Dietary Choline Intake Research Articles

Plasma Concentrations and Dietary Intakes of Choline and Betaine in Association With Atrial Fibrillation Risk: Results From 3 Prospective Cohorts With Different Health Profiles.

BackgroundAlthough choline metabolism has been associated with atherosclerotic heart disease, less research attention has been paid to the associations of choline and its oxidative metabolite betaine with cardiac arrhythmias.Methods and ResultsWe evaluated associations of plasma concentrations and dietary intakes of choline and betaine with long‐term atrial fibrillation (AF) risk in a community‐based cohort, HUSK ([the Hordaland Health Study] n=6949), and validated the findings in 2 patient cohorts: the Western Norway Coronary Angiography Cohort (n=4164) and the NORVIT (Norwegian B‐Vitamin) Trial (n=3733). Information on AF was obtained from the CVDNOR (Cardiovascular Disease in Norway) project. In HUSK, WECAC (Western Norway Coronary Angiography Cohort), and NORVIT, 552, 411, and 663 AF cases were identified during a median follow‐up time of 10.9, 7.3, and, 8.7 years, respectively. Plasma concentrations of choline and betaine were significantly positively associated with later AF risk after multivariable adjustments in HUSK. Such associations were independently replicated in the 2 external prospective patient cohorts. The pooled hazard ratio was 1.13 (95% confidence interval 1.08‐1.19, P<0.001) and 1.16 (95% confidence interval 1.10‐1.22, P<0.001) per SD increment for log‐transformed choline and betaine, respectively. Moreover, dietary intake of choline was marginally associated with AF risk (pooled hazard ratio 1.29, 95% confidence interval 1.01‐1.66, fifth versus first quintile), whereas no significant association was observed between dietary betaine and AF risk.ConclusionsOur findings indicate that plasma concentrations as well as dietary intake of choline, but not betaine, are associated with subsequent risk of AF, suggesting a potential role of choline metabolism in the pathogenesis of AF.Clinical Trial RegistrationURL: https://www.clinicaltrials.gov.Unique identifier: NCT00671346.

Association between choline intake during pregnancy and choline metabolism in parturients and infants

Objective To investigate the association between choline intake during pregnancy and choline metabolism in parturients and infants, and to analyze the difference in plasma choline level between premature and healthy full-term infants at birth. Methods Neonates who were born in the Department of Obstetrics of Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from September 2014 to May 2016 were enrolled. Demographic and clinical information of these neonates and their mothers were recorded. Dietary choline intake during pregnancy was determined on the second day after delivery using food frequency questionnaires. Free choline levels in plasma of all parturients and neonates were measured. Then, data were collected and analyzed by independent samples t-test, trend Chi-square test, Chi-square test and linear regression methods. Results (1) A total of 134 parturients and their neonates were enrolled in this study including 80 full-term infants and 54 premature infants. Compared with the full-term group, the parturients in the premature group had higher pregestational BMI (22.7±3.2 vs 20.8±2.3, t=-3.720) and less education background (trend χ2=4.020) (both P<0.05). (2) The food frequency questionnaires showed that 30.0% (24/80) of pregnant women in the full-term group reached adequate intake (AI) of choline during pregnancy, while only 11.1% (6/54) in the premature group did. (3) Plasma choline level in maternal peripheral blood was positively associated with maternal dietary choline intake during pregnancy (r=0.882, r²=0.778, P<0.001). Moreover, plasma choline level in the umbilical artery was closely related to maternal plasma choline level (r=0.965, r²=0.931, P<0.001). (4) The dietary choline intake during pregnancy, maternal plasma choline level and plasma choline level in umbilical artery in premature infant group were all lower than those of full-term group [(305.24±102.17) vs (386.16±121.36) mg/d, t=4.026; (5.23±0.79) vs (7.18±1.51) μmol/L, t=9.783; (20.68±3.52) vs (27.96±3.94) μmol/L, t=10.930; all P<0.01]. Conclusions Insufficient dietary intake of choline during pregnancy is common. The dietary choline intake during pregnancy in parturients of preterm delivery group is lower than that in full-term group. Dietary choline intake during pregnancy is related to plasma choline level in umbilical artery. Therefore, dietary guidance should be emphasized for pregnant and lactating women to increase the intake of foods rich in choline. It is also important to provide premature infants with choline in time to meets the needs of their development. Key words: Pregnancy; Choline; Metabolism; Dietary supplements; Diet; Infant, premature

Association between Serum Unmetabolized Folic Acid Concentrations and Folic Acid from Fortified Foods

Objective: To investigate the association between serum unmetabolized folic acid (UMFA) concentrations and folic acid from fortified foods and nutrients known as dietary methyl-group donors (folate, methionine, choline, betaine and vitamins B2, B6 and B12) in participants exposed to mandatory fortification of wheat and maize flours with folic acid.Methods: Cross-sectional study carried out with 144 healthy Brazilian participants, both sexes, supplement nonusers. Serum folate, UMFA, vitamin B12 and total plasma homocysteine (tHcy) were biochemically measured. Dietary intake was assessed by 2 non-consecutive 24-hour dietary recalls (24-HRs) and deattenuated energy-adjusted nutrient data were used for statistical analysis.Results: Ninety eight (68.1%) participants were women. Median (interquartile range) age was 35.5 (28.0–52.0) years. Elevated serum folate concentrations (>45 nmol/L) were found in 17 (11.8%), while folate deficiency (<7 nmol/L) in 10 (6.9%) participants. No one had vitamin B12 deficiency (<148 pmol/L). An elevated serum UMFA concentration was defined as > 1 nmol/L (90th percentile). UMFA concentrations were positively correlated with folic acid intake and negatively correlated to choline, methionine and vitamin B6 intakes. Participants in the lowest quartile of UMFA concentrations had lower dietary intake of total folate (DFEs) and folic acid, and higher dietary intake of methionine, choline and vitamin B6 than participants in the highest quartile of UMFA. Folic acid intake (OR [95% CI] = 1.02 [1.01–1.04)] and being a male (OR [95% CI] = 0.40 [0.19–0.87) were associated with increased and reduced odds for UMFA concentrations > 0.55 nmol/L (median values), respectively.Conclusion: UMFA concentrations were directly influenced by folic acid intake from fortified foods in a healthy convenience sample of adult Brazilians exposed to mandatory flour fortification with folic acid.

Neuroprotective Actions of Dietary Choline.

Choline is an essential nutrient for humans. It is a precursor of membrane phospholipids (e.g., phosphatidylcholine (PC)), the neurotransmitter acetylcholine, and via betaine, the methyl group donor S-adenosylmethionine. High choline intake during gestation and early postnatal development in rat and mouse models improves cognitive function in adulthood, prevents age-related memory decline, and protects the brain from the neuropathological changes associated with Alzheimer’s disease (AD), and neurological damage associated with epilepsy, fetal alcohol syndrome, and inherited conditions such as Down and Rett syndromes. These effects of choline are correlated with modifications in histone and DNA methylation in brain, and with alterations in the expression of genes that encode proteins important for learning and memory processing, suggesting a possible epigenomic mechanism of action. Dietary choline intake in the adult may also influence cognitive function via an effect on PC containing eicosapentaenoic and docosahexaenoic acids; polyunsaturated species of PC whose levels are reduced in brains from AD patients, and is associated with higher memory performance, and resistance to cognitive decline.

Abstract 2273: Serum choline, methionine, betaine, dimethylglycine, and trimethylamine-N-oxide in relation to pancreatic cancer risk in two nested case-control studies in Asian populations

Abstract Background: Choline, methionine, and betaine are methyl group donors associated with DNA methylation. Diets deficient in choline and methionine have been shown to promote pancreatic carcinogenesis in experimental animals. We have previously reported an inverse association between dietary intake of choline and pancreatic cancer risk in a prospective cohort of Singapore Chinese. In the present study biomarkers of dietary choline and other methyl donor nutrients were evaluated in relation to pancreatic cancer risk. Method: Two case-control studies were nested within the Shanghai Cohort Study (129 cases and 258 matched controls) and the Singapore Chinese Health Study (58 cases and 104 matched controls). Concentrations of choline, methionine, betaine, dimethylglycine (DMG), and trimethylamine-N-oxide (TMAO) were measured by LC-MS/MS in pre-diagnostic serum samples. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression method with adjustment for potential confounders. Results: Choline, methionine, and betaine were moderately associated with each other (spearman correlation coefficient: 0.28 ~0.43). In the pooled analysis, serum choline, betaine, and methionine were inversely associated with risk of pancreatic cancer, while TMAO, an oxidative metabolite of choline produced by gut microbiota, was positively associated with risk of pancreatic cancer. Compared with the lowest quartile, ORs (95%CIs) of pancreatic cancer for the highest quartiles of choline, methionine, betaine, and TMAO were 0.37 (0.17-0.80), 0.39 (0.22-0.69), 0.49 (0.28-0.85), and 1.60 (0.94-2.74), respectively (all Ps for trend &amp;lt; 0.05). DMG was not associated with pancreatic cancer risk. Conclusion: The novel inverse associations of serum choline, methionine, and betaine with risk of pancreatic cancer support the notion that methyl groups related to DNA methylation may modulate the risk of pancreatic cancer development. The positive association between TMAO and pancreatic cancer risk suggested gut microbiota may play an important role in pancreatic carcinogenesis. Citation Format: Joyce Huang, Lesley Butler, Øivind Midttun, Renwei Wang, Aizhen Jin, Yu-Tang Gao, Per Ueland, Woon-Puay Koh, Jian-Min Yuan. Serum choline, methionine, betaine, dimethylglycine, and trimethylamine-N-oxide in relation to pancreatic cancer risk in two nested case-control studies in Asian populations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2273. doi:10.1158/1538-7445.AM2017-2273

Higher dietary intakes of choline and betaine are associated with a lower risk of primary liver cancer: a case-control study

The dietary intake of methyl donors is favorably associated with many diseases, but the findings regarding primary liver cancer (PLC) risk are limited. This study investigated the association between the intake of choline, betaine and methionine and PLC risk in adults. This 1:1 matched case-control study enrolled 644 hospital-based PLC patients and 644 community-based controls who were matched by sex and age, in Guangzhou, China. An interviewer-administered questionnaire and a food-frequency questionnaire were used to collect general information and dietary intake information. Conditional logistic regression showed a significantly inverse association between total choline and betaine intakes and PLC risk. The multivariable-adjusted odds ratios (ORs) and their 95% confidence intervals (CIs) for PLC for the top (vs. bottom) tertile were 0.34 (0.24–0.49; P-trend < 0.001) for total choline and 0.67 (0.48–0.93; P-trend = 0.011) for betaine. No significant association was observed between the intake of methionine and PLC risk (P > 0.05). For individual choline compounds, higher consumptions of free choline, glycerophosphocholine, phosphocholine, phosphatidylcholine and sphingomyelin were associated with a lower PLC risk (all P-trend < 0.05). The studied associations were not significantly modified by the folate intake (P-interactions: 0.488–0.890). Our findings suggest that higher choline and betaine intakes may be associated with a lower risk of PLC.

Dietary Choline Intake Is Directly Associated with Bone Mineral Density in the Hordaland Health Study

BackgroundCholine is an important nutrient either obtained from a variety of foods or synthesized endogenously, and it is the precursor of betaine. We previously reported positive associations between plasma free choline and bone mineral density (BMD). Animal studies suggest an impact of dietary choline on bone metabolism, but the role of dietary intake of choline and betaine for human bone health is unknown. ObjectiveThe main aims were to examine the associations of dietary choline, choline species, and betaine with BMD and to study the relations between dietary and plasma free choline and betaine. MethodsStudy subjects were participants in the Hordaland Health Study, including 2649 women and 1983 men (aged 46–49 or 71–74 y). BMD was measured by dual-energy X-ray absorptiometry, and dietary intake was obtained by using a validated 169-item food-frequency questionnaire. Risk associations were assessed by logistic regression and correlations by ρ (Spearman's bivariate rank order correlation). ResultsSubjects in the lowest compared with the highest tertile of dietary total choline, free choline, glycerophosphocholine, phosphocholine, phosphatidylcholine, and sphingomyelin had a higher risk of low–femoral neck BMD, defined as the lowest BMD quintile. Particularly strong associations were found among middle-aged men for intake of free choline (OR: 1.83; 95% CI: 1.24, 2.69; P = 0.002) and glycerophosphocholine (OR: 2.13; 95% CI: 1.43, 3.16; P < 0.001) and among elderly women for total choline (OR: 1.96; 95% CI: 1.33, 2.88; P = 0.001) and phosphatidylcholine (OR: 1.94; 95% CI: 1.33, 2.84: P = 0.001) intake. No significant associations were observed between dietary betaine and BMD. Dietary total choline, free choline, glycerophosphocholine, phosphatidylcholine, and sphingomyelin correlated weakly with plasma free choline (ρ: 0.07, 0.05, 0.07, 0.07, and 0.05, respectively; P < 0.01). Dietary betaine correlated with plasma betaine (ρ: 0.23; P < 0.001). ConclusionsDietary choline was positively associated with BMD in middle-aged and elderly participants.

Combined Supplementation of Choline and Docosahexaenoic Acid during Pregnancy Enhances Neurodevelopment of Fetal Hippocampus.

Choline is an essential nutrient for humans which plays an important role in structural integrity and signaling functions. Docosahexaenoic acid (DHA) is a polyunsaturated fatty acid, highly enriched in cell membranes of the brain. Dietary intake of choline or DHA alone by pregnant mothers directly affects fetal brain development and function. But no studies show the efficacy of combined supplementation of choline and DHA on fetal neurodevelopment. The aim of the present study was to analyze fetal neurodevelopment on combined supplementation of pregnant dams with choline and DHA. Pregnant dams were divided into five groups: normal control [NC], saline control [SC], choline [C], DHA, and C + DHA. Saline, choline, and DHA were given as supplements to appropriate groups of dams. NC dams were undisturbed during entire gestation. On postnatal day (PND) 40, brains were processed for Cresyl staining. Pups from choline or DHA supplemented group showed significant (p < 0.05) increase in number of neurons in hippocampus when compared to the same in NC and SC groups. Moreover, pups from C + DHA supplemented group showed significantly higher number of neurons (p < 0.001) in hippocampus when compared to the same in NC and SC groups. Thus combined supplementation of choline and DHA during normal pregnancy enhances fetal hippocampal neurodevelopment better than supplementation of choline or DHA alone.

Randomized, double-blind, placebo-controlled clinical trial of choline supplementation in school-aged children with fetal alcohol spectrum disorders

Background: Prenatal alcohol exposure results in a broad range of cognitive and behavioral impairments. Because of the long-lasting problems that are associated with fetal alcohol spectrum disorders (FASDs), the development of effective treatment programs is critical. Preclinical animal studies have shown that choline, which is an essential nutrient, can attenuate the severity of alcohol-related cognitive impairments.Objective: We aimed to translate preclinical findings to a clinical population to investigate whether choline supplementation can ameliorate the severity of memory, executive function, and attention deficits in children with FASDs.Design: In the current study, which was a randomized, double-blind, placebo-controlled clinical trial, we explored the effectiveness of a choline intervention for children with FASDs who were aged 5–10 y. Fifty-five children with confirmed histories of heavy prenatal alcohol exposure were randomly assigned to either the choline (n = 29) or placebo (n = 26) treatment arms. Participants in the choline group received 625 mg choline/d for 6 wk, whereas subjects in the placebo group received an equivalent dose of an inactive placebo treatment. Primary outcomes, including the performance on neuropsychological measures of memory, executive function, and attention and hyperactivity, were assessed at baseline and postintervention.Results: Compared with the placebo group, participants in the choline group did not differentially improve in cognitive performance in any domain. Treatment compliance and mean dietary choline intake were not predictive of treatment outcomes.Conclusions: Findings of the current study do not support that choline, administered at a dose of 625 mg/d for 6 wk, is an effective intervention for school-aged (5–10 y old) children with FASDs. This research provides important information about choline’s therapeutic window. Combined with other studies of choline and nutritional interventions in this population, this study emphasizes a further need for the continued study of the role of nutritional status and supplementation in children with FASDs and the contributions of nutrition to neurocognition. This trial was registered at clinicaltrials.gov as NCT01911299.

High dietary choline and betaine intake is associated with low insulin resistance in the Newfoundland population

ObjectiveDietary betaine supplement could ameliorate insulin resistance (IR) in animals, but no data are available for choline. Reports on humans are rare. The aim of this study was to investigate the association between dietary choline and betaine intake and IR in humans. MethodsWe assessed 2394 adults from the CODING (Complex Diseases in the Newfoundland population: Environment and Genetics) study. Intake of dietary choline and betaine was evaluated from the Willett Food Frequency Questionnaire. IR was estimated by homeostatic model assessment (HOMA-IR) and the quantitative insulin-sensitivity check index (QUICKI). Partial correlation analysis was used to determine the correlations of dietary choline and betaine intake with IR adjusted for major confounding factors. ResultsDietary choline and betaine intake was inversely correlated with levels of fasting glucose and insulin, HOMA-IR, HOMA-β (r = −0.08 to −0.27 for choline and r = −0.06 to −0.16 for betaine; P < 0.05) and positively related to QUICKI (r = 0.16–0.25 for choline and r = 0.11–0.16 for betaine; P < 0.01) in both sexes after controlling for age, total calorie intake, and physical activity level. The significant associations disappeared in men after percent trunk fat was added as a confounding factor. Furthermore, individuals with the highest tertile of dietary choline and betaine intake had the lowest IR severity. Dietary choline and betaine intake, however, was the lowest in the high IR group, intermediate in the medium group, and the highest in the low IR group. ConclusionThis study demonstrated that higher intake of dietary choline and betaine is associated with lower IR in the general population.

Dietary choline and betaine; associations with subclinical markers of cardiovascular disease risk and incidence of CVD, coronary heart disease and stroke: the Jackson Heart Study.

Several mechanisms have been described through which dietary intake of choline and its derivative betaine may be associated in both directions with subclinical atherosclerosis. We assessed the association of dietary intake of choline and betaine with cardiovascular risk and markers of subclinical cardiovascular disease. Data from 3924 Jackson Heart Study (JHS) African-American participants with complete food frequency questionnaire at baseline and follow-up measurements of heart disease measures were used. Multivariable linear regression models were employed to assess associations between choline and betaine intake with carotid intima-media thickness, coronary artery calcium, abdominal aortic calcium and left ventricular mass. Cox proportional hazards regression models were used to estimate associations with time to incident coronary heart disease (CHD), ischemic stroke and cardiovascular disease (CVD). During an average nine years of follow-up, 124 incident CHD events, 75 incident stroke events and 153 incident CVD events were documented. In women, greater choline intake was associated with lower left ventricular mass (p=0.0006 for trend across choline quartiles) and with abdominal aortic calcium score. Among all JHS participants, there was a statistically significant inverse association between dietary choline intake and incident stroke, β=-0.33 (p=0.04). Betaine intake was associated with greater risk of incident CHD when comparing the third quartile of intake with the lowest quartile of intake (HR 1.89, 95% CI 1.14, 3.15). Among our African-American participants, higher dietary choline intake was associated with a lower risk of incident ischemic stroke, and thus putative dietary benefits. Higher dietary betaine intake was associated with a nonlinear higher risk of incident CHD.

A family-based study of gene variants and maternal folate and choline in neuroblastoma: a report from the Children's Oncology Group.

Neuroblastoma is a childhood cancer of the sympathetic nervous system with embryonic origins. Previous epidemiologic studies suggest maternal vitamin supplementation during pregnancy reduces the risk of neuroblastoma. We hypothesized offspring and maternal genetic variants in folate-related and choline-related genes are associated with neuroblastoma and modify the effects of maternal intake of folate, choline, and folic acid. The Neuroblastoma Epidemiology in North America (NENA) study recruited 563 affected children and their parents through the Children's Oncology Group's Childhood Cancer Research Network. We used questionnaires to ascertain pre-pregnancy supplementation and estimate usual maternal dietary intake of folate, choline, and folic acid. We genotyped 955 genetic variants related to folate or choline using DNA extracted from saliva samples and used a log-linear model to estimate both child and maternal risk ratios and stratum-specific risk ratios for gene-environment interactions. Overall, no maternal or offspring genotypic results met criteria for a false discovery rate (FDR) Q-value<0.2. Associations were also null for gene-environment interaction with pre-pregnancy vitamin supplementation, dietary folic acid, and folate. FDR-significant gene-choline interactions were found for offspring SNPs rs10489810 and rs9966612 located in MTHFD1L and TYMS, respectively, with maternal choline dietary intake dichotomized at the first quartile. These results suggest that variants related to one-carbon metabolism are not strongly associated with neuroblastoma. Choline-related variants may play a role; however, the functional consequences of the interacting variants are unknown and require independent replication.

Dietary choline and folate relationships with serum hepatic inflammatory injury markers in Taiwanese adults.

The relationships of dietary choline and folate intake with hepatic function have yet to be established in the Taiwanese population. We investigated the associations of choline and folate intake with hepatic inflammatory injury in Taiwanese adults. Blood samples and data on dietary choline components and folate intake from 548 Taiwanese adults without pathological liver disease were collected. Dietary intake was derived using a semiquantitative food-frequency questionnaire. Serum liver injury markers of alanine transaminase, aspartate transaminase, and hepatitis viral infection were measured. Elevated serum hepatic injury markers (>40 U/L) were associated with low folate and free choline intake (p<0.05). Folate intake was the most significant dietary determinant of serum aspartate transaminase concentration (beta=-0.05, p=0.04), followed by free choline intake (beta=-0.249, p=0.055). Folate intake exceeding the median level (268 μg/d) was correlated with a reduced rate of hepatitis viral infection (p=0.032) and with normalized serum aspartate transaminase (odds ratio [OR]=0.998, 95% confidence interval [CI]=0.996-1, p=0.042) and alanine transaminase (OR=0.998, 95% CI=0.007-1, p=0.019). Total choline intake exceeding the median level (233 mg/d) was associated with normalized serum aspartate transaminase (OR=0.518, 95% CI=0.360-0.745, p=0.018). The newly established relationships of dietary intake of total choline and folate with normalized hepatic inflammatory markers can guide the development of dietary choline and folate intake recommendations for Taiwanese adults.

Dietary choline and betaine intake, choline-metabolising genetic polymorphisms and breast cancer risk: a case-control study in China.

Choline and betaine are essential nutrients involved in one-carbon metabolism and have been hypothesised to affect breast cancer risk. Functional polymorphisms in genes encoding choline-related one-carbon metabolism enzymes, including phosphatidylethanolamine N-methyltransferase (PEMT), choline dehydrogenase (CHDH) and betaine-homocysteine methyltransferase (BHMT), have important roles in choline metabolism and may thus interact with dietary choline and betaine intake to modify breast cancer risk. This study aimed to investigate the interactive effect of polymorphisms in PEMT, BHMT and CHDH genes with choline/betaine intake on breast cancer risk among Chinese women. This hospital-based case-control study consecutively recruited 570 cases with histologically confirmed breast cancer and 576 age-matched (5-year interval) controls. Choline and betaine intakes were assessed by a validated FFQ, and genotyping was conducted for PEMT rs7946, CHDH rs9001 and BHMT rs3733890. OR and 95 % CI were estimated using unconditional logistic regression. Compared with the highest quartile of choline intake, the lowest intake quartile showed a significant increased risk of breast cancer. The SNP PEMT rs7946, CHDH rs9001 and BHMT rs3733890 had no overall association with breast cancer, but a significant risk reduction was observed among postmenopausal women with AA genotype of BHMT rs3733890 (OR 0·49; 95 % CI 0·25, 0·98). Significant interactions were observed between choline intake and SNP PEMT rs7946 (P interaction=0·029) and BHMT rs3733890 (P interaction=0·006) in relation to breast cancer risk. Our results suggest that SNP PEMT rs7946 and BHMT rs3733890 may interact with choline intake on breast cancer risk.

The association of serum choline with linear growth failure in young children from rural Malawi

Choline is an essential nutrient for cell structure, cell signaling, neurotransmission, lipid transport, and bone formation. Choline can be irreversibly converted to betaine, a major source of methyl groups. Trimethylene N-oxide (TMAO), a proatherogenic molecule, is produced from the metabolism of dietary choline by the gut microbiome. The relation between serum choline and its closely related metabolites with linear growth in children is unknown. The aim was to characterize the relation between serum choline and its closely related metabolites, betaine and TMAO, with linear growth and stunting in young children. We measured serum choline, betaine, and TMAO concentrations by using liquid chromatography isotopic dilution tandem mass spectrometry in a cross-sectional study in 325 Malawian children, aged 12-59 mo, of whom 62% were stunted. Median (25th, 75th percentile) serum choline, betaine, and TMAO concentrations were 6.4 (4.8, 8.3), 12.4 (9.1, 16.3), and 1.2 (0.7, 1.8) μmol/L, respectively. Spearman correlation coefficients of age with serum choline, betaine, and TMAO were -0.57 (P < 0.0001), -0.26 (P < 0.0001), and -0.10 (P = 0.07), respectively. Correlation coefficients of height-for-age z score with serum choline, betaine-to-choline ratio, and TMAO-to-choline ratio were 0.31 (P < 0.0001), -0.24 (P < 0.0001), and -0.29 (P < 0.0001), respectively. Serum choline concentrations were strongly and significantly associated with stunting. Children with and without stunting had median (25th, 75th percentile) serum choline concentrations of 5.6 (4.4, 7.4) and 7.3 (5.9, 9.1) μmol/L (P < 0.0001). Linear growth failure in young children is associated with low serum choline and elevated betaine-to-choline and TMAO-to-choline ratios. Further work is needed to understand whether low dietary choline intake explains low circulating choline among stunted children living in low-income countries and whether increasing choline intake may correct choline deficiency and improve growth and development. This trial was registered in the ISRCTN registry (www.isrctn.com) as ISRCTN14597012.

Higher Dietary Choline and Betaine Intakes Are Associated with Better Body Composition in the Adult Population of Newfoundland, Canada.

BackgroundCholine is an essential nutrient and betaine is an osmolyte and methyl donor. Both are important to maintain health including adequate lipid metabolism. Supplementation of dietary choline and betaine increase muscle mass and reduce body fat in animals. However, little data is available regarding the role of dietary choline and betaine on body composition in humans.ObjectiveTo investigate the association between dietary choline and betaine intakes with body composition in a large population based cross-sectional study.DesignA total of 3214 subjects from the CODING (Complex Disease in Newfoundland population: Environment and Genetics) study were assessed. Dietary choline and betaine intakes were computed from the Willett Food Frequency questionnaire. Body composition was measured using dual-energy X-ray absorptiometry following a 12-hour fast. Major confounding factors including age, sex, total calorie intake and physical activity level were controlled in all analyses.ResultSignificantly inverse correlations were found between dietary choline and betaine intakes, with all obesity measurements: total percent body fat (%BF), percent trunk fat (%TF), percent android fat (%AF), percent gynoid fat (%GF) and anthropometrics: weight, body mass index, waist circumference, waist-to-hip ratio in both women and men (r range from -0.13 to -0.47 for choline and -0.09 to -0.26 for betaine, p<0.001 for all). Dietary choline intake had stronger association than betaine. Moreover, obese subjects had the lowest dietary choline and betaine intakes, with overweight subjects in the middle, and normal weight subjects consumed the highest dietary choline and betaine (p<0.001). Vice versa, when subjects were ranked according to dietary choline and betaine intakes, subjects with the highest intake of both had the lowest %TF, %AF, %GF, %BF and highest %LM among the groups in both sexes.ConclusionOur findings indicate that high dietary choline and betaine intakes are significantly associated with favorable body composition in humans.

Spontaneous Preterm Delivery, Dietary Choline Intake and DNA Hypomethylation of Tumor Related Genes in Pregnant Women

AimsPreterm delivery and sub‐optimal fetal growth are associated with each other and affect both mother and infant. Our aims were to determine (1) whether changes in maternal DNA methylation from entry are associated with spontaneous preterm delivery with and without reduced fetal growth and (2) whether dietary nutrient intake including choline and folate are different between preterm cases and term controls.MethodsWe conducted a case‐control study nested within a large prospective cohort (Camden Study). Gene specific methylation was measured by Methyl‐Profiler PCR Array in a Human Breast Cancer Signature Panel of 24 genes from maternal peripheral leukocytes genomic DNA at entry to care and the 3rd trimester (sampled at 16 and 30 weeks of gestation, respectively). Clonal bisulfite DNA sequencing was performed to confirm the changes in selected genes (CYP1B1, GADD45A and CXCL12). A 24‐hour recall of the previous day's diet was obtained at entry (&lt;20 weeks) and weeks 20 and 28 gestation. The total daily intake of nutrients from all three 24‐hour recalls was averaged for the pregnancy. Multivariable ANOVA with control for confounding was used for data analysis.ResultsThere was significantly increased DNA unmethylation in 15 of 24 genes during the 3rd trimester in cases of spontaneous preterm delivery (n=23) as compared to the controls (n=19) (p&lt;0.05 ‐ p&lt;0.01 for each gene). Similar results were observed by bisulfite sequencing for 3 genes. The change in DNA methylation between late and early gestation was significantly different in cases (overall increase in unmethylation was 4.5 ± 1.4%) compared to the controls (overall decrease in unmethylation was −13.6 ± 2.8%, p&lt;0.0001). A graded pattern of DNA unmethylation was observed in 15 genes. Cases who delivered preterm with reduced fetal growth had the highest level of unmethylation, cases delivering preterm without reduced fetal growth were next and term controls were lowest in unmethylation (p for trend &lt;0.05 to p&lt;0.01 for each gene). Cases of preterm delivery had significantly lower dietary free (p&lt;0.05) and total choline intake (p&lt;0.01) as well as a trend toward lower folate intake (p&gt;0.05). There were no differences in the intake of macronutrients or other B vitamins.ConclusionsThese data are potentially significant for the identification of women at risk of preterm delivery as well as for the identification of modifiable factors like diet that modulate or influence epigenetic regulation.Support or Funding InformationNIH ‐ National Institute of Minority and Health Disparities (1R01MD007828 to XC) and University of Medicine and Dentistry of New Jersey Foundation Grant (PC75‐12 to XC).

Choline Supplementation With a Structured Lipid in Children With Cystic Fibrosis: A Randomized Placebo-Controlled Trial.

Choline depletion is seen in cystic fibrosis (CF) and pancreatic insufficiency in spite of enzyme treatment and may result in liver, fatty acid, and muscle abnormalities. This study evaluated the efficacy and safety of an easily absorbed choline-rich structured lipid (LYM-X-SORB™ [LXS]) to improve choline status. Children with CF and pancreatic insufficiency were randomized to LXS or placebo in a 12-month double blind trial. Dietary choline intake, plasma cholines, plasma and fecal phospholipids, coefficient of fat absorption, pulmonary function, growth status, body composition, and safety measures were assessed. Magnetic resonance spectroscopy for calf muscle choline and liver fat were assessed in a subgroup and compared with a healthy comparison group matched for age, sex, and body size. A total of 110 subjects were enrolled (age 10.4 ± 3.0 years). Baseline dietary choline, 88% recommended, increased 3-fold in the LXS group. Plasma choline, betaine, and dimethylglycine increased in the LXS but not placebo (P = 0.007). Plasma lysophosphatidylcholine and phosphatidylcholine increased, and fecal phosphatidylcholine/phosphatidylethanolamine ratio decreased (P ≤ 0.05) in LXS only, accompanied by a 6% coefficient of fat absorption increase (P = 0.001). Children with CF had higher liver fat than healthy children and depleted calf muscle choline at baseline. Muscle choline concentration increased in LXS and was associated with improvement in plasma choline status. No relevant changes in safety measures were evident. LXS had improved choline intake, plasma choline status, and muscle choline stores compared with placebo group. The choline-rich supplement was safe, accepted by participants, and improved choline status in children with CF.

Exercise‐induced muscle damage in healthy men with low choline intake

Both very low choline intake and intense exercise in healthy men can trigger peak muscle soreness a few days later and a rise of creatine kinase (CK) activity in peripheral blood indicating muscle damage.We wanted to know whether men susceptible to exercise‐induced muscle damage have lower dietary choline intake than men with more robust muscles and whether their heightened muscle fragility is associated with low lean body mass.We investigated in 58 healthy Caucasian men the increase of CK activity three days after 12 eccentric elbow flexors (Biodex 4, Biodex Medical Systems Inc., Shirley, NY) with the non‐dominant arm. This single bout of exercise took little more than one minute to complete. The dynamometer tracked the patient's torque and provided instant feedback throughout the exercises. The same measurements and exercises were done on the non‐dominant arm at the initial visit and three days later. Participants indicated on an analog scale after each exercise test the level of discomfort or pain they had experienced. A whole body dual energy x‐ray absorptiometry scan (Lunar iDXA, GE Healthcare) was used for the assessment of body composition and to estimate total and regional lean body masses. A trained dietitian supervised the automated 24‐hour diet recall assessments on days 1 and 4 for each subject with the ASA24 online system, demonstrated food models for improved accuracy of portion sizes, confirmed reported food items and probed for missing food items prior to submission, and asked additional quality control questions to promote comprehensive reporting. The recall on day 2 was reviewed and discussed with the participant over the phone.The study was registered at Clinicaltrials.gov (NCT01722448).The median change of CK activity three days after the initial bout of exercise was +49 U/L (+36%). We classified a significant minority (9 of 58) of the investigated men as high responders (HR) because they had exceptionally high CK activity after the exercise (between 4 and 27 times of the upper reference limit). At the other end of the spectrum were men (19 of 58) with no increase of CK activity (non‐responders, NR); their median change of CK activity was −22 U/L (−20%).The single bout of eccentric arm flexor exercise greatly reduced arm strength in HR when assessed three days later, but changed strength very little in NR. Average power in HR was 32% lower than initially (p&lt;0.0005), while NR had an average decrease of 7%. The difference in response between the two groups was statistically highly significant (p&lt;0.00001). Lean body mass was 10% lower in HR than in NR (17.1 vs. 19.1 kg/m2, p&lt;0.04).More HR reported low choline intake (less than an average of 330 mg/day or 60% of adequate intake, AI) than NR (7 of 9 vs. 6 of 19, p&lt;0.05). Men with higher choline intake also tended to have less muscle soreness (r = −0.261, p&lt;0.05), better muscle performance after exercise (r = 0.310, p&lt;0.02), and higher lean body mass (r = 0.383, p&lt;0.005).These findings support our initial hypothesis that men susceptible to exercise‐induced muscle damage are more likely to have low choline intake than men with more resilient muscles. Increased vulnerability to intense exercise may discourage HR men to engage in physical activities and limit their ability to build up and maintain high muscle mass.Support or Funding InformationSupported by a grant from the UNC Nutrition Research Institute

Child Stunting is Associated with Low Circulating Essential Amino Acids

BackgroundStunting affects about one-quarter of children under five worldwide. The pathogenesis of stunting is poorly understood. Nutritional interventions have had only modest effects in reducing stunting. We hypothesized that insufficiency in essential amino acids may be limiting the linear growth of children. MethodsWe used a targeted metabolomics approach to measure serum amino acids, glycerophospholipids, sphingolipids, and other metabolites using liquid chromatography-tandem mass spectrometry in 313 children, aged 12–59months, from rural Malawi. Children underwent anthropometry. FindingsSixty-two percent of the children were stunted. Children with stunting had lower serum concentrations of all nine essential amino acids (tryptophan, isoleucine, leucine, valine, methionine, threonine, histidine, phenylalanine, lysine) compared with nonstunted children (p<0.01). In addition, stunted children had significantly lower serum concentrations of conditionally essential amino acids (arginine, glycine, glutamine), non-essential amino acids (asparagine, glutamate, serine), and six different sphingolipids compared with nonstunted children. Stunting was also associated with alterations in serum glycerophospholipid concentrations. InterpretationOur findings support the idea that children with a high risk of stunting may not be receiving an adequate dietary intake of essential amino acids and choline, an essential nutrient for the synthesis of sphingolipids and glycerophospholipids.