Prenatal choline supplementation improves biomarkers of maternal docosahexaenoic acid (DHA) status among pregnant participants consuming supplemental DHA: a randomized controlled trial.

BACKGROUND: Dietary methyl donors (e.g., choline) support the activity of the phosphatidylethanolamine N-methyltransferase (PEMT) pathway, which generates phosphatidylcholine (PC) molecules enriched in DHA that are exported from the liver and made available to extrahepatic tissues. OBJECTIVES: This study investigated the effect of prenatal choline supplementation on biomarkers of DHA status among pregnant participants consuming supplemental DHA. METHODS: Pregnant participants (n = 30) were randomly assigned to receive supplemental choline intakes of 550 mg/d [500 mg/d d0-choline + 50 mg/d deuterium-labeled choline (d9-choline); intervention] or 25 mg/d (25 mg/d d9-choline; control) from gestational week (GW) 12-16 until delivery. All participants received a daily 200-mg DHA supplement and consumed self-selected diets. Fasting blood samples were obtained at baseline, GW 20-24, and GW 28-32; maternal/cord blood was obtained at delivery. Mixed-effects linear models were used to assess the impact of prenatal choline supplementation on maternal and newborn DHA status. RESULTS: Choline supplementation (550 vs. 25 mg/d) did not achieve a statistically significant intervention × time interaction for RBC PC-DHA (P = 0.11); a significant interaction was observed for plasma PC-DHA and RBC total DHA, with choline supplementation yielding higher levels (+32-38% and +8-11%, respectively) at GW 28-32 (P < 0.05) and delivery (P < 0.005). A main effect of choline supplementation on plasma total DHA was also observed (P = 0.018); its interaction with time was not significant (P = 0.068). Compared with controls, the intervention group exhibited higher (P = 0.007; main effect) plasma enrichment of d3-PC (d3-PC/total PC). Moreover, the ratio of d3-PC to d9-PC was higher (+50-67%; P < 0.001) in the choline intervention arm (vs. control) at GW 20-24, GW 28-32, and delivery. CONCLUSIONS: Prenatal choline supplementation improves hepatic DHA export and biomarkers of DHA status by bolstering methyl group supply for PEMT activity among pregnant participants consuming supplemental DHA. This trial is registered at www.clinicaltrials.gov as NCT03194659.

Choline metabolome response to prenatal choline supplementation across pregnancy: A randomized controlled trial.

Pregnancy places a unique stress upon choline metabolism, requiring adaptations to support both maternal and fetal requirements. The impact of pregnancy and prenatal choline supplementation on choline and its metabolome in free-living, healthy adults is relatively uncharacterized. This study investigated the effect of prenatal choline supplementation on maternal and fetal biomarkers of choline metabolism among free-living pregnant persons consuming self-selected diets. Participants were randomized to supplemental choline (as choline chloride) intakes of 550 mg/d (500 mg/d d0-choline + 50 mg/d methyl-d9-choline; intervention) or 25 mg/d d9-choline (control) from gestational week (GW) 12-16 until Delivery. Fasting blood and 24-h urine samples were obtained at study Visit 1 (GW 12-16), Visit 2 (GW 20-24), and Visit 3 (GW 28-32). At Delivery, maternal and cord blood and placental tissue samples were collected. Participants randomized to 550 (vs. 25) mg supplemental choline/d achieved higher (p < .05) plasma concentrations of free choline, betaine, dimethylglycine, phosphatidylcholine (PC), and sphingomyelin at one or more study timepoint. Betaine was most responsive to prenatal choline supplementation with increases (p ≤ .001) in maternal plasma observed at Visit 2-Delivery (relative to Visit 1 and control), as well as in the placenta and cord plasma. Notably, greater plasma enrichments of d3-PC and LDL-C were observed in the intervention (vs. control) group, indicating enhanced PC synthesis through the de novo phosphatidylethanolamine N-methyltransferase pathway and lipid export. Overall, these data show that prenatal choline supplementation profoundly alters the choline metabolome, supporting pregnancy-related metabolic adaptations and revealing biomarkers for use in nutritional assessment and monitoring during pregnancy.

Tolerance to graded dosages of histidine supplementation in healthy human adults.

BACKGROUND: Histidine is an essential amino acid with health benefits that may warrant histidine supplementation; however, the clinical safety of histidine intake above the average dietary intake (1.52-5.20 g/d) needs to be vetted. OBJECTIVES: We aimed to determine the tolerance to graded dosages of histidine in a healthy adult population. METHODS: Healthy adults aged 21-50 y completed graded dosages of histidine supplement (4, 8, and 12 g/d, Study 1) (n = 20 men and n = 20 women) and/or a 16-g/d dosage of histidine (Study 2, n = 21 men and n = 19 women); 27 participants (n = 12 men and n = 15 women) completed both studies. After study enrollment and baseline measures, participants consumed encapsulated histidine for 4 wk followed by a 3-wk recovery period. Primary outcomes included vitals, select biochemical analytes, anthropometry, serum zinc, and body composition (via DXA). RESULTS: No changes in vitals or body composition occurred with histidine supplementation in either study. Plasma histidine (measured in subjects who completed all dosages for Studies 1 and 2) was elevated at the 12- and 16-g/d dosages (compared with 0-8 g/d, P < 0.05) and blood urea nitrogen increased with dosage (P = 0.013) and time (P < 0.001) in Study 1 and with time in Study 2 (P < 0.001). In Study 1, mean ferritin concentrations were lower in 12 g/d (46.0 ng/mL; 95% CI: 34.8, 60.9 ng/mL) than in 4 g/d (51.6 ng/mL; 95% CI: 39.0, 68.4 ng/mL; P = 0.038). In Study 2, 16 g/d increased mean aspartate aminotransferase from baseline (19 U/L; 95% CI: 17, 22 U/L) to week 4 (24 U/L; 95% CI: 21, 27 U/L; P < 0.001) and mean serum zinc decreased from baseline (0.75 µg/dL; 95% CI: 0.71, 0.80 µg/dL) to week 4 (0.70 µg/dL; 95% CI: 0.66, 0.74 µg/dL; P = 0.011). CONCLUSIONS: Although values remained within the normal reference ranges for all analytes measured, in all dosages tested, the human no-observed adverse effect level was determined to be 8 g/d owing to changes in blood parameters at the 12-g/d dosage.This trial was registered at clinicaltrials.gov as NCT04142294.