In 1957 the University of London found that dietary cod liver oil suppressed the multiplication of Plasmodium berghei in mice (DG Godfrey, Experimental Parasitology, 1957, 6, 555-565), of Babesia rodhaini (DG Godfrey, Experimental Parasitology 1957, 6-5, 465-485) and of Trypanosoma congolense (D G Godfrey , Experimental Parasitology, 1958, 3, 255-268).
Why was this research lead never taken up by Bigpharma-WHO? An attitude similar to the 20 year long contempt for the Chinese herb Artemisia annua. Probably because you cannot make money with an herb or a fish oil accessible to everybody !
THE ANTI-OXIDANT, PRO-OXIDANT CONTROVERSY
Research on dietary fish oil and diseases was only resumed in the nineties. A Chinese paper confirmed that fish liver oil protected mice from Plasmodium (Zhuang Guozheng et al., Medicinal J of National Defending Forces in Southwest China 1998-06). A Dutch team studied the effects of artemisinin and a fish oil, separately or in combination, against Klebsiella pneumoniae and Plasmodium berghei (W Blok et al., J Infect Dis. 1992, 165, 898-903). After a low inoculum of K.pneumoniae 90% of fish-oil-fed mice survived and 0% in normal chow fed mice. Cerebral malaria developed in 23% of the fish-oil-fed mice and 75% in the control. The positive effect of dietary fish oil on survival after infection with Klebsiella pneumoniae could be confirmed in Iceland (V Stefansson Thors et al., Scand J Infect Dis 2004, 36, 102-105).
One important element in the work of Godfrey needs to be mentionned: large doses of vitamin E completely reversed the suppressive action due to cod liver oil. The author advances the following hypothesis : the unsaturated fatty acids of the cod liver oil are oxidised by the host to peroxides. These create a pro-oxidant state inimical to the parasites. Vitamin E (tocopherol) prevents the peroxidation by virtue of its strong strong anti-oxidant properties.
A USDA team extensively studied this effect of vitamin E (O Levander et al., Am J Clin Nutr. 1989, 50, 346-52) on malarial parasites. Vitamin E deficiency enhanced the antimalarial action of artemisinin against Plasmodium yoelii, both in terms of decreased parasitemia and improved survival. A vitamin E-deficient diet containing 5% cod-liver oil had such strong antimalarial activity in itself that no additional therapeutic effect of artemisinin could be demonstrated. The same effect was noticed for the fish-body oil from the Atlantic menhaden fish (O Levander et al, Am J Clin Nutr. 1989, 50, 1237-9) or for anchovy and salmon oil.
The University of Lagos found that the effect of artesunate was significantly reduced when co-administered with vitamin E (O Awodele et al., Afr J Biomed Res, 2007, 10, 51-57) or that animals receiving the combination of both artesunate and cod liver oil demonstrated a better clearance with 98.9 suppression on day 7 (O Awodele et al.,Nigerian J Health and Biomed Sc. 2006, 5, 74-78).
If vitamin E is really enhancing parasitaemia, caution is recommended in the use of Moringa oleifera. This plant is claimed to contain 113 mg of vitamin E per 100 g, 10 times more than the recommended daily intake.
THE ARGININE – NITRIC OXIDE HYPOTHESIS
Fish oil and seafood are very rich in arginine : 1g/100g. Much more than vegetables. Arginine is the amino acid which generates NO via the NOS enzymes. Nitric oxide is a strong pro-oxidant which kills the parasites (see my blog „Arginine a deadly weapon..“ on www.malariaworld.org). Palm oil, corn oil also inhibit parasitemia but the effect is negligible compared to fish oil. The arginine contained in fish oil leads to CD4 T-cell proliferation (MM Kai Kang et al., Asia Pacif J Clin Nutr 2014 23 351-359).
THE UNSATURATED FATTY ACID HYPOTHESIS Fish oils are rich in polyunsaturated fatty acids (PUFA), often of the so called omega-type. Some of them like docosahexaenoic acid (DHA), eicosapentaeonic acid (EPA), arachidonic acid cause marked in vitro growth inhibition of Plasmodium falciparum. Parasite killing is significantly increased when oxidised forms of polyunsaturated fatty acids are used. Saturated fatty acids are less effective because they are more resistant to oxidative attack. It is even likely that oxidation of polyunsaturated fatty acids is a defense mechanism of the host. Similar effects were seen in vivo on mice infected with Plasmodium berghei and treated during 4 days with these acids, The effect is thus not only prophylactic but also suppressive. But antioxidants like vitamin E, catalase, superoxide dismutase or commercial antioxidant food additives markedly reduce the antimalarial activity of fatty acids (L Kumaratilake et al., J Clin Invest 1992, 89 , 961-967). Neutrophils are the first line of defense against infection and their involvement in the control of blood parasites of malaria is known. In a subsequent study the same authors showed that the antiparasitic activity of neutrophils can be greatly increased by treatment with fatty acids with 20 to 24 carbon atoms and at least 3 double bonds. Fatty acids with 18 or 28 carbon atoms were less efficient in neutrophil-mediated killing of Plasmodium falciparum parasites (S Kumaratilake et al., Infection and Immunity, 1997,65, 4152-57).
Plants of the Artemisia family also contain unsaturated fatty acids ranging from 0,3 to 1.7 %. The acids with 18 carbon atoms are more abundant than those with 20 carbons. The predominant acid in all species were linoleic and linolenic acid (IS Carvalho et al., Food Science and Technology, 2011,44, 293-298).
Linoleic acid plays a complex and ambigous role in malaria. The antimalarial activity of unsaturated fatty acids and particularly linoleic acid has been well documented. Their action is very rapid, in less than 30 minutes (M Krugliak et al., Exp Parasitol 1995, 81, 97-105). In vivo trials on Plasmodium berghei in mice by oral administration test of a mixture of linoleic and linolenic acids in a suppressive assay showed that after a 4 day treatment parasitemia was reduced to 0.5% and the growth inhibition of the parasite was 96% versus 69% for the chloroquine control. Since exogenous unsaturated fatty acids are toxic to malaria parasites, how do these protect themselves from this expanded pool of fatty acids, The situation is complex because Plasmodium has its own biosynthetic machinery for the production of fatty acids in the apicoplast and these lipids are used for the biocrystallization of heme into hemozoin When the parasite is invading a host it needs protecting itself from the immune system of the host by creating a so-called parasitophorous vacuole. One possibility is sequestration of these endogenous lipids in the acidic food vacuole. The unsaturated lipid would precipitate with hemozoin. The insoluble precipitate renders the unsaturated lipid nontoxic, while hemozoin polymerization proceeds (CD Finch et al., Biochimica and Biophysica Acta, 2000, 1335, 45-49).
STRENGTHENING OF THE IMMUNE SYSTEM
The effect of dietary fish oils appears to be long lasting ; and not instantaneous or reduced to a few hours or days like common antimalarial drugs (chloroquine, artemisinine, lumefantrine…). For mice fed a fish-oil-diet poor in vitamin E the survival rate improved to at least 70%. Protection against malaria did not seem to be related to the fish oil dose used. Increasing the fish oil dose above 2% in the chow did not seem to increase protection. However a shorter prefeeding interval of two weeks was generally less effective than four weeks of prefeeding. Furthermore all the mice surviving the primary infection survived the rechallenge infection with low parasitaemias and the resistance against reinfection was enhanced for some time after discontinuing fish oil intake (P Fevang et al., Lipids, 1995, 30 437-41).
Dietary consumption of fish oil and/or polyunsaturated fatty acids may lead to an effect which is similar to acquired immunity in high endemic areas. The results suggest that an acquired immune response involving T and B cells may be an important component in both cases. IL-1α and TNFα are significantly enhanced in fish oil-fed mice compared with controls (WL Blok et al., J Infect Dis, 1992, 165, 898-903).
Concerning vitamin D in fish oil, although many anecdotical reports suggest that it may play a role in modulating immune functions, no strong evidence exists in the scientific literature. The antirachitic claim used 50 years for the oral gavage of children with fish oil was probably a blunt sales tool to sell a surplus of fish oil.
ACTION AGAINST OTHER PARASITES
Fish oil is effective against helminthic diseases like trichinellosis. A reduction of 30,6 % of adult worms in Wistar rats was noticed in a fish oil group as compared to the standard diet group (V Gomez Carcia et al., Veterinary Parasitology, 2003, 117, 85-97). For schistosomiasis trials were made with castor oil, praziquantel and fish oil. The oils, particularly castor oil, given by oral gavage for 7 days had the unexpected result to reduce cercarial penetration by 93% (B Salafsky et al., Exp Parasitol. 1989, 69, 263-271). This observation suggests that dietary supplementation of lipids may lead to prophylaxis by an antipenetration activity. Polyunsaturated fatty acids kill methicillin-resistant Straphylococcus aureus ((MI McDonald et al., Lancet, 1981, 2, 1056). Several recent studies are devoted to the impact of polyunsaturated acids on tuberculosis (NM Carballeira, Prog Lipid Res, 2006, 47, 50-61). Nitric oxide has a well known anti-leishmanial effect. But artemisinin contributes very little to NO production (S Nemati et al., Adv Stud Biol. 2013, 5, 27-36). Arginine seems to play a key role against this disease not only by NO production but also by CD4 proliferation (M Munder et al, Eur J Immunol, 2009, 39, 2161-72)
Research on fish oils against malaria has again disappeared from our screens over the last 5 years. Maybe it is time to resume it. Appropriate testing of fish oils in humans should be encouraged by WHO, like it is done for the chemical vaccines of the pharmaceutical industry