The antimalarial properties of milk

It all begins in 1952 with the work of the Liverpool School of Tropical Medicine B. G. Maegraith, T. Deegan, and E. Sherwood JonesSuppression of Malaria (P. Berghei) by Milk. Br Med J. 1952 Dec 27; 2(4799): 1382–1384. Audrey A. N. Keppie. Modified Course of T. congolense Infection in Mice Given Diets with Milk Casein. Br Med J. 1953 Oct 17; 2(4841): 853–857. They found that in rats inoculated with Plasmodium berghei and living on a diet of milk there was a strong suppression of the growth of the parasites. This was valid for retail whole cow’s milk, reconstituted dried milk from different origins and human milk. Most rats on normal laboratory diet died in a few days. The authors suggested that the milk might contain an inhibitory substance and that herein lies the explanation of the common observation that severe malaria is not often seen in very young infants. In these first experiments only blood-transmitted malaria had been studied. The London School of Tropical Medicine followed-up on this early work and confirmed that a milk diet had a suppressive action on Plasmodium cynomogi in monkeys. But after a return to normal diet a severe recrudescence took place. Bray RS, , .Effect of milk diet on P. cynomolgi infections in monkeys. British medical journal 1953-May;1()1200-1 DOI: Fulani are a widely spread African ethnic group characterized by lower susceptibility to Plasmodium falciparum and clinical malaria morbidity. They are characterized by a higher rate of lactase persistance.This trait is common in Europe and certain African people with traditions of raising cattle. Lactase non-persistance in other African tribes is often called lactase intolerance. The potential immunoprotective properties of dietary cow milk as a reason for the malaria resistance of Fulani warrant further investigation. I Lokki, I Järvelä, V Holmberg. Lactase persistance genotypes and malaria susceptibility in Fulani in Mali. Malaria Journal, 2011, 10 :9 Formula-fed babies contract gastroenteritis more than breast-fed babies, which is of concern to mothers who cannot breastfeed or, as with HIV-infected mothers, are discouraged from breastfeeding. The ability of endogenous breastmilk xanthine oxidase to generate the antimicrobial radical nitric oxide has been measured and its influence on the growth of Escherichia coli and Salmonella enteritides examined. Breastmilk, but not formula feed, generated nitric oxide. Xanthine oxidase activity substantially inhibited the growth of both bacteria. An important natural antibiotic system is missing in formula feeds; the addition of xanthine oxidase may improve formula for use when breastfeeding is not a safe option. Stevens CR, Millar TM, Clinch JG, Kanczler JM, Bodamyali T, Blake DR. Antibacterial properties of xanthine oxidase in human milk. Lancet. 2000 Sep 2;356(9232):829-30. Work done on the shores of lake Victoria suggested that milk might be deficient in certain nutrients required by the parasite, but that these are present in any normal diet. For the first three months in life children are exclusively breast-fed and they stay malaria free. At the third or fourth month mothers usually start giving them a variety of foods in addition to the breastmilk, and these extras might supply the nutrients required by the parasite. The National Institute for Medical Research finds that milk contains very little p-aminobenzoic acid (PABA), not more than 0.004 ppm. F. Hawking. Milk, p-Aminobenzoate, and Malaria of Rats and Monkeys. Br Med J. 1954 Feb 20; 1(4859): 425–429. This substance is much more plentiful in some of the constituents of a good laboratory diet, where the vegetal components contain up to 60 ppm of PABA. In vitro Plasmodium requires PABA for satisfactory growth. Experiments were undertaken to study this possibility. Rats were maintained on different diets: normal diet, milk, milk with 1000 ppm of PABA. Only the rats on the milk diet stayed free of P. berghei on day 12. Plasmodium requires exogenous dietary PABA for survival. Gregory A. Kicska, Li-Min Ting, Vern L. Schramm and Kami Kim. Effect of Dietary p-Aminobenzoic Acid on Murine Plasmodium yoelii Infection. JID 2003, 188, 1776-1783) In 1980 the University of Minnesota showed that milk had a salutary effect on amoebiasis. Murray, M.J., A. Murray and C.J. Murray .The salutary effects of milk on amoebissis and its reversal by iron. British Medical Journal i, 1980, 1351-2. In an outbreak of Plasmodium falciparum malaria following refeeding after famine cerebral malaria was restricted to children eating grain. Those given grain were more likelly to experience cerebral malaria. Nomad children consuming a predominantly milk diet were free of this complication despite an equivalent incidence of uncomplicated malaria. Freedom of nomads from cerebral complications may be due to inhibition by the milk diet of rapid division of the parasite combined with delayed recovery after famine of T cell function Murray MJ, Murray AB, Murray NJ, Murray MB. Diet and cerebral malaria: the effect of famine and refeeding. Am J Clin Nutr. 1978 Jan;31(1):57-61. Milk-drinking African nomads show an unusual freedom from infection with Entamoeba histolytica compared with similar nomads taking a mixed diet. The authors related this to a low content in iron in cow’s milk. A personal communication from Dr Patrick Ogwang informs that in Uganda malaria is highest in East and North Uganda where the staple food is cereals with high iron content, in western Uganda where milk and low iron foods are eaten most malaria is low. In the past however, people in East and North also kept cows (zebu) and took milk regularly and malaria was not as rampant. In 1983 a five month study was undertaken in Brazil to test the effect of a total milk diet on the susceptibility of mice to various doses of a the rodent malaria P berghei. The development of humoral immunity was followed by quantitation of the specific serum immunoglobulins (IgG and IgM). High levels of IgG antibodies persisted for 150 days, IgM antibodies were only observed during the two first weeks of infection. The results indicated that a milk diet administered to mice as the only source of food protected them against fatal malaria infection regardless of the number of parasites inoculated. The acquired immunity was still present in the mice at 150 days post inoculation. Ferraroni, J. J.. Título: Efeito da dieta lactea na supressao da parasitemia. Mem. Inst. Oswaldo Cruz; 1983, 78(1):27-35, But these very promising treatments were ignored by Bigpharma and subsidized research. Obviously dairy milk or dried milk is not an interesting cash cow in the fight against malaria. Only more recently, in the light of resistance to most, if not all, of the pharmaceutical molecules (chloroquine, amodiaquine, lumefantrine, chloroquine, sulfadoxine-pyrimethmine) some research groups have tried to better understand these fifty years old findings. And the proposed detrimental role of PABA (p-aminobenzoic acid) seems to be confirmed. Glenn A. McConkey. Targeting the Shikimate Pathway in the Malaria Parasite Plasmodium falciparum. Antimicrob Ag Chemotherapy, 1999, 43-1, 175-177 Kretschmar W, Voller A. Suppression of Plasmodium falciparum malaria in Aotus monkeys by milk diet. Z Tropenmed Parasitol. 1973 Mar;24(1):51-9 Jacobs RL Role of p-aminobenzoic acid in Plasmodium berghei infection in the mouse.Exp Parasitol. 1964 Jun;15:213-25 . Nowell F. The effect of a milk diet upon Plasmodium berghei, Nuttallia (=Babesia) rodhaini and Trypanosoma brucei infections in mice. Parasitology. 1970 Dec;61(3):425-33 Plasmodium generates its own PABA in its apicomplexan organelle, but not in quantities sufficient to guarantee survival and multiplication of trophozoites and schizonts in the infected erythrocyte. And as the human body does not generate its own PABA or folates, but takes them essentially from green vegetables, the parasite has to rely on this supply. If the diet is exclusively on milk it has no chance to survive. PABA is an intermediate in the synthesis of folate. And the folate supplements sold in our nutrition might be harmful to African newborns infected by malaria. Carter JY, Loolpapit MP, Lema OE, Tome JL, Nagelkerke NJ, Watkins WM. Reduction of the efficacy of antifolate antimalarial therapy by folic acid supplementation. Am J Trop Med Hyg. 2005 Jul;73(1):166-70. Iron is essential for the survival and multiplication of the Plasmodium parasite. In humans iron deficiency appears to protect against severe malaria while iron supplementation increases risks of infection and disease. It would thus be advisable to keep the iron concentrations rather on the low side. This can be achieved by drinking milk. Lactoferrin, a glycoprotein found in milk, has the ability to bind Fe ions with high affinity and to regulate iron distribution within the body. Heather M. BakerEdward N. Lactoferrin and Iron: structural and dynamic aspects of binding and release. Biometals June 2004, Volume 17, Issue 3, pp 209–216 Zinc is an essential element with strong bactericidal properties and very efficient against diarrhoea and other diseases. UNICEF estimates that a formula-fed child living in unhygienic conditions is between 6 and 25 times more likely to die of diarrhea and four times more likely to die of pneumonia than a breastfed child (Wikipedia, 2007). Zinc stimulates the immune system and increases CD4 Eugenio Mocchegiani, Zinc and ageing: third Zincage conference Immunity & Ageing20074:5 DOI: 10.1186/1742-4933-4-5 This might be one of the reasons why human milk is rich in zinc. The zinc content of milk varies with species, lower in cow milk, and stage of lactation, much higher in colostrum. This is probably contributing to the immunity of newborns against malaria. Most medical plants like Artemisia are rich in zinc. The zinc content of milk varies with species and stage of lactation, and it is much higher in colostrum. This is probably contributing to the immunity of newborns against malaria. Variations in zinc absorption from different milks and formulas employed in infant feeding are of serious concern K Hambidge, CE Casey, NF Krebs, In : Mertz W (ed), Trace elements in human and animal nutrition , 1986, Academic Press. Orlando, FL. There is considerable evidence to suggest that the bioavailability from human milk is especially favorable. The superior bioavailabity of zinc from human milk has been confirmed with radioactive zinc studies in adults in whom absorption with mature human milk averaged 57% compared with 32% for cow’s milk. Hence, zinc plasma concentrations of infants fed with cow’s milk-based infant formula was significantly lower. Zinc absorption from soy-based infant formulas is especially poor. The poor absorption of zinc from soy formulas has been found to be attributable to the phytate present in these formulas. Potassium concentrations in mother’s milk are 2 times higher at postpartum in colostrum than 1 month later in mature milk. Silprasert A, Leelapat PPruenglampoo, Composition of sodium, potassium, calcium, magnesium and phosphorus in human g breat-milk at different stages of lactation period, 1991. Http://thaiagris.lib.ku.ac.th It is likely that potassium plays a key role. The potassium concentration in the plasma of neonates is much higher than in the plasma of the mothers: 5.9 mmol/l versus 3.8 mmol/l Martinerie L, Pussard E, Foix-L'Hélias L, Petit F, Cosson C, Boileau P, Lombès M. Physiological partial aldosterone resistance in human newborns. Pediatr Res. 2009 Sep;66(3):323-8. doi: 10.1203/PDR.0b013e3181b1bbec. The content of selenium in colostrum is significantly higher (28.6 ng/ml) than that of in mature milk (15.1 ng/ml) KIM ES, KIM JS, Tamari Y. Quantitation of taurine and selenium levels in human milk. Adv Exp Med Biol 1998 442 477-486. Monoterpenes are well present in milk. A French INRA study found that the most abundant monoterpenes (essential oils) in milk from cows grazing natural diversified pasture were alpha-pinene, beta-pinene and limonene Tornambé G, Cornu A, Verdier-Metz I, Pradel P, Kondjoyan N, Figueredo G, Hulin S, et al. 2008. "Addition of pasture plant essential oil in milk: influence on chemical and sensory properties of milk and cheese." Journal of dairy science 91 (1): 58-69. doi:10.3168/jds.2007-0154. Mother’s milk is rich in cholesterol. During the course of human lactation the cholesterol concentration decreases from 31mg/100cm³(colostrum) to 16 mg/100cm³. Kamelska AM, Pietrzak R, Bryl K, Variation of the cholesterol content in breast milk during 10 days collection at early stages of lactation, Acta Biochim Pol 2012, 59(2) 243.7 After 3 months of breastfeeding the plasma cholesterol is higher than for neonates fed on formula milk. Jooste PL, Rossouw LJ, Steenkamp, Effect of brestfeeding on the plasma cholesterol and growth of infants. J Pediatr Gastroenterol Nutr 1991 13(2) 139-42 Akeson PM, Axelsson IE, Raiha NC, Plasma lipids in breastfed and formula-fed Swedish infants, 1999, jan 88(1) 1-6 D Harit, MM Faridi, SB Sharma, Lipid profile of term infants on exclusive breastfeeding and mixed feeding: a comparative study. Europ J Clin Nutr 2007 1-7 Wagner V, von Stockhausen HB, The effect of feeding human milk and adapted formulae on serum lipid level of young infants, Eur J Pediatr 1988 147(3), 292-5 Human milk contains n-3 and n-6 long chain polyunsaturated fatty acids, which are absent from many infant formulas. During neonatal life, there is a rapid accretion of arachidonic and docodahexaenoic acid in infant brain. Cognitive development of breast-fed infants is generally better. Fleith M, Clandinin MT. Dietary PUFA for preterm and term infants: review of clinical studies. Crit Rev Food Sci Nutr 2005, 45, 205-29. Lauritzen L, Carlson SE. Maternal fatty acid status during pregnancy and lactationand relation to newborn and infant status. Matern Child Nutr 2011 41-58. Innis SM. Human milk: maternal dietary lipids and infant development. Proc Nutr Soc, 2007, 66, 397-404. Arachidonic acid also has strong antimalarial properties via PGE production. Already in 2000 it had been demonstrated in a study on Gabonese children with and without malaria that prostaglandins are important pro-inflammatory mediators of the host-immune response to infection. Douglas J. Perkins, Peter G. Kremsner and J. Brice Weinberg. Inverse Relationship of Plasma Prostaglandin E2 and Blood Mononuclear Cell Cyclooxygenase-2 with Disease Severity in Children with Plasmodium falciparum Malaria. J Infect Dis. (2001) 183 (1): 113-118. doi: 10.1086/317660 The concentration of arachidonic acid is on the average 0.5% by wt in breast milk. The IUPAC Lipid Handbook confirms that human milk contains AA, but cow's milk doesn't. Arachidonic acid is essential for the brain development of infants. JH Brenna, B Varamini, R Jensen, D Diersen -Schade, L Arterburn. Docosahexaeonic and arachidonic acid concentrations in human n breast milk worldwide. Am J Clin Nutr 2007, 85 no 6 1457-1464 Kim H, Kang S, Jung BM, Brest milk fatty acid composition and fatty acid intake of lactating mothers in South Korea. Br J Nutr 2017, 13, 1-6. Henjum S, Lie O, Chandyo RK, Kiellevold M, Erythrocyte fatty acid composition of Nepal breast-fed infants. Eur J Nutr 2017, Feb 25 B Koletzko. Human milk lipids. Ann Nutr Metab 2016;69 Suppl2 28-40 Without the provision of preformed ARA in human milk the growing infant cannot maintain ARA levels from the synthetic pathways alone that are sufficient to meet metabolic demand. During late infancy and early childhood the amount of dietary ARA provided by solid foods is low. Arachidonic acid is 20 times higher in human than in bovine milk. Yushi Sueyoshi, Hanako Oda, Comparative study on amounts of polyunsaturated fatty acids in human and cow’s milk. Keio J of Medicine, 1963, 12, 27-29 Mother’s milk is rich in taurine: 358 mg/kg. Cow’s milk only contains 50 mg/kg and formula milk 30. Mother’s milk is rich in hydrogen peroxide in the first postpartum week. EAA Al Kerwi, A Al Hashimi, A Salman, Mother’s milk and hydrogen peroxide. Asia Pac J Clin Nutr 2005, 14 428-431 Estimation of nitrate and nitrite concentrations of milk sources may provide another insight. Human milk is known to confer significant nutritional and immunological benefits for the infant. In colostrum (1-3 days postpartum) nitrite concentrations are much higher than in mature milk (0.08 mg/100mL versus 0.001). Norman G. Hord, Janine S. Ghannam, Harsha K. Garg, Pamela D. Berens, Nitrate and Nitrite Content of Human, Formula, Bovine, and Soy Milks: Implications for Dietary Nitrite and Nitrate Recommendations Breastfeed Med. 2011 Dec; 6(6): 393–399. doi: 10.1089/bfm.2010.0070 According to the authors this change is partly due to the changing intestinal microflora in the baby and the changing metabolic demands as the baby grows. The beneficial effects of NO in adult stomachs on gastroprotective and immunomodulatory functions is known. Arginine plays a key role in the metabolism of nitrates. Therefore, it is reasonable to surmise that nitrite must be supplied to the newborn by colostrum. A recent thesis from Sweden confirms and documents well all these positive elements. Dietary nitrates have potent anti-inflammatory effects, without impairing the ability to clear an infection. They are able to restore the gastric and colonic mucus layer in case of colitis. C Jädert, Diet and inflammation, The role of nitrate and conjugated linoleic acid. Akademisk afhandeling, thesis, Karolinska Institutet, 2014 In breastfed infants “good bacteria” of the gut are important in determining the “direction” of maturation of immunity. Together with other maternal and infant factors, the breastfed infant's mucosal and systemic immune responses are influenced by a different micro eco milieu of the gut compared to the formula fed infant. An environment that does not encourage the hatching of Trichuris trichuria eggs due to the absence of the required ‘pro hatching’ bacteria. Escherechia coli in the gut in the breastfed, is deemed another indirect anti-parasitic potential that lies within breast milk. Prameela Kannan Kutty. Breastfeeding and risk of parasitic infection-a review. Asian Pacific Journal of Tropical Biomedicine. Volume 4, Issue 11, November 2014, Pages 847–858 Several protector mechanisms have been proposed for Lactobacillus against gastroenteritis. The most likely mechanism is its role as immunomodulator. Higher bottle feeding with milk poorer than breast milk in Lactobacillus increases the risk of diarrhea. In a trial probiotics Lactobacillus and Bifidobacterium shortened duration of diarrhea to 34.1hrs versus 58 hrs with placebo and reduced the number of stools (7.3 vs 15.9 with placebo). S. Rerksuppaphol and L. Rerksuppaphol. Lactobacillus acidophilus and Bifidobacterium bifidum stored at ambient temperature are effective in the treatment of acute diarrhea. Ann Trop Paediatr. 2010 Dec; 30(4): 299–304. doi: 10.1179/146532810X12858955921159 Newburg DS, Pickering. Fucosylated oligosaccharides of human milk protect suckling mice from heat-stabile E coli. J Inf Diseases 1990. 162, 1075-1080 . Ruiz-Palacios GM, Cervantes LE, Ramos P, Role of human milk lactadherin in protection against symptomatic rotavirus. Lancet 1998 351:1160-1164 Potassium concentrations in mother’s milk are 2 times higher at postpartum in colostrum than 1 month later in mature milk. Silprasert A, Leelapat PPruenglampoo, Composition of sodium, potassium, calcium, magnesium and phosphorus in human g breat-milk at different stages of lactation period, 1991. Http://thaiagris.lib.ku.ac.th So maybe the message of Melinda Gates in the Wall Street Journal of May 20, 2016 has a lot of merit "Many newborn deaths can be prevented by simple, inexpensive measures- such as teaching women to breast-feed, which immediatela gives a baby nutrients and hydration, and guards against infection, one of the biggest killers of newborns. Each year 2.9 million infants die in their first 28 days of life"