Choline Supplementation Research Articles

Assessing the Benefit of Dietary Choline Supplementation Throughout Adulthood in the Ts65Dn Mouse Model of Down Syndrome

Background/Objectives: Down syndrome (DS) is the most common cause of early-onset Alzheimer’s disease (AD). Dietary choline has been proposed as a modifiable factor to improve the cognitive and pathological outcomes of AD and DS, especially as many do not reach adequate daily intake levels of choline. While lower circulating choline levels correlate with worse pathological measures in AD patients, choline status and intake in DS is widely understudied. Perinatal choline supplementation (Ch+) in the Ts65Dn mouse model of DS protects offspring against AD-relevant pathology and improves cognition. Further, dietary Ch+ in adult AD models also ameliorates pathology and improves cognition. However, dietary Ch+ in adult Ts65Dn mice has not yet been explored; thus, this study aimed to supply Ch+ throughout adulthood to determine the effects on cognition and DS co-morbidities. Methods: We fed trisomic Ts65Dn mice and disomic littermate controls either a choline normal (ChN; 1.1 g/kg) or a Ch+ (5 g/kg) diet from 4.5 to 14 months of age. Results: We found that Ch+ in adulthood failed to improve genotype-specific deficits in spatial learning. However, in both genotypes of female mice, Ch+ significantly improved cognitive flexibility in a reverse place preference task in the IntelliCage behavioral phenotyping system. Further, Ch+ significantly reduced weight gain and peripheral inflammation in female mice of both genotypes, and significantly improved glucose metabolism in male mice of both genotypes. Conclusions: Our findings suggest that adulthood choline supplementation benefits behavioral and biological factors important for general well-being in DS and related to AD risk.

Prenatal choline supplementation enhances metabolic outcomes with differential impact on DNA methylation in Wistar rat offspring and dams

Choline is an essential nutrient required for proper functioning of organs and serves as a methyl donor. In liver where choline metabolism primarily occurs, glucose homeostasis is regulated through insulin receptor substrates (IRS) 1 and 2. The objective of this research was to determine the role of prenatal choline as a modulator of metabolic health and DNA methylation in liver of offspring and dams. Pregnant Wistar rat dams were fed an AIN-93G diet and received drinking water either with supplemented 0.25% choline (w/w) as choline bitartrate or untreated control. All offspring were weaned to a high-fat diet for 12 weeks. Prenatal choline supplementation led to higher insulin sensitivity in female offspring at weaning as well as lower body weight and food intake and higher insulin sensitivity in female and male adult offspring compared to offspring from untreated dams. Higher hepatic betaine concentrations were observed in dams and female offspring of choline-supplemented dams at weaning and higher glycerophosphocholine in female and male offspring at postweaning compared to the untreated control, suggestive of sustaining different choline pathways. Hepatic gene expression of Irs2 was higher in dams at weaning and female offspring at weaning and postweaning, whereas Irs1 was lower in male offspring at postweaning. Gene-specific DNA methylation of Irs2 was lower in female offspring at postweaning and Irs1 methylation was higher in male offspring at postweaning that exhibited an inverse relationship between methylation and gene expression. In conclusion, prenatal choline supplementation contributes to improved parameters of insulin signaling but these effects varied across time and offspring sex.

The role of choline in the physiology of reproductivity

Choline is an essential nutrient, but intake among pregnant women is insufficient – only 7% of them consume adequate amounts of choline. The discrepancy between choline requirements and actual intake raises questions about the need for choline supplementation and its potential benefits for pregnant women. The diet of the expectant mother, rich in choline, in the preconception period ensures folliculogenesis and better quality of oocytes, changes the foetal epigenome, counteracting genomic defects during intrauterine development and reducing the susceptibility to metabolic changes in adulthood. Choline is a source of methyl groups and its consumption reduces the risk of NTDs by 7 times, so a promising trend in nutritional support of pregnancy and prevention of NTDs is the intake of folates and choline in combination with other micronutrients. Choline promotes the growth, proliferation and functioning of placental cells, transport of macronutrients, and has an anti-inflammatory effect. The risk of low foetal weight is reduced by 69% when choline is added to the mother’s regular diet. A significant connection has been shown between high levels of choline in the mother and a 2-fold reduction in the risk of preeclampsia, premature birth and a significant effect on the neurodevelopment and mental health of the child – improving neurocognitive functions and reducing the risk of autism and attention deficit hyperactivity disorder. A choline supplement at a dose of 130 mg/day as part of the vitamin-mineral complex Femibion 1 is sufficient to meet the needs for this nutrient during the preconception period and in the first trimester of pregnancy. The need for choline supplementation in the pregravid period and the first trimester of pregnancy is because on folliculogenesis and oocyte protection, epigenetic programming, the effectiveness of preventing congenital malformations of the foetus, participation in metabolic and physiological processes in the placenta, reducing the risk of placenta-associated complications, influence on the development of nervous tissue and brain of the foetus and newborn.

Vertical Association Between Dietary Total Choline and L-alpha-glycerylphosphorylcholine and the Cognitive Function in Chinese Adults Aged over 55, Result from China Health and Nutrition Survey 1997-2018.

With the aging process in China showing an accelerated trend, cognitive decline and impairment have become a major issue in older people. Dietary choline supplement may be a changeable lifestyle to improve this situation. We analyzed 7659 adults aged over 55 in the China Health and Nutrition Survey (CHNS), evaluated cognitive function by the global cognition score, and found the association between cognitive function and dietary intake of total choline or L-alpha-glycerylphosphorylcholine (GPC). Linear and logistic mixed models with three levels were applied to analyze the association between dietary total choline/GPC intake and global cognition score, and the risk of poor cognition. The average dietary intake at baseline was 178.8 mg/d for total choline, and 16.3 mg/d for GPC. After an average follow up of 6.8 years, we found that higher intake of total choline (β = 0.083, 95%CI: 0.046,0.119, p < 0.001) and GPC (β = 0.073, 95%CI: 0.034-0.111, p < 0.001) had positively associated with global cognitive scores. Additionally, higher intake of total choline had a better effect on improving the cognitive function of women (β = 0.092, 95%CI: 0.042-0.142, p < 0.01) and individuals between 55-65 years old (β = 0.089, 95%CI: 0.046-0.132, p < 0.01). However, higher GPC intake had a better effect on the cognitive function of men (β = 0.080, 95%CI: 0.020-0.141, p < 0.05). Higher total choline intake had a protective factor against poor cognition (OR = 0.762, 95%CI: 0.676,0.860, p < 0.001); the protective effect was more pronounced for women (OR = 0.750, 95%CI: 0.639,0.879, p < 0.001) and individuals aged 55-65 (OR = 0.734, 95%CI: 0.636-0.848, p < 0.001). higher dietary choline and GPC intake were beneficial for cognitive function, although we found that higher dietary choline was more effective in improving global cognitive scores at older ages; dietary choline should be supplemented as early as possible in old age to prevent poor cognition.

The Importance of Gut Microbiota on Choline Metabolism in Neurodegenerative Diseases.

The gut microbiota is a complex ecosystem that influences digestion, immune response, metabolism, and has been linked to health and well-being. Choline is essential for neurotransmitters, lipid transport, cell-membrane signaling, methyl-group metabolism and is believed to have neuroprotective properties. It is found in two forms, water-soluble and lipid-soluble, and its metabolism is different. Long-term choline deficiency is associated with many diseases, and supplements are prescribed for improved health. Choline supplements can improve cognitive function in adults but not significantly. Choline is a precursor of phospholipids and an acetylcholine neurotransmitter precursor and can be generated de novo from phosphatidylcholine via phosphatidylethanolamine-N-methyltransferase and choline oxidase. Choline supplementation has been found to have a beneficial effect on patients with neurodegenerative diseases, such as Alzheimer's disease (AD), by increasing amyloid-β, thioflavin S, and tau hyper-phosphorylation. Choline supplementation has been shown to reduce amyloid-plaque load and develop spatial memory in an APP/PS1 mice model of AD. Choline is necessary for normative and improved function of brain pathways and can reduce amyloid-β deposition and microgliosis. Clinical research suggests that early neurodegenerative diseases (NDs) can benefit from a combination of choline supplements and the drugs currently used to treat NDs in order to improve memory performance and synaptic functioning.

Oral supplementation of choline attenuates the development of alcohol-related liver disease (ALD)

BackgroundChronic alcohol intake is associated with alterations of choline metabolism in various tissues. Here, we assessed if an oral choline supplementation attenuated the development of alcohol-related liver disease (ALD) in mice.MethodsFemale C57BL/6 J mice (n = 8/group) were either pair-fed a liquid control diet, or a Lieber DeCarli liquid diet (5% ethanol) ± 2.7 g choline/kg diet for 29 days. Liver damage, markers of intestinal permeability and intestinal microbiota composition were determined. Moreover, the effects of choline on ethanol-induced intestinal permeability were assessed in an ex vivo model.ResultsALD development as determined by liver histology and assessing markers of inflammation (e.g., nitric oxide, interleukin 6 and 4-hydroxynonenal protein adducts) was attenuated by the supplementation of choline. Intestinal permeability in small intestine being significantly higher in ethanol-fed mice was at the level of controls in ethanol-fed mice receiving choline. In contrast, no effects of the choline supplementation were found on intestinal microbiota composition. Choline also significantly attenuated the ethanol-induced intestinal barrier dysfunction in small intestinal tissue ex vivo, an effect almost entirely abolished by the choline oxidase inhibitor dimbunol.ConclusionOur results suggest that an oral choline supplementation attenuates the development of ALD in mice and is related to a protection from intestinal barrier dysfunction.

Choline supplementation reduces cadmium uptake and alleviates cadmium toxicity in Solanum lycopersicum seedlings

Sustainable plant production in soil polluted with heavy metals requires that novel strategies are developed for the benefit of humans and other living things. Cadmium (Cd) is a common heavy metal pollutant for plants, and there is limited information on the use of exogenous bio-regulators to reduce the accumulation and toxic effects of Cd pollution in plants. Choline is an endogenous quertarnary amine that is known to improve stress tolerance in plants, while its mechanism of action in certain conditions is yet to be determined. This study investigated the effects of foliar choline supplementation (10 mM) on Solanum lycopersicum seedlings exposed to Cd application (50 mg/L in soil). The seedlings were randomized to five groups: Control (E1), Cd stress (E2), Choline supplementation after Cd stress (E3), Choline (E4), and Choline supplementation before Cd stress (E5). Following the applications, the Cd content, growth and development parameters (chlorophyll content, fresh and dry weight), oxidative stress parameters (H2O2 and MDA contents), as well as antioxidative defense system (SOD, GSH, AsA, and TPC contents) were analyzed. Choline supplementation after Cd stress reduced the enhanced Cd content in roots by 38% but did not alter it in leaves (p > 0.05) compared to the Cd group. Choline supplementation before Cd stress decreased Cd content both in roots by 87.5% and in leaves by 50%. Choline supplementation after and before Cd stress increased fresh and dry weights in both roots and leaves. While the Cd group (E2) increased the H2O2 level and SOD activity, no remarkable change was observed in H2O2 levels in all choline supplementations (E3, E4, E5). Therefore, lipid peroxidation (MDA) was not observed in choline supplementation before Cd stress (E5), however, when the choline was applied after Cd stress (E3) MDA content was reduced by 40% compared with the Cd stress group (E2). Choline supplementations after and before Cd stress (E3, E5) increased AsA content by 30%, while the Cd group (E2) decreased it by 60% compared with the control group (E1). Choline supplementations before Cd stress (E5) increased TPC by 33%, while the Cd group (E2) decreased it by 18%, moreover, when choline was applied after Cd stress (E3), no change was observed compared to the control group. These data suggest that choline prevents inhibition of plant growth due to Cd toxicity by reducing Cd uptake. The results provided in the present study are likely to enhance the quality and efficiency of crop production in heavy metal-polluted areas.

Inulin does not affect trimethylamine N-oxide formation in mice with a high-fat diet combined with choline and L-carnitine.

Emerging evidence suggests that gut bacteria-derived trimethylamine N-oxide (TMAO) elevates the risk of cardiovascular disease, and dietary fiber holds the potential to attenuate TMAO formation. However, the effectiveness of dietary fiber, such as inulin, in inhibiting TMAO formation remains controversial. Therefore, this study investigated the effect of inulin supplementation on TMAO formation in mice with high TMAO levels induced by a high-fat diet (HFD) combined with choline and L-carnitine. Results showed that HFD treatment significantly elevated blood TMAO concentrations and increased the abundances of TMAO formation-associated gut bacteria, as well as the abundances of functional genes responsible for TMA formation. While the supplementation of choline and L-carnitine greatly enhanced blood trimethylamine (TMA) and TMAO levels, inulin supplementation did not significantly affect TMAO levels and had limited impact on TMA-associated gut bacteria, except for Desulfitobacterium hafniense.

Thermodynamic Study on Biomimetic Legionella gormanii Bacterial Membranes.

The presented studies were aimed at determining the interactions in model membranes (Langmuir monolayers) created of phospholipids (PL) isolated from Legionella gormanii bacteria cultured with (PL + choline) or without (PL - choline) choline and to describe the impact of an antimicrobial peptide, human cathelicidin LL-37, on PL's monolayer behavior. The addition of choline to the growth medium influenced the mutual proportions of phospholipids extracted from L. gormanii. Four classes of phospholipids-phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylglycerol (PG), cardiolipin (CL), and their mixtures-were used to register compression isotherms with or without the LL-37 peptide in the subphase. Based on them the excess area (Ae), excess (ΔGe), and total (ΔGm) Gibbs energy of mixing were determined. The thermodynamic analyses revealed that the PL - choline monolayer showed greater repulsive forces between molecules in comparison to the ideal system, while the PL + choline monolayer was characterized by greater attraction. The LL-37 peptide affected the strength of interactions between phospholipids' molecules and reduced the monolayers stability. Accordingly, the changes in interactions in the model membranes allowed us to determine the difference in their susceptibility to the LL-37 peptide depending on the choline supplementation of bacterial culture.

Maternal choline supplementation rescues early endosome pathology in basal forebrain cholinergic neurons in the Ts65Dn mouse model of Down syndrome and Alzheimer’s disease

Individuals with DS develop Alzheimer’s disease (AD) neuropathology, including endosomal-lysosomal system abnormalities and degeneration of basal forebrain cholinergic neurons (BFCNs). We investigated whether maternal choline supplementation (MCS) affects early endosome pathology within BFCNs using the Ts65Dn mouse model of DS/AD. Ts65Dn and disomic (2N) offspring from dams administered MCS were analyzed for endosomal pathology at 3–4 months or 10–12 months. Morphometric analysis of early endosome phenotype was performed on individual BFCNs using Imaris. The effects of MCS on the endosomal interactome were interrogated by relative co-expression (RCE) analysis. MCS effectively reduced age- and genotype-associated increases in early endosome number in Ts65Dn and 2N offspring, and prevented increases in early endosome size in Ts65Dn offspring. RCE revealed a loss of interactome cooperativity among endosome genes in Ts65Dn offspring that was restored by MCS. These findings demonstrate MCS rescues early endosome pathology, a driver of septohippocampal circuit dysfunction. The genotype-independent benefits of MCS on endosomal phenotype indicate translational applicability as an early-life therapy for DS as well as other neurodevelopmental/neurodegenerative disorders involving endosomal pathology.

Modulation of liver cholesterol homeostasis by choline supplementation during fibrosis resolution

Liver fibrosis is a critical global health challenge, often leading to severe liver diseases without timely intervention. Choline deficiency has been linked to metabolic dysfunction associated steatohepatitis (MASH) and liver fibrosis, suggesting choline supplementation as a potential therapeutic approach. This study aimed to explore the therapeutic potential of choline supplementation in liver fibrosis resolution and its effects on cholesterol homeostasis using a mouse model with induced liver fibrosis. Our findings reveal that choline supplementation significantly decreases blood lactate dehydrogenase (LDH) and non-high-density lipoprotein cholesterol (non-HDL-C) levels. Transcriptome analysis showed that choline supplementation primarily induces genes related to cholesterol homeostasis, suggesting a significant impact on liver cholesterol synthesis. However, choline supplementation did not significantly alter the expression of fibrosis-related, choline metabolism-related, or epigenetics-related genes. This study provides novel insights into the role of choline in liver health and cholesterol metabolism, potentially informing treatments for liver fibrosis and related conditions.

Deficiency of flavin-containing monooxygenase 3 protects kidney function after ischemia–reperfusion in mice

The kidney is vulnerable to ischemia and reperfusion (I/R) injury that can be fatal after major surgery. Currently, there are no effective treatments for I/R-induced kidney injury. Trimethylamine N-oxide (TMAO) is a gut-derived metabolite linked to many diseases, but its role in I/R-induced kidney injury remains unclear. Here, our clinical data reveals an association between preoperative systemic TMAO levels and postoperative kidney injury in patients after post-cardiopulmonary bypass surgery. By genetic deletion of TMAO-producing enzyme flavin-containing monooxygenase 3 (FMO3) and dietary supplementation of choline to modulate TMAO levels, we found that TMAO aggravated acute kidney injury through the triggering of endoplasmic reticulum (ER) stress and worsened subsequent renal fibrosis through TGFβ/Smad signaling activation. Together, our study underscores the negative role of TMAO in I/R-induced kidney injury and highlights the therapeutic potential through the modulation of TMAO levels by targeting FMO3, thereby mitigating acute kidney injury and preventing subsequent renal fibrosis.

Maternal choline supplementation modulates cognition and induces anti-inflammatory signaling in the prefrontal cortices of adolescent rats exposed to maternal immune activation

Maternal infection has long been described as a risk factor for neurodevelopmental disorders, especially autism spectrum disorders (ASD) and schizophrenia. Although many pathogens do not cross the placenta and infect the developing fetus directly, the maternal immune response to them is sufficient to alter fetal neurodevelopment, a phenomenon termed maternal immune activation (MIA). Low maternal choline is also a risk factor for neurodevelopmental disorders, and most pregnant people do not receive enough of it. In addition to its role in neurodevelopment, choline is capable of inducing anti-inflammatory signaling through a nicotinic pathway. Therefore, it was hypothesized that maternal choline supplementation would blunt the neurodevelopmental impact of MIA in offspring through long-term instigation of cholinergic anti-inflammatory signaling.To model MIA in rats, the viral mimetic polyinosinic:polycytidylic acid (poly(I:C)) was used to elicit a maternal antiviral innate immune response in dams both with and without choline supplementation. Offspring were reared to both early and late adolescent stages (postnatal days 28 and 50, respectively), where anxiety-related behaviors and cognition were examined. After behavioral testing, animals were euthanized, and their prefrontal cortices (PFCs) were collected for analysis. MIA offspring demonstrated sex-specific patterns of altered cognition and repetitive behaviors, which were modulated by maternal choline supplementation. Choline supplementation also bolstered anti-inflammatory signaling in the PFCs of MIA animals at both early and late adolescent stages. These findings suggest that maternal choline supplementation may be sufficient to blunt some of the behavioral and neurobiological impacts of inflammatory exposures in utero, indicating that it may be a cheap, safe, and effective intervention for neurodevelopmental disorders.

Influence of choline and follistatin supplementation during in vitro bovine oocyte maturation on oocyte competence and blastocyst development.

Metabolite supplementation during in vitro embryo development improves blastocyst quality, however, our understanding of the incorporation of metabolites during in vitro maturation (IVM) is limited. Two important metabolites, follistatin and choline, have beneficial impacts during in vitro culture; however, effects of supplementation during IVM are unknown. The objective of this study was to investigate combining choline and follistatin during IVM on bovine oocytes and subsequent early embryonic development. We hypothesized that supplementation of choline with follistatin would synergistically improve oocyte quality and subsequent early embryonic development. Small follicles were aspirated from slaughterhouse ovaries to obtain cumulus oocyte complexes for IVM with choline (0, 1.3 or 1.8 mM) and follistatin (0 or 10 ng/mL) supplementation in a 3 × 2 design. A subset of oocytes underwent transcriptomic analysis, the remaining oocytes were used for IVF and in vitro culture (IVC). Transcript abundance of CEPT1 tended to be reduced in oocytes supplemented with 1.8 mM choline and follistatin compared to control oocytes (P = 0.07). Combination of follistatin with 1.8 mM choline supplementation during maturation, tended (P = 0.08) to reduce CPEB4 in oocytes. In the blastocysts, HDCA8, NANOG, SAV1 and SOX2 were increased with choline 1.8 mM supplementation without follistatin (P < 0.05), while HDCA8 and SOX2 were increased when follistatin was incorporated (P < 0.05). The combination of choline and follistatin during oocyte maturation may provide a beneficial impact on early embryonic development. Further research is warranted to investigate the interaction between these two metabolites during early embryonic development and long-term influence on fetal development.

Effects of Donepezil on Clinical Symptoms, Language, and Executive Skills in Individuals with Autism Spectrum Disorder: A Systematic Review

Background. This study assessed the potential efficacy of donepezil in treating autism spectrum disorder (ASD), a neurodevelopmental condition characterized by social communication difficulties and repetitive behaviors. Donepezil, primarily used to treat Alzheimer’s disease as an acetylcholinesterase inhibitor, has gained attention as a potential treatment for ASD symptoms. Methods. Following PRISMA guidelines, a systematic review was conducted to investigate the effects of donepezil on individuals with ASD. Outcome measures assessed various aspects of ASD, including language skills, executive function, behavior, and core symptoms. Nine studies were identified, including four randomized controlled trials (RCTs), three retrospective studies, one open-label trial, and one case report. Results. One RCT reported significant improvements in expressive and receptive language skills, especially in younger children. Another study combining donepezil with choline supplementation showed enhanced receptive language skills, particularly in younger participants. An open-label trial indicated improved rapid eye movement sleep patterns in autistic children treated with donepezil. Several retrospective studies reported improvements in behavioral symptoms, such as aggression and hyperactivity. However, other RCTs did not find statistically significant improvements in executive functioning. Conclusion. In general, donepezil use in ASD demonstrates promise in specific areas, notably language development and behavioral symptom management. However, the results are contradictory, requiring further research to clarify its role, optimal dosing, long-term effects, and potential side effects in individuals with ASD. Practical Implications. Donepezil can be used to improve the clinical global impression and language skills of people with ASD.

Choline supplementation in early life improves and low levels of choline can impair outcomes in a mouse model of Alzheimer’s disease

Choline supplementation in early life improves and low levels of choline can impair outcomes in a mouse model of Alzheimer’s disease

Choline supplementation in early life improves and low levels of choline can impair outcomes in a mouse model of Alzheimer's disease.

Maternal choline supplementation (MCS) improves cognition in Alzheimer's disease (AD) models. However, the effects of MCS on neuronal hyperexcitability in AD are unknown. We investigated the effects of MCS in a well-established mouse model of AD with hyperexcitability, the Tg2576 mouse. The most common type of hyperexcitability in Tg2576 mice are generalized EEG spikes (interictal spikes [IIS]). IIS also are common in other mouse models and occur in AD patients. In mouse models, hyperexcitability is also reflected by elevated expression of the transcription factor ∆FosB in the granule cells (GCs) of the dentate gyrus (DG), which are the principal cell type. Therefore, we studied ΔFosB expression in GCs. We also studied the neuronal marker NeuN within hilar neurons of the DG because reduced NeuN protein expression is a sign of oxidative stress or other pathology. This is potentially important because hilar neurons regulate GC excitability. Tg2576 breeding pairs received a diet with a relatively low, intermediate, or high concentration of choline. After weaning, all mice received the intermediate diet. In offspring of mice fed the high choline diet, IIS frequency declined, GC ∆FosB expression was reduced, and hilar NeuN expression was restored. Using the novel object location task, spatial memory improved. In contrast, offspring exposed to the relatively low choline diet had several adverse effects, such as increased mortality. They had the weakest hilar NeuN immunoreactivity and greatest GC ΔFosB protein expression. However, their IIS frequency was low, which was surprising. The results provide new evidence that a diet high in choline in early life can improve outcomes in a mouse model of AD, and relatively low choline can have mixed effects. This is the first study showing that dietary choline can regulate hyperexcitability, hilar neurons, ΔFosB, and spatial memory in an animal model of AD.

Choline Supplementation for Infants, Children, and Pregnant People

What Is the Issue? Choline is an essential nutrient produced by humans and animals and is important during pregnancy, fetal growth, and the development of the brain and nervous system. Most people do not get enough choline from their diet. Fetal alcohol spectrum disorders (FASD) are a set of conditions where fetuses have been exposed to alcohol and this affects memory, learning, and development from early childhood to later life. Choline supplements are products used to complement choline-deficient diets. Given the role of choline in fetal development, choline supplements are a potential intervention to support pregnancy or to mitigate the developmental harms in children from prenatal exposure to alcohol if supported by evidence of their effectiveness for these purposes. What Did We Do? To inform decisions about the use and timing of choline supplementation to support health outcomes in infants and children, CADTH sought to identify and summarize the literature about the effectiveness and safety of choline supplementation given to any pregnant people or given to children with either prenatal alcohol exposure or FASD. We also attempted to identify evidence-based recommendations for using choline supplementation in these populations. We searched key resources and conducted a focused internet search for relevant evidence published since 2014. One reviewer screened articles for inclusion based on predefined criteria, critically appraised the included studies, and narratively summarized the findings. What Did We Find? We found few publications investigating this topic, and several studies had low statistical power and imprecise results. The clinical evidence was mixed depending on whether choline was given to the pregnant person or child, which interventional groups were compared, what the clinical exposures or diagnoses were in the study population, the time point and duration of choline supplementation, which outcomes were measured, and how old children were during follow-up. For choline supplementation in healthy pregnant people, evidence was mixed for infant and child neurocognitive and neurodevelopmental outcomes or behavioural symptoms; there were little-to-no differences in safety outcomes. For choline supplementation in pregnant people exposed to alcohol, evidence was mixed for infant and child neurocognitive and neurodevelopmental outcomes, body size, and brain region sizes; some minor side effects were reported overall. For choline supplementation in children with FASD, most evidence showed little-to-no benefits for neurocognitive and neurodevelopmental outcomes, and brain structure; limited evidence showed higher fishy body odour and some other unspecified adverse symptoms for children given choline. Guidelines based mostly on low-quality evidence or expert opinion recommend that all pregnant people, including those with gestational diabetes mellitus or on vegan or vegetarian diets, increase their choline intake through diet or supplements. We did not find clinical effectiveness evidence for choline supplementation in infants with FASD, or guidelines regarding choline supplementation in either infants or children with FASD, that met inclusion criteria for our report. What Does it Mean? Health care professionals and decision-makers can use this evidence to inform decisions around applicability of choline supplementation for pregnant people, or for infants and children with FASD, in their practice. There may be a need to balance the knowledge that choline intake is low at the population level and important for fetal development with the identified clinical effectiveness evidence for choline supplementation, which was limited and mixed for all evaluated patient populations. Careful consideration of the following may also be important to inform decisions about the appropriateness of choline supplementation: the care plan and other intensive and concurrent interventions for children with FASD; stigma and challenges faced by pregnant people and children in the context of prenatal alcohol exposure; cultural dietary practices; and accessibility, cost, and availability of supplements.

Evidence and Perspectives for Choline Supplementation during Parenteral Nutrition-A Narrative Review.

Choline is an essential nutrient, with high requirements during fetal and postnatal growth. Tissue concentrations of total choline are tightly regulated, requiring an increase in its pool size proportional to growth. Phosphatidylcholine and sphingomyelin, containing a choline headgroup, are constitutive membrane phospholipids, accounting for >85% of total choline, indicating that choline requirements are particularly high during growth. Daily phosphatidylcholine secretion via bile for lipid digestion and very low-density lipoproteins for plasma transport of arachidonic and docosahexaenoic acid to other organs exceed 50% of its hepatic pool. Moreover, phosphatidylcholine is required for converting pro-apoptotic ceramides to sphingomyelin, while choline is the source of betaine as a methyl donor for creatine synthesis, DNA methylation/repair and kidney function. Interrupted choline supply, as during current total parenteral nutrition (TPN), causes a rapid drop in plasma choline concentration and accumulating deficit. The American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) defined choline as critical to all infants requiring TPN, claiming its inclusion in parenteral feeding regimes. We performed a systematic literature search in Pubmed with the terms "choline" and "parenteral nutrition", resulting in 47 relevant publications. Their results, together with cross-references, are discussed. While studies on parenteral choline administration in neonates and older children are lacking, preclinical and observational studies, as well as small randomized controlled trials in adults, suggest choline deficiency as a major contributor to acute and chronic TPN-associated liver disease, and the safety and efficacy of parenteral choline administration for its prevention. Hence, we call for choline formulations suitable to be added to TPN solutions and clinical trials to study their efficacy, particularly in growing children including preterm infants.

Developmental ethanol exposure produces deficits in long-term potentiation invivo that persist following postnatal choline supplementation.

Fetal alcohol spectrum disorder (FASD) is one of the leading causes of neurodevelopmental disorder for which there is a pressing need for an effective treatment. Recent studies have investigated the essential nutrient choline as a postnatal treatment option. Supplementation with choline has produced improvements in behavioral tasks related to learning and memory and reverted changes in methylation signature following third-trimester equivalent ethanol exposure. We examined whether there are related improvements in hippocampal synaptic plasticity invivo. Sprague-Dawley offspring were administered binge-levels of ethanol from postnatal day (PND) 4 to 9, then treated with choline chloride (100 mg/kg/day) from PND 10 to 30. Invivo electrophysiology was performed on male and female offspring from PND 55 to 70. Long-term potentiation (LTP) was induced in the medial perforant pathway of the dentate gyrus using a theta-burst stimulation (TBS) protocol, and field-evoked postsynaptic potentials (EPSPs) were evoked for 60 min following the conditioning stimulus. Developmental ethanol exposure caused long-lasting deficits in LTP of the slope of the evoked responses and in the amplitude of the population spike potentiation. Neither deficit was rescued by postnatal choline supplementation. In contrast to our prior findings that choline can improve hippocampal plasticity (Nutrients, 2022, 14, 2004), here we found that deficits in hippocampal synaptic plasticity due to developmental ethanol exposure persisted into adulthood despite adolescent choline supplementation. Future research should examine more subtle changes in synaptic plasticity to identify synaptic changes that mirror behavioral improvements.