FEMS Immunology and Medical Microbiology 29 (2000) 323^328
www.fems-microbiology.org
Immune cell functions, lipids and host natural resistance
Manuel A. de Pablo *, M
a
è ngeles Puertollano, Gerardo A
è lvarez de Cienfuegos
A
University of Jaën, Faculty of Experimental Sciences, Department of Health Sciences, Unit of Microbiology, E-23071, Jaën, Spain
Received 30 September 2000; accepted 18 October 2000
Abstract
Nutritional status may exert a profound effect on immune system functions. Hence, several parameters of immune system are modified by
dietary lipid administration, as lymphocyte proliferation, cytokine production, natural killer activity, antigen presentation, etc. Thus,
numerous studies have indicated the key role of lipids as immune response modulators. These properties have been applied in the treatment
of autoimmune and inflammatory diseases. As a result, the reduction or suppression of immune status due to lipid incorporation promotes
an impairment in the ability of host natural response to eliminate infectious microorganisms as bacteria or parasites. In the present review,
we analyze the current status about the relationship among dietary lipids, reduction of immune parameters and reduction of host natural
response against infectious diseases. Many discrepancies are discussed, although several studies indicate a close association between dietary
lipid manipulation and impairment in the elimination of bacteria, viruses or parasites. On the other hand, other studies point out a beneficial
effect of dietary lipid manipulation on the host natural response. Future investigations will determine the events involved in the regulation of
immune response by fatty acids and their role in the elimination of pathogenic agents. ß 2000 Federation of European Microbiological
Societies. Published by Elsevier Science B.V. All rights reserved.
Keywords : Dietary lipid; n33 Polyunsaturated fatty acid; Monounsaturated fatty acid ; Fish oil; Olive oil ; Lymphocyte; Macrophages/monocyte ;
Immunomodulation ; Natural resistance
1. Introduction
Immune system functions may be in£uenced by the nutritional status of both animals and humans. Hence, it is
generally assumed that many infectious diseases in the
human populations are associated to a nutritional de¢ciency which generates a suppression of immune response.
As crucial components in the diets, lipids are substances
that exert a profound e¡ect in the modulation of the immune system. This argument has been demonstrated in
numerous experimental studies which have reported the
in£uence of dietary lipid manipulation upon the immune
system. Based on this hypothesis, in the 1980's, an epidemiological study revealed the low incidence of autoimmune diseases in Greenland Eskimos, who consume in
their diets a great amount of ¢sh oil [1]. Subsequently,
* Corresponding author. Tel. : +34 (953) 012 160;
Fax: +34 (953) 012 141; E-mail : [email protected]
Abbreviations : DHA, docosahexaenoic acid ; EPA, eicosapentaenoic
acid ; IFN-Q, interferon-Q; IL-1, interleukin-1 ; NK, natural killer cell;
PUFAs, polyunsaturated fatty acids; SFAs, saturated fatty acids ; TNF,
tumor necrosis factor
other studies have demonstrated that dietary ¢sh oil modulates several immune system functions [2^5]. However,
other ¢ndings have indicated that di¡erent fats such as
olive oil supplied into diets (other than ¢sh oil) or free
fatty acids as oleic acid added to cellular cultures (distinct
to eicosapentaenoic (EPA) or docosahexaenoic (DHA)
acids, that belong to n33 polyunsaturated fatty acids)
participate actively in the modulation of immune functions
[6^9]; although in general, polyunsaturated fatty acids
(PUFAs) have been demonstrated to be more immunosuppressive than saturated fatty acids (SFA). Results from
both animals and humans fed dietary lipids have suggested
that dietary PUFAs may interfere in the reduction of lymphocyte proliferation [5^7], cytokine synthesis [5], natural
killer cell (NK) activity [10,11], antibody production [12],
membrane surface molecules synthesis [13], etc. Overall, all
of these observations have revealed the important properties of fatty acids concerning their ability to modulate the
immune response. Therefore, these ¢ndings demonstrated
that dietary lipids may be applied as natural anti-in£ammatory substances in the treatment of important autoimmune diseases, which are characterized by in£ammatory
processes and, in general, by an overactivation of immune
system, as in rheumatoid arthritis [14], psoriasis [15], sys-
0928-8244 / 00 / $20.00 ß 2000 Federation of European Microbiological Societies. Published by Elsevier Science B.V. All rights reserved.
PII: S 0 9 2 8 - 8 2 4 4 ( 0 0 ) 0 0 2 2 4 - 8
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temic erythematosus lupus [16], multiple sclerosis [17], etc.
However, it has been described that irrespective of these
bene¢cial e¡ects in both animals or humans, dietary lipid
manipulation may produce undesirable e¡ects on the immune response due to the reported reduction of host natural resistance against infectious diseases as a consequence
of their reduction of immune functions. This event may
lead to a marked reduction of survival percentage in animals experimentally infected or to an important impairment of bacterial clearance. Hence, the alteration of immune system functions due to dietary lipid administration
should be balanced as a consequence of the reduction of
host natural resistance and, therefore, it is necessary to
establish the protocols that confer minimal risk of patients
to infectious processes.
Numerous studies have reported the in£uence of dietary
lipids on the immune response of experimental animals
infected with di¡erent pathogens (bacteria, viruses or parasites), and they have described especially the e¡ects of
diets containing ¢sh oil upon the immune system which
have a crucial importance in this discipline. Nevertheless,
relatively little is known about the e¡ects of olive oil or
oleic acid on immune system functions, and particularly
the in£uence of olive oil upon an e¡ective immune response in the course of an infectious process carried out
in vivo. Hence, this paper analyzes the current status in
relation to the knowledge on lipids, immune system functions, and the susceptibility of host resistance to di¡erent
microorganisms or infectious agents responsible for many
pathologies in both humans and animals.
2. E¡ects of dietary lipids on immune cell functions:
immune system parameters modulated by dietary lipid
manipulation
Previous to the description of the e¡ects of di¡erent
microorganisms on the immune response of both animals
or humans fed dietary lipids, it is important to note the
in£uence of lipids on immune system modulation (Fig. 1).
As mentioned previously, several immune parameters are
susceptible to be modi¢ed by dietary lipid manipulation.
Thus, lymphocyte proliferation is reduced after incorporating dietary lipids [2] or adding free fatty acids to in
vitro cultured cells [9]. However, not all lipids are capable
of modulating the immune response, or at least not all of
them may exert the immunomodulatory e¡ects described
previously. In fact, as mentioned above, unsaturated fatty
acids are more immunosuppressive than SFAs [2], and
n33 fatty acid series contained mainly in ¢sh oil have
been reported to be the most suppressive, as EPA and
DHA acids, which are derived from marine products.
Nevertheless, not only EPA or DHA have been demonstrated to exert a crucial suppression of the immune system functions, but also oleic acid (a monounsaturated
fatty acid, that belongs to n39 series, which is the most
Fig. 1. E¡ects of dietary lipids manipulation on immune system functions. Dietary lipids a¡ect numerous immune parameters. These events
may alter the host natural resistance to di¡erent pathogenic agents.
important fatty acid contained in olive oil) has been described to modulate the immune response [6^8]. Cytokine
production is also reduced by dietary lipid manipulation in
both animals and humans fed n33, n36 or n39 fatty acid
series, although in animals fed diets containing these fats
some discrepancies have been reported. Interleukin-1 (IL1) [5], IL-2 [18], IL-6 [19], tumor necrosis factor (TNF) [5],
or interferon-Q (IFN-Q) have been described to be reduced
particularly by unsaturated fatty acids after incorporating
the lipids into the diets [20], while other ¢ndings have
reported contradictory results [21,22]. Concerning to the
modulation of the immune system by dietary lipids in experimentally infected animals, recent studies have reported
that the production of IFN-Q is increased during an infection with Listeria monocytogenes in mice fed a diet containing ¢sh oil [23]. Although many discrepancies have
been reported with respect to cytokine production and
dietary lipids in experimental animals [24], it is not clear
at present whether these facts occur within the cell population studied or if they can be attributed to di¡erences
among animal species. NK activity is also modulated by
fatty acids, and several studies have demonstrated that
dietary lipids are capable of reducing the activity of these
cells which participate as important mediators in tumoricidal processes or in the elimination of virus-invaded cells
[10,11]. In addition, a reduction of antibody synthesis and
surface markers have been reported after the administration of dietary lipids [12,13,25]. Inhibition of the function
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of antigen-presenting cells has also been proposed as a
mechanism that explains, at least in part, the modulation
of the immune system due to dietary lipid manipulation
[26]. Overall, some studies underline the importance of
fatty acids for the regulation of some functions of the
immune system. Owing to the immunosuppressive e¡ects
of fatty acids on immune cell functions, further investigations will describe the involvement of unsaturated fatty
acids in the modi¢cation of host resistance against microorganisms responsible for causing di¡erent pathologies.
3. Dietary fatty acids : in£ammatory and autoimmune
diseases
As mentioned previously, a classical study demonstrated
the low incidence of autoimmune disorders in Greenland
Eskimos who incorporate in their diets great amounts of
¢sh oil [1]. Therefore, a strong relationship between nutrition and modulation of immune response could be established. Subsequently, several studies revealed the importance of fatty acids in the diet, and their application on
the reduction of typical symptomatologies found in patients su¡ering from autoimmune diseases which are characterized by an inappropriate activation of immune system
producing host tissue destruction. The bene¢cial aspects of
dietary lipids (particularly unsaturated fatty acids) on the
reduction of several parameters that participate in the immune response have been studied in a great number of
clinical trials carried out in patients su¡ering from auto-
325
immune and in£ammatory diseases. n-3 fatty acids
(present in ¢sh oil) have shown a signi¢cant reduction of
in£ammation in patients su¡ering from rheumatoid arthritis [14], psoriasis [15], systemic lupus erythematosus [27],
multiple sclerosis [17], etc. Olive oil has also been described as an important substance able to diminish the
incidence of rheumatoid arthritis [28] and the typical
symptomatology of this autoimmune abnormality [14],
which is characterized by an in£ammatory response.
4. Role of dietary fatty acids in host natural resistance to
infectious diseases
A suppression of immune system functions implies an
inability of the immune response to eliminate e¤ciently
the infectious agents responsible for these processes; accordingly, this immune state generates a signi¢cant reduction of host natural resistance. Therefore, the study of
host natural response to di¡erent microorganisms (bacteria, parasites) or pathogenic agents (viruses) should be
carried out in order to determinate the general e¡ects induced by dietary lipid manipulation upon the immune
system functions. Results from numerous investigations
that describe these data are summarized in Table 1.
4.1. E¡ects of dietary lipids on the survival of experimental
animals
Concerning the survival of experimental animals fed di-
Table 1
In£uence of dietary lipid manipulation on immune system functions in animals infected with di¡erent pathogenic agents
Microorganisms
n33
L. monocytogenes
b
Impaired the survival of mice
b
Increased recovery from mice spleen
Reduced IFN-Q receptor
No e¡ect in the microorganism
resistance
Impaired resistance to infection in
guinea pigs
Increased survival of mice
Reduced survival rate in mice
Impaired bacterial clearance in
neonatal rabbits
Did not impair macrophage
bactericidal functions of rats
Reduced survival rates in mice
No e¡ect in the microorganism
resistance
No e¡ect in the microorganism
resistance
Modulated the levels of cytokines
(TNF-K, Il-1L, IL-2)
No e¡ect in the microorganism
resistance
n36
n39
Reference
Less immunosuppressive than n33
fatty acids
Reduced the recovery from mice
spleen
b
[23,29]
b
[29]
[34]
[38]
b
b
M. tuberculosis
K. pneumoniae
S. typhimurium
S. aureus
No e¡ect in the resistance to
infection
Reduced survival of mice
b
b
b
b
b
b
b
Impaired bacterial clearance
Murine AIDS
Murine cytomegalovirus
Reduced survival of mice
[21,33]
[31]
[39]
[44]
[38]
b
b
C. albicans
b
[40]
b
P. aeruginosa
[30]
b
[38]
b
[41]
b
[38]
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etary lipids, contradictory results have been reported,
although this aspect depends on numerous factors as
type of oil added into experimental diets, concentration
of fatty acids, duration of fatty acid supplementation in
the diet or type of infectious agents. The most extended
results suggest that dietary lipids may impair the host resistance to microbial infection [23,29,30] (Table 1). Nevertheless, the detrimental e¡ect of dietary lipids has not been
demonstrated in all of the studies performed. As a consequence of the suppressive e¡ect induced by dietary lipid
administration upon immune functions, in general, a reduction of survival percentage in mice has been reported
[23,29], particularly in animals fed a diet containing ¢sh
oil. Hence, results from numerous studies carried out with
experimental animals fed diets containing ¢sh oil has
shown the lowest values of survival rate to infection
with intracellular pathogens such as L. monocytogenes
[23,29]. Similarly, guinea pigs infected with Mycobacterium
tuberculosis and fed with n33 and n36 fatty acids showed
impaired resistance of the animals against bacterial infection [30]. Experimental infection with Salmonella typhimurium reduced the survival rate in mice fed a diet rich in ¢sh
oil in comparison to values from mice fed a diet containing hydrogenated coconut oil [31]. Likewise, a recent study
carried out in our laboratory has con¢rmed the previous
results and has also demonstrated that a ¢sh oil enriched
diet decreases the survival of mice after experimental infection with L. monocytogenes [29]. Therefore, the elimination of intracellular microorganisms in experimental animals is impaired as a consequence of the immune system
modulation promoted by dietary lipids and especially PUFAs. Nevertheless, conclusive evidence indicated that
monounsaturated and particularly SFAs improve the survival of mice infected with L. monocytogenes [23,29].
In addition to bacteria, animals fed dietary lipids have
also been infected with viruses. Thus, experimental results
obtained from mice fed a diet rich in n33 fatty acids and
infected with a T cell lymphoma virus showed a marked
reduction in the animal survival [32], in comparison to
survival values found in animals fed a diet containing
n36 PUFAs.
Impairment of survival of animals fed dietary PUFAs
and infected with pathogenic agents is the most usual result. In contrast, other studies carried out with Klebsiella
pneumoniae have revealed an increase of survival percentage of mice fed a diet containing ¢sh oil [21,33]. Thus,
these results seem to indicate that the immunosuppressive
e¡ects of long-chain fatty acids do not necessarily lead to
a decreased resistance to natural infection. Hence, the contradictory results could be associated with several factors
such as experimental animals, type of lipids, size of inoculum or may be due to an enhanced ex vivo production of
cytokines by cells from animals fed ¢sh oil diet. Overall,
the importance of all of these factors in the survival of
animals fed dietary lipids after experimental infection
needs to be established.
4.2. E¤cient elimination of bacteria and viruses in animals
fed dietary lipids
A possible explanation for the e¡ects of lipids upon
immune system modulation may be attributed to changes
in cytokine production after dietary lipid administration.
Thus, as mentioned previously, production of IL-1, TNF,
IL-2, IL-6 and IFN-Q have been modi¢ed by dietary lipids,
and particularly by ¢sh oil. A recent ¢nding has underlined the important role of dietary lipids on the IFN-Q
production during experimental infection with L. monocytogenes. IFN-Q production from serum or spleen cells fed a
¢sh oil diet was markedly increased during the infectious
process with L. monocytogenes. However, these authors
suggest that the increase in the production of IFN-Q may
be due to an alteration in the expression of IFN-Q receptor
function rather than changes in the production of this
cytokine [34]. On the contrary, a recent study has reported
that ¢sh oil diet supplied to mice promotes a signi¢cant
reduction of IFN-Q production as well as an impairment of
in£uenza virus clearance from lung after experimental infection, whereas virus clearance was more e¤cient in
groups fed a diet containing SFAs [25]. In addition, the
infection of mice with in£uenza virus impaired T lymphocyte cytotoxicity and had no e¡ect on NK cell activity,
despite an increase in lymphocyte proliferation exerted
by the diet containing ¢sh oil [35], therefore, this fact
could be responsible for the delayed virus clearance [25].
Numerous studies have carried out the isolation of inoculated bacteria from spleen or liver after experimental infection and the results con¢rm that diets containing ¢sh oil
increase the recovery of microorganisms from these organs. In fact, Shinomiya [36] observed an increase in the
number of L. monocytogenes isolated from the liver of
mice fed a high-fat diet. Similarly, Fritsche [23] demonstrated that the clearance of L. monocytogenes from spleen
or liver was greatest in the group fed ¢sh oil [23], whereas
clearance from mice fed a diet containing hydrogenated
coconut oil as well as survival percentage were lower
[29]. Bacterial enumeration of M. tuberculosis from spleens
was also increased in animals fed n33 PUFAs [30]. However, as mentioned previously, several lines of evidence
have indicated that recovery of L. monocytogenes from
spleens of experimentally infected animals fed a diet rich
in SFAs (lard or hydrogenated coconut oil diet) was signi¢cantly diminished [23,29]. Reduction of eicosanoid
products, as a consequence of PUFAs administration
could explain in part the defect in bacterial clearance
that implies reduced phagocytic activity and killing of bacteria [37]. Nevertheless, it is noteworthy that many discrepancies have been reported concerning the bene¢cial
or detrimental e¡ects of dietary lipids upon natural resistance as a consequence of immune system modulation.
Thus, animals fed diets containing melted beef tallow or
¢sh oil and infected with four di¡erent classes of microorganisms or pathogenic agents (L. monocytogenes, Pseu-
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domonas aeruginosa, Candida albicans and murine cytomegalovirus) did not modify the susceptibility to any of
these systemic infections. Therefore, these authors concluded that the anti-in£ammatory e¡ects of ¢sh oil are
not related to an increased risk to infectious pathogens
[38]. In contrast, the reduction of bacterial clearance has
not only been observed in mice, but also in neonatal rabbits fed a diet containing ¢sh oil. Bacterial clearance of
Staphylococcus aureus was lower in these animals than
those fed a diet containing sa¥ower oil [39]. Nevertheless,
the bactericidal activity of macrophages from rats fed diets
containing EPA or DHA did not impair the bactericidal
function of these cells incubated with S. aureus [40].
The e¡ect of dietary lipid manipulation on immune response has also been analyzed in animals infected with
viruses. In this way, ¢ndings from a recent study carried
out with in£uenza virus are in accordance to previous
results from animals infected with bacteria. Although the
virus strain used in this study did not cause death, a delay
in virus clearance has been reported in mice fed ¢sh oil.
These e¡ects may be attributed to a reduced IFN-Q production, as well as a reduction of antibody synthesis as a
consequence of dietary lipid administration [25]. On the
contrary, mice infected with a murine AIDS (LP-BM5, a
murine retrovirus) and fed with a diet containing ¢sh oil
have demonstrated a reduction in the progression of murine AIDS by modulating macrophage-derived cytokines as
well as IL-2 [41]. This diet also prevented the depression of
ConA-stimulated splenocyte proliferation after infection
with this virus [41,42].
In addition to studies that demonstrate the crucial role
of PUFAs in the host natural resistance to bacteria or
viruses, the parasite development appears to be reduced
in chicken fed diets containing n33 fatty acids [43]. Hence,
the regulation of immune response by dietary lipids in
animals infected with di¡erent biological agents (bacteria,
viruses or parasites) generally depends on numerous factors which may be responsible for the contradictory results
described previously (Table 1).
5. Concluding remarks
The important role of dietary lipids in the modulation
of the immune system may be applied in the treatment of
autoimmune abnormalities, such as rheumatoid arthritis,
psoriasis, multiple sclerosis, etc, because, n33 PUFAs may
diminish the incidence and severity of immunologically
mediated diseases as a consequence of a alteration of different immune parameters (Fig. 1). However, this event
has a detrimental e¡ect on the host resistance to infectious
microorganisms or pathogenic agents, such as bacteria,
parasites or viruses. Although this argument generates several contradictory results, due particularly to numerous
studies that have described an increase of natural resis-
327
tance to experimental infection after dietary lipid administration (Table 1).
The mechanisms by which fatty acids exert immune system modulation are still poorly understood. However,
many hypotheses suggest that the immuno-modulatory effects of dietary lipids are mediated through changes in the
phospholipid pro¢les of the cell membrane, alteration of
eicosanoid production, formation of lipid peroxides or
regulation of gene expression. Thus, alteration of eicosanoid biosynthesis and regulation of gene expression appear
to be the most important factors responsible in part for
the e¡ects exerted by lipids upon immune system functions. However, further studies will be needed in order
to determine the e¡ects induced by fatty acid manipulation
on the immune response, the host resistance of experimental animals fed dietary lipids to infectious microorganisms
and the e¤cient elimination of these foreign agents.
The reported e¡ects of lipids on immune functions provide a new insight into how dietary fatty acids might play
a critical role in health and disease. Accordingly, the study
of dietary lipids and their in£uence on the immune response will allow a better understanding of the possible
e¡ects of these substances on the host natural resistance to
pathogenic agents.
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