Choline

Choline has been recognized as an essential nutrient by the Food and Nutrition Board of the National Academies of Medicine since 1998. Its metabolites have structural, metabolic, and regulatory roles within the body. Humans can endogenously produce small amounts of choline via the hepatic phosphatidylethanolamine N-methyltransferase pathway. However, the nutrient must be consumed exogenously to prevent signs of deficiency. The Adequate Intake (AI) for choline was calculated at a time when dietary intakes across the population were unknown for the nutrient. Unlike the traditional National Academy of Medicine approach of calculating an AI based on observed or experimentally determined approximations or estimates of intake by a group (or groups) of healthy individuals, calculation of the AI for choline was informed in part by a depletion-repletion study in adult men who, upon becoming deficient, developed signs of liver damage. The AI for other gender and life-stage groups was calculated based on standard reference weights, except for infants 0 to 6 months, whose AI reflects the observed mean intake from consuming human breast milk. Recent analyses indicate that large portions of the population (ie, approximately 90% of Americans), including most pregnant and lactating women, are well below the AI for choline. Moreover, the food patterns recommended by the 2015–2020 Dietary Guidelines for Americans are currently insufficient to meet the AI for choline in most age-sex groups. An individual’s requirement for choline is dependent on common genetic variants in genes required for choline, folate, and 1-carbon metabolism, potentially increasing more than one-third of the population’s susceptibly to organ dysfunction. The American Medical Association and American Academy of Pediatrics have both recently reaffirmed the importance of choline during pregnancy and lactation. New and emerging evidence suggests that maternal choline intake during pregnancy, and possibly lactation, has lasting beneficial neurocognitive effects on the offspring. Because choline is found predominantly in animal-derived foods, vegetarians and vegans may have a greater risk for inadequacy. With the 2020–2025 Dietary Guidelines for Americans recommending expansion of dietary information for pregnant women, and the inclusion of recommendations for infants and toddlers 0 to 2 years, better communication of the role that choline plays, particularly in the area of neurocognitive development, is critical. This narrative review summarizes the peer-reviewed literature and discussions from the 2018 Choline Science Summit, held in Washington, DC, in February 2018.

[1]  E. Lewis,et al.  The dietary form of choline during lactation affects maternal immune function in rats , 2018, European Journal of Nutrition.

[2]  T. Wallace A Comprehensive Review of Eggs, Choline, and Lutein on Cognition Across the Life-span , 2018, Journal of the American College of Nutrition.

[3]  M. Georgieff,et al.  Advocacy for Improving Nutrition in the First 1000 Days to Support Childhood Development and Adult Health , 2018, Pediatrics.

[4]  R. Canfield,et al.  Maternal choline supplementation during the third trimester of pregnancy improves infant information processing speed: a randomized, double‐blind, controlled feeding study , 2017, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[5]  M. Roberson,et al.  Maternal Choline Supplementation Modulates Placental Nutrient Transport and Metabolism in Late Gestation of Mouse Pregnancy. , 2017, The Journal of nutrition.

[6]  S. Zeisel,et al.  Trimethylamine N-Oxide, the Microbiome, and Heart and Kidney Disease. , 2017, Annual review of nutrition.

[7]  M. Caudill,et al.  Common Genetic Variants Alter Metabolism and Influence Dietary Choline Requirements , 2017, Nutrients.

[8]  V. Fulgoni,et al.  Usual Choline Intakes Are Associated with Egg and Protein Food Consumption in the United States , 2017, Nutrients.

[9]  J. Blusztajn,et al.  Neuroprotective Actions of Dietary Choline , 2017, Nutrients.

[10]  M. Caudill,et al.  Pressing the trimethylamine N -oxide narrative , 2017 .

[11]  E. Lewis,et al.  Feeding a Mixture of Choline Forms during Lactation Improves Offspring Growth and Maternal Lymphocyte Response to Ex Vivo Immune Challenges , 2017, Nutrients.

[12]  K. Meyer,et al.  Dietary Choline and Betaine and Risk of CVD: A Systematic Review and Meta-Analysis of Prospective Studies , 2017, Nutrients.

[13]  J. Manson,et al.  Gut Microbiota Metabolites and Risk of Major Adverse Cardiovascular Disease Events and Death: A Systematic Review and Meta‐Analysis of Prospective Studies , 2017, Journal of the American Heart Association.

[14]  M. Roberson,et al.  Maternal choline supplementation during murine pregnancy modulates placental markers of inflammation, apoptosis and vascularization in a fetal sex-dependent manner. , 2017, Placenta.

[15]  C. Cho,et al.  Trimethylamine-N-Oxide: Friend, Foe, or Simply Caught in the Cross-Fire? , 2017, Trends in Endocrinology & Metabolism.

[16]  Anita G. Ganti,et al.  Genetic Variation in Choline-Metabolizing Enzymes Alters Choline Metabolism in Young Women Consuming Choline Intakes Meeting Current Recommendations , 2017, International journal of molecular sciences.

[17]  W. Gulliver,et al.  Higher Dietary Choline and Betaine Intakes Are Associated with Better Body Composition in the Adult Population of Newfoundland, Canada , 2016, PloS one.

[18]  T. Altes,et al.  Choline Supplementation With a Structured Lipid in Children With Cystic Fibrosis: A Randomized Placebo-Controlled Trial , 2016, Journal of pediatric gastroenterology and nutrition.

[19]  S. Zeisel,et al.  Maternal dietary intake of choline in mice regulates development of the cerebral cortex in the offspring , 2016, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[20]  A. Sulpizio,et al.  L‐carnitine intake and high trimethylamine N‐oxide plasma levels correlate with low aortic lesions in ApoE−/− transgenic mice expressing hCETP , 2016, Atherosclerosis.

[21]  V. Fulgoni,et al.  Assessment of Total Choline Intakes in the United States , 2016, Journal of the American College of Nutrition.

[22]  Jeroen Raes,et al.  Microbiology Meets Big Data: The Case of Gut Microbiota-Derived Trimethylamine. , 2015, Annual review of microbiology.

[23]  M. Caudill,et al.  Choline intakes exceeding recommendations during human lactation improve breast milk choline content by increasing PEMT pathway metabolites. , 2015, The Journal of nutritional biochemistry.

[24]  B. Hommel,et al.  Improved human visuomotor performance and pupil constriction after choline supplementation in a placebo-controlled double-blind study , 2015, Scientific Reports.

[25]  Donal N. Gorman,et al.  Effects of choline on health across the life course: a systematic review. , 2015, Nutrition reviews.

[26]  C. Coles,et al.  Dose and Timing of Prenatal Alcohol Exposure and Maternal Nutritional Supplements: Developmental Effects on 6-Month-Old Infants , 2015, Maternal and Child Health Journal.

[27]  M. Roberson,et al.  Maternal Choline Supplementation Alters Fetal Growth Patterns in a Mouse Model of Placental Insufficiency , 2017, Nutrients.

[28]  P. Ueland,et al.  Maternal choline concentrations during pregnancy and choline-related genetic variants as risk factors for neural tube defects. , 2014, The American journal of clinical nutrition.

[29]  Anita G. Ganti,et al.  Choline Inadequacy Impairs Trophoblast Function and Vascularization in Cultured Human Placental Trophoblasts , 2014, Journal of cellular physiology.

[30]  K. Costa,et al.  Identification of new genetic polymorphisms that alter the dietary requirement for choline and vary in their distribution across ethnic and racial groups , 2014, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[31]  Derick R. Peterson,et al.  Plasma phospholipids identify antecedent memory impairment in older adults , 2014, Nature Medicine.

[32]  M. Gillman,et al.  Choline intake during pregnancy and child cognition at age 7 years. , 2013, American journal of epidemiology.

[33]  Martin T. Wells,et al.  A higher maternal choline intake among third‐trimester pregnant women lowers placental and circulating concentrations of the antiangiogenic factor fms‐like tyrosine kinase‐1 (sFLT1) , 2013, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[34]  R. Freedman,et al.  Perinatal choline effects on neonatal pathophysiology related to later schizophrenia risk. , 2013, The American journal of psychiatry.

[35]  Stacey A. Kenfield,et al.  Choline intake and risk of lethal prostate cancer: incidence and survival. , 2012, The American journal of clinical nutrition.

[36]  R. Dyer,et al.  Early Second Trimester Maternal Plasma Choline and Betaine Are Related to Measures of Early Cognitive Development in Term Infants , 2012, PloS one.

[37]  F. Vermeylen,et al.  Maternal choline intake alters the epigenetic state of fetal cortisol‐regulating genes in humans , 2012, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[38]  M. Gillman,et al.  Maternal intake of methyl-donor nutrients and child cognition at 3 years of age. , 2012, Paediatric and perinatal epidemiology.

[39]  D. Vance,et al.  Phosphatidylcholine biosynthesis and lipoprotein metabolism. , 2012, Biochimica et biophysica acta.

[40]  P. Wolf,et al.  The relation of dietary choline to cognitive performance and white-matter hyperintensity in the Framingham Offspring Cohort. , 2011, The American journal of clinical nutrition.

[41]  S. Zeisel,et al.  Elevating Awareness and Intake of Choline: An Essential Nutrient for Public Health , 2011 .

[42]  J. Galanko,et al.  Aberrant Estrogen Regulation of PEMT Results in Choline Deficiency-associated Liver Dysfunction* , 2010, The Journal of Biological Chemistry.

[43]  S. Zeisel,et al.  Choline intake and genetic polymorphisms influence choline metabolite concentrations in human breast milk and plasma. , 2010, The American journal of clinical nutrition.

[44]  G. Shaw,et al.  Periconceptional nutrient intakes and risks of neural tube defects in California. , 2010, Birth defects research. Part A, Clinical and molecular teratology.

[45]  R. Rozen,et al.  Low dietary choline and low dietary riboflavin during pregnancy influence reproductive outcomes and heart development in mice. , 2010, The American journal of clinical nutrition.

[46]  S. Zeisel,et al.  Choline: an essential nutrient for public health. , 2009, Nutrition reviews.

[47]  S. Zeisel,et al.  Lecithin and choline in human health and disease. , 2009, Nutrition reviews.

[48]  S. Zeisel Importance of methyl donors during reproduction. , 2009, The American journal of clinical nutrition.

[49]  Warren H. Meck,et al.  Developmental Periods of Choline Sensitivity Provide an Ontogenetic Mechanism for Regulating Memory Capacity and Age-Related Dementia , 2008, Frontiers in integrative neuroscience.

[50]  J. Troendle,et al.  Choline concentrations in human maternal and cord blood and intelligence at 5 y of age. , 2008, The American journal of clinical nutrition.

[51]  D. Panagiotakos,et al.  Dietary choline and betaine intakes in relation to concentrations of inflammatory markers in healthy adults: the ATTICA study. , 2008, The American journal of clinical nutrition.

[52]  W. Willett,et al.  Dietary choline and betaine and the risk of distal colorectal adenoma in women. , 2007, Journal of the National Cancer Institute.

[53]  K. Costa,et al.  Phosphatidylethanolamine N‐methyltransferase (PEMT) gene expression is induced by estrogen in human and mouse primary hepatocytes , 2007, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[54]  S. Zeisel,et al.  Sex and menopausal status influence human dietary requirements for the nutrient choline. , 2007, The American journal of clinical nutrition.

[55]  B. Ames,et al.  An overview of evidence for a causal relationship between dietary availability of choline during development and cognitive function in offspring , 2006, Neuroscience & Biobehavioral Reviews.

[56]  S. Zeisel Choline: critical role during fetal development and dietary requirements in adults. , 2006, Annual review of nutrition.

[57]  G. Shaw,et al.  Maternal Nutrient Intakes and Risk of Orofacial Clefts , 2006, Epidemiology.

[58]  M. Kohlmeier,et al.  Genetic variation of folate-mediated one-carbon transfer pathway predicts susceptibility to choline deficiency in humans. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[59]  F. Bäckhed,et al.  Obesity alters gut microbial ecology. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[60]  Shuli Wang,et al.  Polymorphism of the PEMT gene and susceptibility to nonalcoholic fatty liver disease (NAFLD) , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[61]  M. Fioravanti,et al.  Cytidinediphosphocholine (CDP-choline) for cognitive and behavioural disturbances associated with chronic cerebral disorders in the elderly. , 2005, The Cochrane database of systematic reviews.

[62]  Marshall H. Montrose,et al.  Osmotic regulation of renal betaine transport: transcription and beyond , 2004, Pflügers Archiv.

[63]  G. Shaw,et al.  Periconceptional dietary intake of choline and betaine and neural tube defects in offspring. , 2004, American journal of epidemiology.

[64]  M. Badea,et al.  Elevated serum creatine phosphokinase in choline-deficient humans: mechanistic studies in C2C12 mouse myoblasts. , 2004, The American journal of clinical nutrition.

[65]  S. J. James,et al.  Increased plasma homocysteine and S-adenosylhomocysteine and decreased methionine is associated with altered phosphatidylcholine and phosphatidylethanolamine in cystic fibrosis. , 2003, The Journal of pediatrics.

[66]  S. Zeisel,et al.  Concentrations of choline-containing compounds and betaine in common foods. , 2003, The Journal of nutrition.

[67]  D. Jenden,et al.  Choline deficiency causes reversible hepatic abnormalities in patients receiving parenteral nutrition: proof of a human choline requirement: a placebo-controlled trial. , 2001, JPEN. Journal of parenteral and enteral nutrition.

[68]  P. Dechent,et al.  Neither short-term nor long-term administration of oral choline alters metabolite concentrations in human brain , 1999, Biological Psychiatry.

[69]  S. Korones,et al.  Lower Incidence of Necrotizing Enterocolitis in Infants Fed a Preterm Formula with Egg Phospholipids , 1998, Pediatric Research.

[70]  J. Blusztajn,et al.  Choline, a Vital Amine , 1998, Science.

[71]  A. Stoll,et al.  Decreased brain choline uptake in older adults. An in vivo proton magnetic resonance spectroscopy study. , 1995, JAMA.

[72]  O. Adeyemo,et al.  Plasma progesterone, estradiol-17 beta and testosterone in maternal and cord blood, and maternal human chorionic gonadotropin at parturition. , 1993, African journal of medicine and medical sciences.

[73]  E. Alexander,et al.  Choline, an essential nutrient for humans , 1991, Nutrition.

[74]  R. Lévy,et al.  A double-blind, placebo controlled trial of high-dose lecithin in Alzheimer's disease. , 1985, Journal of neurology, neurosurgery, and psychiatry.

[75]  R. Wurtman,et al.  Precursor control of neurotransmitter synthesis. , 1980, Pharmacological reviews.

[76]  J. McNamara,et al.  Effects of oral choline on human complex partial seizures , 1980, Neurology.

[77]  K. Davis,et al.  Choline chloride effects on memory: Correlation with the effects of physostigmine , 1980, Psychiatry Research.

[78]  P. Millac,et al.  The use of choline chloride in ataxic disorders. , 1980, Journal of neurology, neurosurgery, and psychiatry.

[79]  J. Growdon,et al.  Choline and lecithin in the treatment of tardive dyskinesia: preliminary results from a pilot study. , 1979, The American journal of psychiatry.

[80]  F. Knüchel [Double-blind study in patients with alcoholic toxic fatty liver. Effect of essential phospholipids on enzyme behavior and lipid composition of the serum]. , 1979, Die Medizinische Welt.

[81]  J. Growdon,et al.  Relations between dietary choline or lecithin intake, serum choline levels, and various metabolic indices. , 1978, Metabolism: clinical and experimental.

[82]  I. Glen,et al.  CLINICAL EFFECTS OF CHOLINE IN ALZHEIMER SENILE DEMENTIA , 1977, The Lancet.

[83]  J. Growdon,et al.  Huntington's disease: Clinical and chemical effects of choline administration , 1977, Annals of neurology.

[84]  I. Sarda,et al.  Hormonal studies in pregnancy. I. Total unconjugated estrogens in maternal peripheral vein, cord vein, and cord artery serum at delivery. , 1976, American journal of obstetrics and gynecology.

[85]  H. Knutsen,et al.  Scientific Opinion on dietary reference values for chloride , 2019 .

[86]  Jian Yan,et al.  Trimethylamine‐N‐oxide (TMAO) response to animal source foods varies among healthy young men and is influenced by their gut microbiota composition: A randomized controlled trial , 2017, Molecular nutrition & food research.

[87]  P. Kidd,et al.  Phosphatidylcholine: A Superior Protectant Against Liver Damage , 1996 .

[88]  J. Blusztajn,et al.  Choline and human nutrition. , 1994, Annual review of nutrition.