Epidemiological studies supported by experimental data from both animals and humans, have made a significant contribution to increasing knowledge of the relationship between diet and the immune system, considering nutrient intake as a critical determinant of immunocompetenceReference Klasing, Leshchinsky, Gershwin, German and Keen1. This association was confirmed after the recognition of long chain n-3 polyunsaturated fatty acids (PUFA) as nutrients that participate in the regulation of immune system functionsReference Calder2. Olive oil, a fundamental constituent of the Mediterranean diet, is also able to modulate the immune system, since it contains numerous components 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-inflammatory properties of other fatty acidsReference Virella, Fourspring, Hyman, Haskill-Stroud, Long, Virella, La Via, Gross and Lopes-Virella3. Overall, the action of MUFA on the human immune system has allowed their application in the resolution or attenuation of diseases characterized by inflammatory disordersReference Kremer, Lawrence, Jubiz, DiGiacomo, Rynes, Bartholomew and Sherman4, Reference Linos, Kaklamanis, Kontomerkos, Koumantaki, Gazi, Vaiopoulos, Tsokos and Kaklamanis5, in the reduction of cancer riskReference Martin-Moreno, Willett, Gorgojo, Banegas, Rodriguez-Artalejo, Fernandez-Rodriguez, Maisonneuve and Boyle6 and in clinical nutritionReference Sala-Vila, Barbosa and Calder7. This article will summarize the current 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 prevalence of inflammatory disorders in this populationReference Kromann and Green8, and the reduction of death from ischemic heart disease, in spite of the consumption of diets high in fat and cholesterolReference Kromhout9, or the low incidence of cancerReference Blot, Lanier, Fraumeni and Bender10. 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 EskimosReference Kaplan, Fraser and Comstock11, 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 microorganismsReference Blok, Vogels, Curfs, Eling, Buurman and van der Meer12. 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, antioxidants, 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 immunosuppressive effects attributed to olive oil are likely due to oleic acid rather than to other minor components of this fatReference Jeffery, Yaqoob, Newsholme and Calder13. However, a recent study has demonstrated that the polyphenolic substances contained in olive oil possess anti-inflammatory propertiesReference Beauchamp, Keast, Morel, Lin, Pika, Han, Lee, Smith and Breslin14.
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 significant reduction of lymphocyte proliferation in response to the mitogen concanavalin A (Con A)Reference Yaqoob, Newsholme and Calder15. 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 lymphocytesReference Yaqoob, Knapper, Webb, Williams, Newsholme and Calder16. 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 contributed approximately 25 to 30 % of total energy in the animal studies, whereas diets constituted by MUFA supplied approximately 18 % of total energy in human studiesReference Yaqoob17. Although some animal investigations have reported a reduction of lymphocyte 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 lipopolysaccharide (LPS)Reference Puertollano, de Pablo and Alvarez de Cienfuegos18. The specific factors that contribute to the contradictory 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 different 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 activate and regulate cells that participate in the inflammatory response. Interleukin-2 (IL-2) is an important cytokine responsible 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 miceReference Yaqoob and Calder19, Reference de Pablo, Ortega, Gallego, Alvarez, Pancorbo and Alvarez de Cienfuegos20. IL-4 production, a cytokine with anti-inflammatory functions was increased in mice after the administration of a diet containing olive oil for 4 weeksReference Puertollano, Puertollano, Ruiz-Bravo, Jimenez-Valera, de Pablo and Alvarez de Cienfuegos21. In contrast, the production of IL-10, a cytokine with similar functions to IL-4, was decreased after the administration of a diet containing olive oil, although the production of IL-10 was not different from that seen after feeding mice a low fat dietReference Yaqoob, Newsholme and Calder15. Finally, the concentration of IL-12, a cytokine that participates as a pro-inflammatory protein, was reduced in mice fed with diets containing olive oilReference Puertollano, Puertollano, Ruiz-Bravo, Jimenez-Valera, de Pablo and Alvarez de Cienfuegos21. 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-α or IL-6 production were increased or not modified in miceReference Yaqoob and Calder22, Reference de Pablo, Ortega, Gallego, Alvarez, Pancorbo and Alvarez de Cienfuegos23. 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 administration 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 lymphocyte 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 activityReference Yaqoob, Newsholme and Calder24. 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 ratsReference Jeffery, Cortina, Newsholme and Calder25. 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 lymphoma), although the greatest suppression was observed in mice fed with a fish oil dietReference Puertollano, Algarra, Ortega, de Pablo and Alvarez de Cienfuegos26. 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 dietReference Yaqoob, Knapper, Webb, Williams, Newsholme and Calder16.
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 suppression of immune system functions exerted by certain dietary lipids may cause a reduction of host resistance to infectionReference de Pablo, Puertollano and Alvarez de Cienfuegos27–Reference Fritsche30. 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 consumption of diets containing very high amounts of long chain n-3 PUFA increases the risk of infection and the incidence of tuberculosis in native EskimosReference Kaplan, Fraser and Comstock11, despite the beneficial effects in the reduction of inflammatory disordersReference Kremer, Lawrence, Jubiz, DiGiacomo, Rynes, Bartholomew and Sherman4, Reference Kromann and Green8. Subsequently, experimental studies have demonstrated a significant reduction of survival percentage as well as an increase of viable bacteria in the spleenReference de Pablo, Puertollano, Gálvez, Ortega, Gaforio and Alvarez de Cienfuegos31 or liverReference Fritsche, Shahbazian, Feng and Berg32 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 microorganismsReference de Pablo, Puertollano and Alvarez de Cienfuegos27–Reference Fritsche30. 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.
Table 1 Summary of human studies examining the effects of olive oil on immune system function
Abbreviation: PBMC, peripheral blood mononuclear cells; ICAM-1, intercellular adhesion molecule-1.
Table 2 Summary of animal studies examining the effects of olive oil on immune system function
Abbreviations: NK, natural killer; LPS, lipopolysaccharide; IL, interleukin; TNF, tumor necrosis factor.
Numerous investigations have reported the involvement of long-chain n-3 PUFA in the modulation of natural resistance against Salmonella typhimurium serovar Typhimurium, Mycobacterium tuberculosis, Listeria monocytogenes, influenza virus or parasitesReference de Pablo, Puertollano and Alvarez de Cienfuegos29, Reference Fritsche30. 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 containing MUFA are able to reduce infection severity and to prolong survival in murine models after the challenge with L. monocytogenes. In addition, the recovery of viable bacteria from spleenReference de Pablo, Puertollano, Gálvez, Ortega, Gaforio and Alvarez de Cienfuegos31 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 oilReference Puertollano, de Pablo and Alvarez de Cienfuegos33. 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 oilReference Puertollano, de Pablo and Alvarez de Cienfuegos18.
An important cytokine involved in the activation of Th1 response is IL-12, which plays a relevant role in the elimination 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-α was modified after L. monocytogenes infection, especially at 24 h of challenge (Fig. 1).
Fig. 1 Pro-inflammatory cytokine concentrations in sera from mice fed an olive oil diet or a low fat diet (control diet) and experimentally infected with Listeria monocytogenes. The concentration of interleukin-1 (IL-1), interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) was measured in the serum of Balb/c mice fed with a low fat diet (open bars) or with an olive oil diet (close bars) for four weeks. After the feeding period, animals were experimentally infected with L. monocytogenes and the serum was collected at 0, 24 and 72 h of challenge. Significant differences (two-way ANOVA) between experimental groups in each time are indicated as follow: *P < 0·05; **P < 0·001.
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 immunosuppression exerted by diets containing fish oil is aggravated in this model, whereas in our experience an olive oil diet moderately reduces host resistance to infection (unpublished results).
Olive oil in clinical nutrition
Lipid emulsions constitute an essential component of total parenteral nutrition, which represents an indispensable strategy to improve nutritional status of critically ill patients. The interaction between fatty acids and the immune system has increased the interest in the manipulation of fatty acid composition 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 infectionReference Reimund, Scheer, Muller, Pinna, Duclos and Baumann34. 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 preservation of mononuclear phagocyte system functionsReference Garnacho-Montero, Ortiz-Leyba, Garnacho-Montero, García-Garmendia, Pérez-Paredes, Moyano-Del Estad, Barrero-Almodóvar and Jiménez-Jiménez35.
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 functionsReference Sala-Vila, Barbosa and Calder7. ClinOleic offers clinical advantages in severally burned patients, with improved liver functions after administrationReference Garcia de Lorenzo36. 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 responseReference Moussa, Le Boucher, García, Thaczok, Ragab, Dutot, Ohayon, Ghisolfi and Thouvenot37, Reference Granato, Blum, Rössle, Le Boucher, Malnoe and Dutot38.
Concluding remarks
Diets containing olive oil may exert beneficial effects when they have been applied in the resolution of inflammatory disorders. Experimental studies have indicated that the immunomodulatory action of olive oil is due to oleic acid, but recent investigations have suggested that anti-inflammatory properties are also attributed to phenolic compounds. The immunosuppressive 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 pathogens. Therefore, it is important to determine the effects produced 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 Diputación Provincial de Jaén by supporting a part of this publication. The authors have no conflicts of interest to report. All authors contributed to co-write the manuscript. MAP and MAdP read and approved the final version of this manuscript.
