Choline to Improve Malnutrition and Enhance Cognition

Severe acute malnutrition (SAM) affects approximately 14 million children worldwide at any one time and has an annual incidence of 3-5x this number. SAM is defined by wasting (mid-upper arm circumference < 11.5 cm or weight-for-length z-score < -3) or presence of bilateral pedal pitting edema. SAM increases short-term risks for infection, hospitalization, and death, as well as longer-term risks for stunted linear growth and impaired cognitive development. This lattermost consequence is increasingly recognized, with studies showing that children who have suffered from SAM score 2-3 standard deviations below age-expected norms on cognitive development tests.

Ready-to-use therapeutic food (RUTF) revolutionized SAM treatment by allowing it to occur in the home setting. RUTF cures most children with SAM and ameliorates many of its worst consequences. RUTF was designed to be food-safe and promote anthropometric recovery. Since its inception, evidence has accumulated suggesting that the original fatty acid content of RUTF was not optimized for cognitive recovery from SAM. A 2021 trial, the Improved PUFA Trial (PMID: 34726694), demonstrated that reducing the omega-6 fatty acid content of RUTF and adding docosahexaenoic acid (DHA) improved cognitive development 6 months after SAM treatment in Malawian children. It is possible that further modifications to RUTF's composition might promote greater cognitive recovery.

Choline is essential for human health and development and is recognized as such by the Institute of Medicine, which designates daily recommended intakes. Choline deficiency has been shown to induce a host of cognitive developmental problems in animal models, is associated with neural tube defects in humans, and mutations of choline transporters in humans yield developmental degenerative conditions which, while rare, shed light on the essential nature of choline in brain development. Several small randomized, controlled trials have shown benefits of choline supplementation during early life on child cognitive development, both in healthy children and in those exposed to insults such as in fetal alcohol syndrome.

Choline plays important roles in brain structure and function and is found primarily in animal-source foods, which are deficient in the diets of children with SAM. Choline is an essential component of the neuronal membrane as well as a precursor for acetylcholine, a key neurotransmitter. In addition, choline plays a role in the trafficking and cell membrane integration of DHA, which rapidly accumulates in the human brain during childhood and ultimately composes 40-50% of brain polyunsaturated fatty acids. Decades of findings from epidemiological studies and laboratory science, including with animal models, support the essential role of DHA in the structure and function of the brain and retina. The Improved PUFA Trial leveraged these insights and showed that the developing brain is sensitive to fatty acid intake in the context of SAM; providing DHA in RUTF improved brain development. Hepatic export of DHA into plasma and its target tissues, including the brain, relies in part on synthesis of phosphatidylcholine (PC) by phosphatidylethanolamine N-methyltransferase (PEMT). DHA-enriched PC molecules (PC-DHA) are generated by PEMT and exported for delivery throughout the body. Indeed, PEMT-deficient mice have reduced DHA plasma concentrations and pups born to PEMT-deficient dams have limited DHA brain accumulation. The PEMT pathway relies on adequate supply of dietary methyl donors such as choline. Pairing (1) choline's ability to increase DHA trafficking to/integration within the brain with (2) the power of DHA in SAM, it is possible that adding choline to RUTF containing DHA might promote cognitive recovery and development among malnourished children.

This will be an individually randomized, investigator/outcomes assessors/caregiver-blinded, controlled clinical trial designed to determine whether the addition of a daily dose of 500mg of choline to ready-to-use therapeutic food (C-RUTF) will improve cognitive development among Malawian children 6-59 months of age with SAM compared with standard RUTF (S-RUTF). This trial will be conducted at 10 rural sites in southern Malawi. 1500 children will be randomized 1:1 to receive 2 sachets per day of either C-RUTF or S-RUTF. Children will receive their allocated RUTF and return to clinic fortnightly for repeat anthropometric measurements, illness questions, and to receive more RUTF until they achieve a clinical outcome or for a maximum of 12 weeks, at which point they will undergo Malawi Developmental Assessment Tool (MDAT) testing and blood spot collection. Participants will be asked to return to clinic 5-7 months later for MDAT testing, the global z-score from which will be the trial's primary outcome.

Inclusion criteria

• 6-59 months of age
• mid-upper arm circumference < 11.5 cm and/or weight-for-length z-score < -3 and/or presence of bilateral pedal pitting edema
• willingness to comply with all study procedures and availability for the duration of the study, including no plan to move from the catchment area of a participating clinic

Exclusion criteria

• features of complicated SAM: inability to tolerate a 30g test dose of RUTF, breathing difficulties, mental status changes, sepsis, or physician/nursing clinical assessment that the child needs immediate hospitalization
• participation in a separate feeding program within the past month
• known allergy to study food ingredient (peanut, milk, fish)
• intention to move away from catchment area within 9 months
• developmental delay
• presence of a chronic severe medical condition (other than TB and HIV), such as congenital heart disease