Dietary Choline Research Articles

Patterns of Egg Consumption Can Help Contribute to Nutrient Recommendations and Are Associated with Diet Quality and Shortfall Nutrient Intakes.

Limited data are available on how eggs are consumed in the typical American eating pattern and the contribution to usual intakes, diet quality and in meeting recommendations. The objectives of the present analysis included identifying how eggs are consumed within U.S. dietary patterns and how these patterns are associated with the usual intakes of shortfall nutrients and diet quality (Healthy Eating Index 2015) using data from the combined National Health and Nutrition Examination Survey (NHANES) from 2001–2016. An additional objective included assessing the differences between egg consumers and egg non-consumers in nutrient intakes and nutrient adequacy. Several egg-containing dietary patterns were identified, and two egg patterns were associated with a greater diet quality compared to a no egg pattern (p < 0.0001). Most egg patterns identified were similar in diet quality scores when compared to the no egg pattern; however, the two egg patterns had lower diet quality scores. Egg consumption combined with a greater intake of total protein foods, seafood and plant protein, total vegetables, total fruit, whole fruit, whole grains and dairy foods, and a lower intake of refined grains and added sugars contributed to an improved diet quality, supporting that no one food is responsible for a healthy dietary pattern. Egg consumers demonstrated significantly higher intakes of dietary fiber, calcium, magnesium, potassium, total choline, vitamin A, vitamin C, vitamin D and vitamin E when compared to egg non-consumers. A comparison of egg consumers and egg non-consumers found egg consumers had significantly less percentages of the population below the EAR for calcium, iron, magnesium, vitamin A, vitamin C and vitamin E. Similarly, the percentage of the population above the recommendations for potassium and choline were greater for egg consumers vs. egg non-consumers. In egg consumers, 24.4% of the population was above the AI for dietary choline when compared to 4.3% of egg non-consumers (p < 0.0001). Findings from the present analysis demonstrate that eggs and egg-containing foods can be an important part of a healthy dietary pattern when balanced accordingly with other nutrient-dense foods.

Choline intake effects on psychophysiological indicators of students in the pre-exam period

Introduction. Choline has a wide range of physiological functions. It has a neuroprotective effect on brain dysfunctions, while its deficiency has a negative effect on antenatal development of the nervous system. We aimed to study the impact of exogenous choline on the psychophysiological indicators in students.&#x0D; Study objects and methods. 87 students were surveyed by questionnaire to determine their background intake of dietary choline. One month before the exams, we measured their simple and complex visual-motor reaction times, functional mobility and balance of nervous processes, as well as indicators of their short-term memory, attention, health, activity, and mood. Then, we divided the students into a control and an experimental group, regardless of their choline intake. The experimental group took 700 mg choline supplements on a daily basis for one month, followed by a second psychophysiological examination.&#x0D; Results and discussion. Students with a low choline intake had lower functional mobility and balance of nervous processes, but better attention stability than students with a high choline intake. The second examination showed improved short-term memory, health, and activity indicators in the experimental group, compared to the control. The visual-motor reaction times also increased, but only in students with an initially low level of choline intake.&#x0D; Conclusion. Choline supplementation can be recommended to students under pre-exam stress to enhance the functional state of their central nervous system.

The rumen microbiome inhibits methane formation through dietary choline supplementation

Enteric fermentation from ruminants is a primary source of anthropogenic methane emission. This study aims to add another approach for methane mitigation by manipulation of the rumen microbiome. Effects of choline supplementation on methane formation were quantified in vitro using the Rumen Simulation Technique. Supplementing 200 mM of choline chloride or choline bicarbonate reduced methane emissions by 97–100% after 15 days. Associated with the reduction of methane formation, metabolomics analysis revealed high post-treatment concentrations of ethanol, which likely served as a major hydrogen sink. Metagenome sequencing showed that the methanogen community was almost entirely lost, and choline-utilizing bacteria that can produce either lactate, ethanol or formate as hydrogen sinks were enriched. The taxa most strongly associated with methane mitigation were Megasphaera elsdenii and Denitrobacterium detoxificans, both capable of consuming lactate, which is an intermediate product and hydrogen sink. Accordingly, choline metabolism promoted the capability of bacteria to utilize alternative hydrogen sinks leading to a decline of hydrogen as a substrate for methane formation. However, fermentation of fibre and total organic matter could not be fully maintained with choline supplementation, while amino acid deamination and ethanolamine catabolism produced excessive ammonia, which would reduce feed efficiency and adversely affect live animal performance.

ON THE BIOLOGICAL ROLE OF CHOLINE IN HUMAN AND HIGHER ANIMAL ORGANISMS (A LITERATURE REVIEW)

Purpose. To provide the reader a detailed literature review regarding the history of the discovery of choline, then the history of further research on its biological role in human and higher animal organisms. Describe in detail the mechanisms of choline biosynthesis, absorption, transport and metabolism in human and higher animals, the variety of physiological functions performed by the choline itself and by its derivatives. Describe the various symptoms of dietary choline deficiency. Provide to the reader the data regarding the US and EU minimum recommended dietary intake of choline.&#x0D; Methodology. We began our work by studying the literature on the history of medicine, as well as encyclopedic literature on vitamins and vitamin-like compounds, and books on biochemistry. Then we used the search engines PubMed and ScienceDirect to find relevant articles discussing the biological role of choline, its biosynthesis, absorption, transport, and symptoms of its deficiency. We then used materials from the US National Academy of Medicine and the European Food Safety Agency’s RDA for choline from food.&#x0D; Results. The data we found and presented in this literature review on the biological role of choline in humans and higher animals convincingly indicate the important role of sufficient consumption of choline in the daily diet for maintaining overall health. Sufficient dietary choline is needed to maintain the normal state of the skin and its appendages, articular cartilage, skeletal muscles, to support the normal functioning of the liver and the endocrine system (especially the cortex and the medulla of the adrenal glands, and the gonads), to prevent stone formation in bile, to improve memory and cognitive functioning, to reduce blood plasma atherogenicity and improve its lipid profile, to delay the development of atherosclerosis.&#x0D; Practical implications. The results we presented there deserve the widest application in various fields of both human medicine and veterinary medicine.

Choline Intake Correlates with Cognitive Performance among Elder Adults in the United States.

Objective This research attempted to explore the neuroprotective effect of choline and establish evidence for future dietary recommendations and nutritional interventions to maintain a proper cognitive function among elders aged >60 years in the US. Method This cross-sectional study retrieved data of 2,393 eligible elderly participants from the 2011-2014 National Health and Nutrition Examination Survey. Combining dietary and supplement choline intake, total choline intake was evaluated using the 24-hour dietary recall method and the dietary supplement questionnaire. Total choline intake was categorized into tertiles, which ranged at <187.60 mg/day (T1), 187.60-399.50 mg/day (T2), and >399.50 mg/day (T3). The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Word Learning subtest, Animal Fluency (AF) test, and Digit Symbol Substitution test (DSST) was used to measure cognitive function. Participants who scored the lowest 25th percentile in each cognitive test were classified in the low cognitive function (LC) group. Logistic regression models were implemented to examine the association between total choline intake and the incidence of LC. Results In the CERAD test, the risk of LC was significantly lower in T2 than T1 (OR: 0.668, 95% CI: 0.493-0.904, and P = 0.006) when adjusted for age, gender, BMI, alcohol consumption, and hypertension. Similarly, T2 was associated with a significantly lower risk of LC when assessed by the AF test (OR: 0.606, 95% CI: 0.580-0.724, and P < 0.001) and DSST (0.584, 95% CI: 0.515-0.661, and P < 0.001). In all three cognitive measures, the T3 of the total choline intake was not associated with cognitive function compared to T1. Conclusion Total choline intake at 187.06-399.50 mg/day reduces the risk of LC by approximately 50% compared to intake at <187.6 mg/day. The findings of this research may be used to establish dietary recommendations and nutritional interventions to optimize the cognitive function among elders.

Enhanced Electrocatalytic Detection of Choline Based on CNTs and Metal Oxide Nanomaterials

Choline is an officially established essential nutrient and precursor of the neurotransmitter acetylcholine. It is employed as a cholinergic activity marker in the early diagnosis of brain disorders such as Alzheimer’s and Parkinson’s disease. Low levels of choline in diets and biological fluids, such as blood plasma, urine, cerebrospinal and amniotic fluid, could be an indication of neurological disorder, fatty liver disease, neural tube defects and hemorrhagic kidney necrosis. Meanwhile, it is known that choline metabolism involves oxidation, which frees its methyl groups for entrance into single-C metabolism occurring in three phases: choline oxidase, betaine synthesis and transfer of methyl groups to homocysteine. Electrocatalytic detection of choline is of physiological and pathological significance because choline is involved in the physiological processes in the mammalian central and peripheral nervous systems and thus requires a more reliable assay for its determination in biological, food and pharmaceutical samples. Despite the use of several methods for choline determination, the superior sensitivity, high selectivity and fast analysis response time of bioanalytical-based sensors invariably have a comparative advantage over conventional analytical techniques. This review focuses on the electrocatalytic activity of nanomaterials, specifically carbon nanotubes (CNTs), CNT nanocomposites and metal/metal oxide-modified electrodes, towards choline detection using electrochemical sensors (enzyme and non-enzyme based), and various electrochemical techniques. From the survey, the electrochemical performance of the choline sensors investigated, in terms of sensitivity, selectivity and stability, is ascribed to the presence of these nanomaterials.

Dietary rumen-protected choline supplementation regulates blood biochemical profiles and urinary metabolome and improves growth performance of growing lambs

This study aimed to assess the growth performance and blood metabolites, as well as metabolic profiles in the urine of lambs fed on dietary rumen-protected choline (RPC). Thirty-six Dorper × Hu lambs weighing approximately 20 kg were equally assigned to three groups, and fed on three diets supplemented with different RPC concentrations (0, 0.25% and 0.75%) for 45 days. Supplementation of RPC significantly increased average daily gain (ADG) and decreased feed-to-gain ratio (F/G) of lambs (p < 0.05). Dietary RPC was significantly associated with elevated plasma high-density lipoprotein (HDL) and suppressed low-density lipoprotein (LDL) levels when compared to the control group (p < 0.05). Moreover, concentrations of very-low-density lipoprotein (VLDL) exhibited an increasing trend (p = 0.065), whereas β-hydroxybutyrate (BHBA) levels decreased (p = 0.086) in plasma. Analysis of urine metabolome revealed that RPC supplementation significantly suppressed urinary concentrations of pyruvate (p < 0.05), while increased urinary concentrations of trimethylamine oxide, p-cresol, phenylacetylglycine and hippurate (p < 0.05). These findings suggest that RPC supplementation can promote weight gain, alter plasma lipid metabolism and modify urinary metabolome which is correlated with energy metabolism, lipid metabolism and intestinal microbial metabolism in lambs. In conclusion, based on our findings, we recommend 0.25% RPC as a supplement for growing lambs.

Proatherogenic gut-microbiome metabolite trimethylamine elicits a gut-liver circuit to regulate TMAO metabolism and atherosclerosis via mediation of CREBH

Abstract Introduction In humans, circulating metabolite Trimethylamine N-oxide (TMAO) is closely associated with higher risk of cardiovascular disease. Trimethylamine (TMA), a precursor of TMAO, is produced by gut microbiome using dietary components, i.e., choline and carnitine, as substrates. The gut-derived TMA is then transferred to the liver where it is further oxidized to TMAO by the flavin-containing monooxygenases (FMOs). The ER-resident transcription factor c-AMP responsive element binding protein H (CREBH/CREB3L3) is exclusively expressed in the liver and intestine. Perturbation of CREBH activity contributes to the development of hyperlipidemia and cardiovascular disease. Therefore, the Purpose of this study is to investigate the regulatory effect of a gut bacterium, Akkermansia muciniphila (A. muciniphila), on TMA and TMAO metabolism and the role of CREBH in this process. Methods Two groups of wild type (WT) and CREBH knockout (CREBH-KO) mice were inoculated with 200 μL of A. muciniphila (2×108 cfu/0.2 mL) in PBS or the vehicle (PBS) alone as control every other day through oral gavage for 2 weeks. Plasmas, liver and intestinal tissues were collected for metabolomics analysis, immunoblotting analysis and q-RT-PCR. Results Metabolomics analysis of the plasmas from the experimental mice revealed that increased colonization of A. muciniphila in the gut significantly reduced circulating TMA in the WT mice but not in CREBH-KO mice (P&amp;lt;0.05), suggesting that depletion of CREBH altered the microenvironment of gut microbiome which affected the metabolism of TMA by gut bacteria. In the livers, A. muciniphila treatment markedly reduced mRNA expression of FMO1 and FMO3 (P&amp;lt;0.05), which subsequently inhibited the enzymatic conversion of TMA to TMAO in hepatocytes. Immunoblotting analysis further revealed that LDL receptor was upregulated whereas ER stress markers, GRP94 and JNK1/2, were downregulated in the A. muciniphila treated KO mice, indicating an acceleration in lipoprotein (VLDL remnant) clearance from the circulation and the improvement of metabolic inflammation. In vitro, incubation of mouse hepatocytes AML12 with TMA (600 mM) for 12 hours stimulated expression of FMOs to facilitate the conversion of TMA to TMAO and induced lipotoxicity. Conclusion CREBH mediates the crosstalk between gut microbiome and liver metabolic system that regulates TMA and TMAO metabolism, which contributes to the induction of metabolic inflammation and atherogenesis. This novel finding may lend support to the therapeutic strategy of atherosclerosis. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): British Heart Foundation

Dietary Choline Deprivation Exacerbates Cardiomyopathy in Streptozotocin-Induced Diabetic Adult Rats

Choline (Ch) is an essential molecule of substantial importance for the optimal development and function of several biological systems. Ch deprivation has been linked with abnormal fat metabolism, insulin resistance, and myocardial dysfunction. The current study provides evidence of an exacerbation of streptozotocin-induced cardiomyopathy in adult diabetic Wistar rats by dietary Ch deprivation through the administration of a Ch-deprived diet (CDD). Twenty-four adult male Wistar rats were randomly separated into four groups: control, diabetic (DM), choline-deprived through choline-deprived diet (CD), and diabetic choline-deprived (DM + CD). After five weeks of dietary intervention, myocardium echocardiographic and histological assessments were performed. Choline-deprived diabetic rats exhibited significantly slower heart rate, significantly higher myocardial ejection velocity and left ventricle wall tension index with a concomitant significant decreased LV posterior wall thickness as compared to diabetic rats fed on a standard diet. Moreover, histopathological evidence demonstrated an exacerbation of myocardial inflammation and fibrosis associated with significant up-regulation of VEGF expression in the diabetic rat myocardium as a result of Ch deprivation. The study’s findings are of particular significance since the examined experimental approach introduces a previously uncharacterised comorbidity simulation with regards to myocardial structure and functional profiling.

PSV-B-19 Dietary choline supplementation increases transmethylation through the one-carbon cycle in overweight cats

Abstract The objective of this study was to determine the dose-response relationship between dietary choline intake and one-carbon cycle activity in overweight cats at maintenance energy requirements. This study was approved by the University of Guelph Animal Care Committee (AUP#4118). Overweight (body condition score:≥6/9) adult male neutered cats (n = 14) received each of five choline chloride doses individually for three weeks in a 5x5 latin square design. Doses were based on body weight (BW) and the daily recommended allowance (RA) for choline for adult cats (63 mg/kg BW0.67). Doses were: 2xRA (126 mg/kg BW0.67), 4xRA (252 mg/kg BW0.67), 6xRA (378 mg/kg BW0.67), 8xRA (504 mg/kg BW0.67), and control (no additional choline). Choline was administered onto the commercial extruded cat food (3620 mg choline/kg diet), given once a day at maintenance energy requirements (130 kcal/kg BW0.4). Fasted serum samples were analyzed for metabolomics through quantitative nuclear magnetic resonance (NMR) spectroscopy and direct infusion mass spectrometry (DI-MS) at the end of each period. Data was analyzed using proc GLIMMIX in SAS, with group and period as the random effects, and dose as the fixed effect. Statistical significance was considered at P &amp;lt; 0.05. Tukey’s post-hoc test was performed to assess multiple comparisons. Choline at 6x and 8x RA appears to increase transmethylation through the one-carbon cycle, as suggested by increased serum betaine, dimethylglycine (DMG) and methionine (P &amp;lt; 0.05). Carnitine, methylated by s-adenosylmethionine (SAM), increased (P &amp;lt; 0.05). Serine and threonine, precursors for the biosynthesis of homocysteine, appear to have been spared (P &amp;lt; 0.05). Supplemental dietary choline (6x and 8xRA) may be beneficial for overweight cats, as it may increase activity of the one-carbon cycle and methyl status; which are necessary for hepatic function. To better understand the impact of choline on methylation reactions, the quantification of specific proteins, gene expression and/or conversion rates is required.

PSV-B-17 Additional dietary choline increases serum metabolites as determined by direct infusion mass spectrometry in post-gonadectomy kittens

Abstract This study aimed to investigate changes in serum metabolites using direct infusion mass spectrometry (Di-MS) after 12 weeks with or without additional choline in growing, post-gonadectomy kittens. The present study was approved by the University of Guelph Animal Care Committee (AUP#4118). Intact, male kittens (3-months old; n = 15) were fed a base-diet to growth requirements (3310mg choline/kg DM) over an 11-week acclimation. Kittens were gonadectomized (week 1) and assigned to base-diet (n = 7) or base-diet with 300mg/kgBW0.75 additional choline (n = 8) and fed to mimic ad libitum food intake (3 meals totaling thrice daily requirements) for 12-weeks. Fasted serum samples were obtained and analyzed for 130 metabolites via Di-MS (week 0 and 12). The proc GLIMMIX procedure (SAS) was used to analyze differences between groups as a repeated measure. Additional choline resulted in higher serum concentrations of one-carbon metabolites such as methionine, serine, betaine, and sarcosine (P &amp;lt; 0.05). As expected, serum concentrations of phosphatidylcholines increased with additional choline, as did serum concentrations of lysophosphatidylcholines and sphingomyelins, compared to no additional choline (P &amp;lt; 0.05). There was minimal impact on acyl carnitines with a decrease in medium length acyl carnitines (P &amp;lt; 0.05). Additionally, there was an increase in serum concentrations of spermine, trans hydroxyproline, methionine sulfoxide, proline, and indole acetic acid, and a decrease in serum trimethylamine N-Oxide compared to control (P &amp;lt; 0.05). Effects of growth stage or gonadectomy may have resulted in increased serum amino acid concentrations such as asparagine, glutamine, glutamic acid, histidine, lysine, methionine, threonine, and tyrosine in both groups (P &amp;lt; 0.05). These results may indicate benefits for providing additional choline to post-gonadectomy kittens on one-carbon metabolism and fatty acid oxidation which could promote healthy weight and body condition. However, more research is warranted to further understand choline’s role in energy balance and its potential in prevention and treatment of feline obesity.

The effect of dietary choline and water temperature on the contribution of raw materials to the muscle tissue of juvenile yellowtail kingfish (Seriola lalandi): An investigation using a stable isotope mixing model

Two independent eight-week experiments were conducted to evaluate the effect of dietary choline content and water temperature on the contribution of major raw materials to the muscle of juvenile yellowtail kingfish (YTK; Seriola lalandi) using stable isotopes and a mixing model. Experiment 1 (dose-response design) focused on rearing fish (mean ± SD; initial weight = 156.3 ± 15.3 g) at 16 °C. Fish were fed six semi-purified research diets with increasing levels of feed-grade choline chloride (CC; 70% CC). The diets contained measured choline content ranging from 0.59 to 6.22 g/kg diet. Except for the control diet, all semi-purified diets contained 0.3% of 2-amino-2-methyl-1-propanol (AMP; de novo choline synthesis inhibitor). Three major raw materials assessed in the semi-purified diets were fishmeal 1, sodium caseinate, and gelatine. In experiment 2 (2 × 3 factorial design), fish (157.3 ± 11.9 g) were reared at 16 °C and 24 °C, and fed three practical diets supplemented with 0.0, 3.0, or 6.0 g CC/kg diet. The six major raw materials assessed in the practical diets were fishmeal 2, poultry meal, meat meal, blood meal, lupin, and wheat flour. Stable isotope ratios of carbon (δ13C) and nitrogen (δ15N) were used as natural tracers and the stable isotope mixing model (SIMM) was based on a Bayesian framework (R package ‘MixSIAR’). In general, the calculated raw material contributions were within the 95% credible intervals range of the SIMM estimates. Based on the SIMM estimate, experiment 1 showed that increasing dietary choline content elevated the mean proportional contribution of sodium caseinate (56.8–81.1%) to the muscle of juvenile YTK. In comparison, fishmeal 1 and gelatine contribution decreased with increasing dietary choline. Unlike experiment 1, experiment 2 showed that choline supplementation and water temperature had little effect on raw material contribution to the muscle of YTK when fed practical diets. In addition, the SIMM estimated contribution of fishmeal 2 (20.7–45.9%) was lower than that of the calculated (47.6%). The study indicated that raw material contributions to muscle of YTK was more profoundly affected by severe choline-deficiency than temperature, at 16 °C and 24 °C. Furthermore, the study indicated that fishmeal inclusion in YTK diet could be reduced. The present study demonstrated the novel use of naturally-occurring stable isotopes and SIMM to evaluate aquafeed down to ingredient level. The findings can guide feed formulation for YTK and other species by demonstrating the potential micronutrient-raw material-environment interactions.

Compositional and functional alterations of gut microbiota in patients with stroke

Background and aimsThere is accumulating evidence that gut microbiota plays a key role in cardiovascular diseases. Gut bacteria can transform dietary choline, l-carnitine, and trimethylamine N-oxide (TMAO) into trimethylamine, which can be oxidized into TMAO again in the liver. However, the alterations of the gut microbiota in large artery atherosclerotic (LAA) stroke and cardioembolic (CE) stroke have been less studied. Methods and resultsWe performed a case–control study in patients with LAA and CE types of strokes. We profiled the gut microbiome using Illumina sequencing of the 16S ribosomal RNA gene (V4–V5 regions), and TMAO was determined via liquid chromatography–tandem mass spectrometry. Our results showed that the TMAO levels in the plasma of patients with LAA and CE strokes were significantly higher than those in controls (LAA stroke, 2931 ± 456.4 ng/mL; CE stroke, 4220 ± 577.6 ng/mL; healthy control, 1663 ± 117.8 ng/mL; adjusted p < 0.05). The TMAO level in the plasma of patients with LAA stroke was positively correlated with the carotid plaque area (rho = 0.333, 95% CI = 0.08–0.55, p = 0.0093). Notably, the composition and the function of gut microbiota in the LAA stroke group were significantly different from those in the control group (FDR-adjusted p-value < 0.05). There was no significant association between gut microbiota and CE stroke in our study. ConclusionThis study provides evidence for significant compositional and functional alterations of the gut microbiome in patients with LAA stroke. Gut microbiota might serve as a potential biomarker for patients with LAA stroke.

Gut microbiota dependent trimethylamine N-oxide aggravates angiotensin II–induced hypertension

Gut microbiota produce Trimethylamine N-oxide (TMAO) by metabolizing dietary phosphatidylcholine, choline, l-carnitine and betaine. TMAO is implicated in the pathogenesis of chronic kidney disease (CKD), diabetes, obesity and atherosclerosis. We test, whether TMAO augments angiotensin II (Ang II)-induced vasoconstriction and hence promotes Ang II-induced hypertension. Plasma TMAO levels were indeed elevated in hypertensive patients, thus the potential pathways by which TMAO mediates these effects were explored. Ang II (400 ng/kg−1min−1) was chronically infused for 14 days via osmotic minipumps in C57Bl/6 mice. TMAO (1%) or antibiotics were given via drinking water. Vasoconstriction of renal afferent arterioles and mesenteric arteries were assessed by microperfusion and wire myograph, respectively. In Ang II-induced hypertensive mice, TMAO elevated systolic blood pressure and caused vasoconstriction, which was alleviated by antibiotics. TMAO enhanced the Ang II-induced acute pressor responses (12.2 ± 1.9 versus 20.6 ± 1.4 mmHg; P < 0.05) and vasoconstriction (32.3 ± 2.6 versus 55.9 ± 7.0%, P < 0.001). Ang II-induced intracellular Ca2+ release in afferent arterioles (147 ± 7 versus 234 ± 26%; P < 0.001) and mouse vascular smooth muscle cells (VSMC, 123 ± 3 versus 157 ± 9%; P < 0.001) increased by TMAO treatment. Preincubation of VSMC with TMAO activated the PERK/ROS/CaMKII/PLCβ3 pathway. Pharmacological inhibition of PERK, ROS, CaMKII and PLCβ3 impaired the effect of TMAO on Ca2+ release. Thus, TMAO facilitates Ang II-induced vasoconstriction, thereby promoting Ang II-induced hypertension, which involves the PERK/ROS/CaMKII/PLCβ3 axis.

The Accumulation and Molecular Effects of Trimethylamine N-Oxide on Metabolic Tissues: It's Not All Bad.

Since elevated serum levels of trimethylamine N-oxide (TMAO) were first associated with increased risk of cardiovascular disease (CVD), TMAO research among chronic diseases has grown exponentially. We now know that serum TMAO accumulation begins with dietary choline metabolism across the microbiome-liver-kidney axis, which is typically dysregulated during pathogenesis. While CVD research links TMAO to atherosclerotic mechanisms in vascular tissue, its molecular effects on metabolic tissues are unclear. Here we report the current standing of TMAO research in metabolic disease contexts across relevant tissues including the liver, kidney, brain, adipose, and muscle. Since poor blood glucose management is a hallmark of metabolic diseases, we also explore the variable TMAO effects on insulin resistance and insulin production. Among metabolic tissues, hepatic TMAO research is the most common, whereas its effects on other tissues including the insulin producing pancreatic β-cells are largely unexplored. Studies on diseases including obesity, diabetes, liver diseases, chronic kidney disease, and cognitive diseases reveal that TMAO effects are unique under pathologic conditions compared to healthy controls. We conclude that molecular TMAO effects are highly context-dependent and call for further research to clarify the deleterious and beneficial molecular effects observed in metabolic disease research.

Understanding Choline Bioavailability and Utilization: First Step Toward Personalizing Choline Nutrition.

Choline is an essential macronutrient involved in neurotransmitter synthesis, cell-membrane signaling, lipid transport, and methyl-group metabolism. Nevertheless, the vast majority are not meeting the recommended intake requirement. Choline deficiency is linked to nonalcoholic fatty liver disease, skeletal muscle atrophy, and neurodegenerative diseases. The conversion of dietary choline to trimethylamine by gut microbiota is known for its association with atherosclerosis and may contribute to choline deficiency. Choline-utilizing bacteria constitutes less than 1% of the gut community and is modulated by lifestyle interventions such as dietary patterns, antibiotics, and probiotics. In addition, choline utilization is also affected by genetic factors, further complicating the impact of choline on health. This review overviews the complex interplay between dietary intakes of choline, gut microbiota and genetic factors, and the subsequent impact on health. Understanding of gut microbiota metabolism of choline substrates and interindividual variability is warranted in the development of personalized choline nutrition.

Longitudinal Plasma Measures of Trimethylamine N-Oxide and Risk of Atherosclerotic Cardiovascular Disease Events in Community-Based Older Adults.

BackgroundTrimethylamine N‐oxide (TMAO) is a gut microbiota‐dependent metabolite of dietary choline, L‐carnitine, and phosphatidylcholine‐rich foods. On the basis of experimental studies and patients with prevalent disease, elevated plasma TMAO may increase risk of atherosclerotic cardiovascular disease (ASCVD). TMAO is also renally cleared and may interact with and causally contribute to renal dysfunction. Yet, how serial TMAO levels relate to incident and recurrent ASCVD in community‐based populations and the potential mediating or modifying role of renal function are not established.Methods and ResultsWe investigated associations of serial measures of plasma TMAO, assessed at baseline and 7 years, with incident and recurrent ASCVD in a community‐based cohort of 4131 (incident) and 1449 (recurrent) older US adults. TMAO was measured using stable isotope dilution liquid chromatography–tandem mass spectrometry (laboratory coefficient of variation, <6%). Incident ASCVD (myocardial infarction, fatal coronary heart disease, stroke, sudden cardiac death, or other atherosclerotic death) was centrally adjudicated using medical records. Risk was assessed by multivariable Cox proportional hazards regression, including time‐varying demographics, lifestyle factors, medical history, laboratory measures, and dietary habits. Potential mediating effects and interaction by estimated glomerular filtration rate (eGFR) were assessed. During prospective follow‐up, 1766 incident and 897 recurrent ASCVD events occurred. After multivariable adjustment, higher levels of TMAO were associated with a higher risk of incident ASCVD, with extreme quintile hazard ratio (HR) compared with the lowest quintile=1.21 (95% CI, 1.02–1.42; P‐trend=0.029). This relationship appeared mediated or confounded by eGFR (eGFR‐adjusted HR, 1.07; 95% CI, 0.90–1.27), as well as modified by eGFR (P‐interaction <0.001). High levels of TMAO were associated with higher incidence of ASCVD in the presence of impaired renal function (eGFR <60 mL/min per 1.73 m2: HR, 1.56 [95% CI, 1.13–2.14]; P‐trend=0.007), but not normal or mildly reduced renal function (eGFR ≥60 mL/min per 1.73 m2: HR, 1.03 [95% CI, 0.85–1.25]; P‐trend=0.668). Among individuals with prior ASCVD, TMAO associated with higher risk of recurrent ASCVD (HR, 1.25 [95% CI, 1.01–1.56]; P‐trend=0.009), without significant modification by eGFR.ConclusionsIn this large community‐based cohort of older US adults, serial measures of TMAO were associated with higher risk of incident ASCVD, with apparent modification by presence of impaired renal function and with higher risk of recurrent ASCVD.

Polymorphisms in SLC44A1 are associated with cognitive improvement in children diagnosed with fetal alcohol spectrum disorder: an exploratory study of oral choline supplementation

The essential nutrient choline provides one-carbon units for metabolite synthesis and epigenetic regulation in tissues including brain. Dietary choline intake is often inadequate, and higher intakes are associated with improved cognitive function. Choline supplements confer cognitive improvement for those diagnosed with fetal alcohol spectrum disorder (FASD), a common set of neurodevelopmental impairments; however, the effect sizes have been modest. In this retrospective analysis, we report that genetic polymorphisms affecting choline utilization are associated with cognitive improvement following choline intervention. Fifty-two children from the upper midwestern United States and diagnosed with FASD, ages 2-5 y, were randomly assigned to receive choline (500 mg/d; n=26) or placebo (n=26) for 9 mo, and were genotyped for 384 choline-related single nucleotide polymorphisms (SNPs). Memory and cognition were assessed at enrollment, study terminus, and at 4-y follow-up for a subset. When stratified by intervention (choline vs. placebo), 14-16 SNPs within the cellular choline transporter gene solute carrier family 44 member 1 (SLC44A1) were significantly associated with performance in an elicited imitation sequential memory task, wherein the effect alleles were associated with the greatest pre-/postintervention improvement. Of these, rs3199966 is a structural variant (S644A) and rs2771040 is a single-nucleotide variant within the 3' untranslated region of the plasma membrane isoform. An additive genetic model best explained the genotype associations. Lesser associations were observed for cognitive outcome and polymorphisms in flavin monooxygenase-3 (FMO3), methylenetetrahydrofolate dehydrogenase-1 (MTHFD1), fatty acid desaturase-2 (FADS2), and adiponectin receptor 1 (ADIPOR1). These SLC44A1 variants were previously associated with greater vulnerability to choline deficiency. Our data potentially support the use of choline supplements to improve cognitive function in individuals diagnosed with FASD who carry these effect alleles. Although these findings require replication in both retrospective and prospective confirmatory trials, they emphasize the need to incorporate similar genetic analyses of choline-related polymorphisms in other FASD-choline trials, and to test for similar associations within the general FASD population. This trial was registered at www.clinicaltrials.gov as NCT01149538.

Association between Dietary Choline Intake and Diabetic Retinopathy: National Health and Nutrition Examination Survey 2005-2008

ABSTRACT Purpose To explore whether there is an association between dietary choline intake and odds of diabetic retinopathy (DR) in the US diabetic population. Methods A cross-sectional study was conducted using the combined data of the National Health and Nutrition Examination Survey (NHANES) 2005–2008 of a complex, multistage, and probability-sampling design. Energy-adjusted choline intake was calculated separately for men and women using the residual method. Binary logistic regression adjusting for covariates was used to identify the variables associated with DR. Results We included 644 male and 628 female diabetic subjects, which were equivalent to a weighted survey sample of 9,339,124 for males and 10,109,553 for females respectively. Female DR patients consumed more choline than non-DR patients (268.6 mg/d vs 250.9 mg/d; p = .046). The estimated prevalence of DR was 17.4%, 21.9%, and 29.7% across three levels of dietary choline intake in females, respectively. In multivariable logistic-regression models, the odds ratio (OR) of DR for female patients in the highest choline intake group was 2.14 (95% confidence interval [CI], 1.38–3.31; p = .001) compared with those in the lowest intake group. This association was positive but not statistically significant in males. Conclusion Higher intake of dietary choline is associated with increased odds of DR in females, but not in males. Further studies are warranted to investigate the direct role of choline in DR development and determine the recommended daily intake of choline for diabetic patients weighing the pros and cons of dietary choline consumption.

Serum Lipid, Amino Acid and Acylcarnitine Profiles of Obese Cats Supplemented with Dietary Choline and Fed to Maintenance Energy Requirements.

Simple SummaryResearch has estimated that the majority of domestic cats are overweight or obese. Current weight-loss plans tend to have disappointing outcomes and are not without risk. During periods of severe energy restriction, obesity predisposes cats to developing fatty liver. Choline has been linked to fat metabolism in other animals but has not been studied in cats. Twelve obese cats were split into two groups and were fed a control diet (n = 6; 4587 mg choline/kg dry matter) or a high choline diet (n = 6; 18,957 mg choline/kg DM) for 5 weeks. Cats were fed to maintain body weight. Choline increased serum cholesterol, triacylglycerides, lipoproteins, and plasma methionine. It also decreased serum blood urea nitrogen and alkaline phosphatase as well as the ratio of plasma acylcarnitine to free carnitine. The results suggest that choline supplementation may increase fat transport out of the liver and help maintain liver health in obese cats. Choline supplementation may prove useful for safe weight loss in obese cats by minimizing the risks of fatty liver.Obesity is a health concern for domestic cats. Obesity and severe energy restriction predispose cats to feline hepatic lipidosis. As choline is linked to lipid metabolism, we hypothesized that dietary choline supplementation would assist in reducing hepatic fat through increased lipoprotein transport and fatty acid oxidation. Twelve obese cats (body condition score [BCS] ≥ 8/9) were split into two groups. Cats were fed a control (n = 6; 4587 mg choline/kg dry matter [DM]) or a high choline diet (n = 6; 18,957 mg choline/kg DM) for 5 weeks, for adult maintenance. On days 0 and 35, fasted blood was collected, and the body composition was assessed. Serum lipoprotein and biochemistry profiles, plasma amino acids and plasma acylcarnitines were analyzed. The body weight, BCS and body composition were unaffected (p > 0.05). Choline increased the serum cholesterol, triacylglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol and plasma methionine (p < 0.05) and decreased the serum blood urea nitrogen and alkaline phosphatase (p < 0.05). Choline also reduced the plasma acylcarnitine to free carnitine ratio (p = 0.006). Choline may assist in eliminating hepatic fat through increased fat mobilization and enhanced methionine recycling.