Reductions in Blood Concentrations of p-aminobenzoic acid (PABA) and Folate are Therapeutic for Malaria Patients
Malaria is one of the most deadly diseases on the planet. It is a life-threatening infection caused by parasites that are transmitted to people through the bites of infected mosquitoes. The disease is responsible for more than 627, 000 deaths worldwide in 2012. Of the estimated deaths, most occur in sub-Saharan Africa (90%) and in children under 5 years of age (77%).
Strategies for the treatment, prevention and control of malaria typically involve pharmaceuticals, insecticides and nettings. Vaccines to prevent this disease have had little or no success to date. Rarely has diet been considered as an effective therapy to prevent or attenuate malarial morbidity (disease incidence) and mortality (disease death rate). Yet, virtually unknown to almost all malaria researchers is the notion that diets maintaining low concentrations of ρ-aminobenzoic acid (PABA) and folate represent an untapped tactic to thwart malarial infection.
How Diet Impacts Malarial Infection
An Achilles heel in the lifecycle of Plasmodia species (the bacteria which causes malaria) is its reliance upon the availability of folate, an essential nutrient for these rapidly growing parasites. Pharmaceuticals such as pyrimethamine and sulfa drugs are somewhat effective anti-malarials because they interfere with the conversion of PABA to folate (depicted in the Shikimate pathway to the left). In vitro (test-tube) experiments indicate that Plasmodia species have the ability to synthesize limited amounts of folate endogenously, however further experiments show that these parasites cannot synthesize sufficient quantities of folate to survive in living animals (in vivo).1 Hence, without adequate supplemental stores of PABA and folate from their host’s tissues, Plasmodia species have no capacity to cause lethal malarial infections. In support of this scenario is an extensive, but older literature reviewed in references2, 3 showing that exclusive milk diets suppress malarial infections in birds, rodents, and primates. Milk contains very little PABA and yields low concentrations of folate (60-90 µg/1000 kcal; ~ 20 % of the DRI for a 3 yr old child). The suppression of malarial symptoms is abrogated when supplemental PABA is added to all milk diets of infected animals.2, 3 Further, rodent models of malaria demonstrate that dietary PABA and folate reduce the efficacy of sulfa drugs,4 and in humans, high blood concentrations of folate also impair the efficacy of pyrimethamine and sulfa drugs.5 An experimental study of 20 West African infants, up to 2 years of age who were naturally infected with Plasmodia falciparum demonstrated that exclusive milk diets reduced parasite density and decreased disease symptoms within a few days in a manner similar to those (n=12) serving as controls and treated with chloroquine therapy.2
The pastoralist Fulani of West and Central Africa exhibit a well established resistance to malaria compared to other non-milk drinking African sympatric ethnic groups that is unexplained by known genetic resistance factors,6 but rather by enhanced immunity.7 Displacement of PABA and folate rich foods by milk in this population may attenuate malaria infection while allowing immune exposure, serving to prevent serious disease sequelae and facilitate the establishment of protective immunity. In support of this concept are data showing a high prevalence of adult lactase persistence (~68 % of the population)8 in the Fulani which may represent a previously unrecognized genetic factor that indirectly reduces malarial mortality. Accordingly, in high malarial regions where adult lactase persistence is widespread, reduced dietary PABA and folate intake caused by high milk consumption may disrupt the life cycle of Plasmodia species by impairing folate metabolism, thereby reducing childhood malaria fatalities and overall morbidity within adults.
Except for a single modern study,1 research involving the efficacy of PABA deficient diets in preventing or attenuating malaria symptoms effectively stopped in the early 1970s with the widespread use of insecticides, nettings and pharmaceuticals.9 One of the major shortcomings in all of these early experiments was the failure to report milk PABA concentrations2, 3 which conceivably could have been quite variable – perhaps caused by various fodders fed to the cows or by different milk processing procedures. Additionally, because PABA is not an essential human nutrient, no tables of the PABA concentrations in common foods have ever been published. To my knowledge only a single study has reported the PABA concentrations in any food items (five vegetables: carrots, spinach, brussel sprouts, endive, and lettuce),10 whereas extensive USDA tables exist showing the folate concentrations in foods. Consequently, a crucial need exists to determine the PABA content of foods so that anti-malarial diets can be formulated and eventually tested.
The formulation of PABA deficient diets for humans will have no adverse health consequences as PABA is not required in human nutrition. Because about 80% of all deaths attributed to malaria occur in sub-Saharan Africa, mainly among children less than 5 years of age,2 the greatest risk to their lives comes not from inadequate folate intake, but rather from malaria.5 At a meeting hosted by the World Health Organization in 2006, five expert reports concluded that reducing folic acid supplementation in sub-Saharan African children may reduce fatal malarial infections.11
PABA deficient diets have virtually no adverse health effects in humans (both children and adults) because PABA is not required for human nutrition. Yet within the confines of the bacteria, Plasmodia species which cause malaria, deficiencies of this compound in their host’s bloodstream may have devastating effects upon the bacteria’s own metabolism and ability to reproduce and elicit lethal infections in humans. Unfortunately, no tables of PABA concentrations in everyday foodstuffs currently exist. Accordingly, we have no idea how to formulate PABA deficient diets in humans to thwart lethal malarial infections.
A good starting point would be descriptive in nature with the goal of characterizing the PABA content of a wide variety of foodstuffs, including sub-Saharan African ethnic foods. This PABA database along with pre-existing folate databases could be employed to formulate low PABA and folate diets that will be nutritionally adequate in all other respects. Further, it may be possible to formulate low PABA and folate diets without the use of milk which is contraindicated in many sub-Saharan African populations because of their inability to digest the milk sugar lactose without gastric upset.
Loren Cordain, Ph.D., Professor Emeritus
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