contract (“Juan de la Cierva” from the
Ministry of Education and Science). EP was the recipient of a
predoctoral fellowship from the Ministry of Education and
Science (Spain). We are grateful to Excelentisima Diputacio
´
n
Provincial de Jae
´
n by supporting a part of this publication. The
authors have no conflicts of interest to report. All authors con-
tributed to co-write the manuscript. MAP and MAdP read and
approved the final version of this manuscript.
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