Gut microbiota metabolites and risk of major adverse cardiovascular events and death: A systematic review and meta-analysis.

BACKGROUND: Gut microbial metabolites such as trimethylamine N-oxide (TMAO) and its precursors, namely betaine, L-carnitine, and choline, have been implicated as risk factors for cardiovascular events and mortality development. Therefore, we aim to perform a systematic review and meta-analysis to assess the validity of these associations. METHODS: MEDLINE and Scopus were queried from their inception to August 2023 to identify studies that quantified estimates of the associations of TMAO with the development of major adverse cardiovascular events (MACE) or death. A random-effects meta-analysis was conducted to pool unadjusted or multivariable-adjusted hazard ratios (HR) and their 95% confidence intervals. The primary endpoint was the risk of MACE and all-cause death. RESULTS: 30 prospective observational studies (n = 48 968) were included in the analysis. Elevated TMAO levels were associated with a significantly greater risk of MACE and all-cause death compared to low TMAO levels (HR: 1.41, 95% CI 1.2-1.54, P < .00001, I2 = 43%) and (HR: 1.55, 95% CI 1.37-1.75, P < .00001, I2 = 46%), respectively. Furthermore, high levels of either L-carnitine or choline were found to significantly increase the risk of MACE. However, no significant difference was seen in MACE in either high or low levels of betaine. CONCLUSION: Elevated concentrations of TMAO were associated with increased risks of MACE and all-cause mortality. High levels of L-carnitine/choline were also significantly associated with an increased risk of MACE. However, no significant difference was found between high or low levels of betaine for the outcome of MACE.

Maternal Docosahexaenoic Acid Supplementation Alters Maternal and Fetal Docosahexaenoic Acid Status and Placenta Phospholipids in Pregnancies Complicated by High Body Mass Index.

INTRODUCTION: An optimal fetal supply of docosahexaenoic acid (DHA) is critical for normal brain development. The relationship between maternal DHA intake and DHA delivery to the fetus is complex and is dependent on placental handling of DHA. Little data exist on placental DHA levels in pregnancies supplemented with the recommended dose of 200 mg/d. Our objective was to determine how prenatal DHA at the recommended 200 mg/d impacts maternal, placental, and fetal DHA status in both normal-weight and high-BMI women compared to women taking no supplements. METHODS: Maternal blood, placenta, and cord blood were collected from 30 healthy pregnant women (BMI 18.9-43.26 kg/m2) giving birth at term. Red blood cells (RBCs) and villous tissue were isolated, and lipids were extracted to determine DHA content by LC-MS/MS. Data were analyzed by supplement group (0 vs. 200 mg/d) and maternal BMI (normal weight or high BMI) using two-way ANOVA. We measured maternal choline levels in maternal and cord plasma samples. RESULTS: Supplementation with 200 mg/d DHA significantly increased (p < 0.05) maternal and cord RBC DHA content only in pregnancies complicated by high BMI. We did not find any impact of choline levels on maternal or cord RBC phospholipids. There were no significant differences in total placental DHA content by supplementation or maternal BMI (p > 0.05). Placental levels of phosphatidylinositol (PI) and phosphatidic acid containing DHA species were higher (p < 0.05) in high-BMI women without DHA supplementation compared to both normal-BMI and high-BMI women taking DHA supplements. CONCLUSION: Maternal DHA supplementation at recommended doses cord increased RBC DHA content only in pregnancies complicated by higher BMI. Surprisingly, we found that obesity was related to an increase in placental PI and phosphatidic acid species, which was ameliorated by DHA supplementation. Phosphatidic acid activates placental mTOR, which regulates amino acid transport and may explain previous findings of the impact of DHA on placental function. Current recommendations for DHA supplementation may not be achieving the goal of improving fetal DHA levels in normal-weight women.

Investigation of laccase activity in cholinium-based ionic liquids using experimental and molecular dynamics techniques.

Laccases hold great potential for biotechnological applications, particularly in environmental pollutant remediation. Laccase activity is governed by the solvent environment, and ionic liquids (ILs) emerge as a versatile solvent for activation or stabilization of enzymes. Herein, effects of cholinium-based ILs formulated with carboxylic acids, inorganic acid, and amino acids as anionic species, on the catalytic activity of laccase from Trametes versicolor were investigated by experimental and computational approaches. Experimental results showed that laccase activity was enhanced by 21.39 % in 0.5 M cholinium dihydrogen citrate ([Cho][DHC]), in relation to the laccase activity in phosphate buffer medium. However, cholinium aminoate ILs negatively affected laccase activity, as evidenced by the partial deactivation of laccase in both cholinium glycinate and cholinium phenylalaninate, at concentrations of 0.1 M and 0.5 M, respectively. Molecular dynamics studies revealed that the enhancement of laccase activity in [Cho][DHC] might be attributed to the highly stabilized and compact structure of laccase, facilitating a better internal electron transfer during the laccase-substrate interactions. Enhanced catalytic performance of laccase in [Cho][DHC] was postulated to be driven by the high accumulation level of dihydrogen citrate anions around laccase's surface. [Cho][DHC] holds great promise as a cosolvent in laccase-catalyzed biochemical reactions.

Association between dietary choline intake and asthma and pulmonary inflammation and lung function: NHANES analysis 2009-2018.

BACKGROUND: Asthma is a chronic inflammatory condition, and choline may alleviate airway inflammation and oxidative stress but studies on the association between dietary choline and asthma remain limited. The purpose of this study is to investigate the associations between dietary choline intake and asthma, as well as pulmonary inflammation and lung function in children and adults. METHODS: In our research, we employed the data of the National Health and Nutrition Examination Survey (NHANES) from 2009 to 2018, including 7,104 children and 16,580 adults. We used fractional exhaled nitric oxide (FENO) to assess pulmonary inflammation and forced expiratory volume in one second (FEV1), forced vital capacity (FVC), the FEV1/FVC ratio, peak expiratory flow rate (PEF), predicted FEV1% and predicted FVC% to assess lung function. Binary logistic regression, linear regression, and the restricted cubic splines were used to analyze the associations between dietary choline intake and asthma and pulmonary inflammation and lung function. RESULTS: In children, we observed the positive associations between the natural logarithmic transformation of choline (ln-choline) and ln-FEV1 [ ß:0.011; 95%CI: (0.004,0.018)] and ln-FVC [ ß:0.009; 95%CI: (0.002,0.016)]. In adult males, the ln-choline was positively associated with ln-FEV1[ ß:0.018; 95%CI: (0.011,0.024)], ln-FVC [ ß:0.020; 95%CI: (0.014,0.026)], ln-PEF [ ß:0.014; 95%CI: (0.007,0.022)], ln-predicted FEV1% [ ß: 0.007; 95%CI: (0.001, 0.013)] and ln-predicted FVC%[ ß: 0.010; 95%CI: (0.005, 0.015)] and negatively associated with FENO [ ß: -0.029; 95%CI: (-0.049, -0.009)]. In unadjusted and partially adjusted models, adult females with ln-choline in the highest quartile had 25.2% (95%CI:9.4-38.3%) and 23.8% (95%CI:7.6-37.1%) decreased odds of asthma compared to those with the lowest quartile group. In the dose-response relationships of dietary choline and pulmonary inflammation and lung function indicators in adults, there existed threshold and saturation effects. CONCLUSION: The associations between dietary choline and lung function indicators such as FEV1 and FVC are positive in children and adults. The association between dietary choline and pulmonary inflammation is negative only in adults.

Risk of malignancy in thyroid nodules with increased 11C-Choline uptake detected incidentally on PET/CT: A diagnostic accuracy study.

PURPOSE: The purpose was to evaluate the pathological nature of focal thyroid uptake seen in 11C-Choline PET/CT performed for prostate cancer. MATERIAL AND METHODS: The study was IRB-approved. All 11C-Choline PET/CT exam reports for studies performed between January 01, 2018, and July 30, 2021, in male patients with prostate cancer in our institution were retrospectively reviewed. Exams with "focal thyroid uptake" on their final report were selected. Patients with surgery or ablation in the thyroid prior to the PET/CT, proven parathyroid adenomas or absent thyroid ultrasound were excluded. Repeated PET/CT exams of same patient were excluded. PET images were analyzed visually and semi-quantitatively by measuring the maximum standardized uptake value (SUVmax) of the focal thyroid uptake. Available thyroid ultrasound images, cytology and pathology reports were reviewed. Statistical analyses were performed. RESULTS: Out of 10,047 sequential 11C-Choline PET/CT studies, 318 reports included "focal thyroid uptake." About 128 of these studies were repeat exams and were excluded. Additional 87 patients were excluded, because the uptake was determined to be adjacent, rather than confined to the thyroid gland. Out of the remaining 103 patients, 74 patients had focal thyroid uptake and concurrent thyroid sonographic evaluation. Out of the 74 focal uptakes evaluated with ultrasound, 21 were presumed benign thyroid nodules based on the ultrasound and 53 had further evaluation with biopsy. Sixty three nodules were benign (21 presumed benign on ultrasound and 42 cytology or surgical pathology-proven), 9 nodules were malignant and 2 remained indeterminate. There was no significant difference between the SUVs of the benign and malignant groups (P > .3). CONCLUSION: In this retrospective study of patients with prostate cancer who underwent 11C-Choline PET/CT, we identified a group of patients who underwent thyroid ultrasound for incidental finding of focal 11C-Choline thyroid uptake. Incidence of malignancy in this group was 12%. Therefore, further investigation with ultrasound and possibly ultrasound-guided biopsy may be warranted when a choline avid thyroid nodule is found incidentally on choline PET.

Maternal Dietary Deficiency in Choline Reduced Levels of MMP-2 Levels in Blood and Brain Tissue of Male Offspring Mice.

Ischemic stroke is one of the leading causes of disability and death globally, with a rising incidence in younger age groups. It is well known that maternal diet during pregnancy and lactation is vital for the early neurodevelopment of offspring. One-carbon (1C) metabolism, including folic acid and choline, plays a vital role in closure of the neural tube in utero. However, the impact of maternal dietary deficiencies in 1C on offspring neurological function following ischemic stroke later in life remains undefined. The aim of this study was to investigate inflammation in the blood and brain tissue of offspring from mothers deficient in dietary folic acid or choline. Female mice were maintained on either a control or deficient diet prior to and during pregnancy and lactation. When offspring were 3 months of age, ischemic stroke was induced. One and a half months later, blood and brain tissue were collected. We measured levels of matrix metalloproteases (MMP)-2 and 9 in both plasma and brain tissue, and reported reduced levels of MMP-2 in ChDD male offspring in both tissue types. No changes were observed in MMP-9. This observation supports our working hypothesis that maternal dietary deficiencies in folic acid or choline during early neurodevelopment impact the levels of inflammation in offspring after ischemic stroke.

Dietary Choline Intake Is Beneficial for Cognitive Function and Delays Cognitive Decline: A 22-Year Large-Scale Prospective Cohort Study from China Health and Nutrition Survey.

Pre-clinical studies have discovered the neuroprotective function and the benefit for cognitive function of choline. However, it remains unclear whether these benefits observed in animal studies also work in humans. The aims of this study are to examine the effects of dietary choline intake on cognitive function and cognitive decline during ageing in middle-aged and elderly Chinese. We included 1887 subjects aged 55~79 years with 6696 observations from the China Health and Nutrition Survey cohort study. The subjects were followed up for 6 to 21 years, with an average of 12.2 years. A dietary survey was conducted over 3 consecutive days with a 24 h recall, using household weight-recording methods. Based on the China Food Composition, data from USDA, and published literature, the dietary choline intake was calculated as the sum of free choline, phosphocholine, phosphatidylcholine, sphingomyelin, and glycerophosphocholine. Cognitive function was assessed using a subset of the Telephone Interview for Cognitive Status-modified (TICS-m) items. In order to eliminate the different weight of scores in each domain, the scores were converted by dividing by the maximum score in each domain, which ranged from 0 to 3 points. Higher cognitive scores represented better cognition. We used two-level mixed effect models to estimate the effects of dietary choline intake on cognitive score and cognitive decline rate in males and females, respectively. The average dietary choline intake was 161.1 mg/d for the baseline. After adjusting for confounders, the dietary choline intake was significantly associated with higher cognitive score in both males and females. The cognitive score in the highest quartile group of dietary choline was 0.085 for males and 0.077 for females-higher than those in the lowest quartile group (p < 0.01 for males, p < 0.05 for females). For every 10-year increase in age, the cognitive score decreased by 0.266 for males and 0.283 for females. The cognitive score decline rate of the third quartile group of dietary choline was 0.125/10 years lower than that of the lowest quartile group in females (p < 0.05). Dietary choline intake not only improves cognitive function, but also postpones cognitive decline during the aging process. The findings of this study highlight the neuroprotective benefit of choline in the middle-aged and elderly Chinese population, especially among females.

Loss of Opi3 causes a lipid imbalance that influences the virulence traits of Cryptococcus neoformans but not cryptococcosis.

The basidiomycete fungus Cryptococcus neoformans is a useful model for investigating mechanisms of fungal pathogenesis in mammalian hosts. This pathogen is the causative agent of cryptococcal meningitis in immunocompromised patients and is in the critical priority group of the World Health Organization fungal priority pathogens list. In this study, we employed a mutant lacking the OPI3 gene encoding a methylene-fatty-acyl-phospholipid synthase to characterize the role of phosphatidylcholine (PC) and lipid homeostasis in the virulence of C. neoformans. We first confirmed that OPI3 was required for growth in nutrient limiting conditions, a phenotype that could be rescued with exogenous choline and PC. Additionally, we established that loss of Opi3 and the lack of PC lead to an accumulation of neutral lipids in lipid droplets and alterations in major lipid classes. The growth defect of the opi3Δ mutant was also rescued by sorbitol and polyethylene glycol (PEG), a result consistent with protection of ER function from the stress caused by lipid imbalance. We then examined the impact of Opi3 on virulence and found that the dependence of PC synthesis on Opi3 caused reduced capsule size and this was accompanied by an increase in shed capsule polysaccharide and changes in cell wall composition. Further tests of virulence demonstrated that survival in alveolar macrophages and the ability to cause disease in mice were not impacted by loss of Opi3 despite the choline auxotrophy of the mutant in vitro. Overall, this work establishes the contribution of lipid balance to virulence factor elaboration by C. neoformans and suggests that host choline is sufficient to support proliferation during disease.

Endometrial cancer risk stratification using MRI radiomics: corroborating with choline metabolism.

BACKGROUND AND PURPOSE: Radiomics offers little explainability. This study aims to develop a radiomics model (Rad-Score) using diffusion-weighted imaging (DWI) to predict high-risk patients for nodal metastasis or recurrence in endometrial cancer (EC) and corroborate with choline metabolism. MATERIALS AND METHODS: From August 2015 to July 2018, 356 EC patients were enrolled. Rad-Score was developed using LASSO regression in a training cohort (n = 287) and validated in an independent test cohort (n = 69). MR spectroscopy (MRS) was also used in 230 patients. Nuclear MRS measured choline metabolites in 70 tissue samples. The performance was compared against European Society for Medical Oncology (ESMO) risk groups. A P < .05 denoted statistical significance. RESULTS: Rad-Score achieved 71.1% accuracy in the training and 71.0% in the testing cohorts. Incorporating clinical parameters of age, tumor type, size, and grade, Rad-Signature reached accuracies of 73.2% in training and 75.4% in testing cohorts, closely matching the performance to the post-operatively based ESMO's 70.7% and 78.3%. Rad-Score was significantly associated with increased total choline levels on MRS (P = .034) and tissue levels (P = .019). CONCLUSIONS: Development of a preoperative radiomics risk score, comparable to ESMO clinical standard and associated with altered choline metabolism, shows translational relevance for radiomics in high-risk EC patients. TRIAL REGISTRATION: This study was registered in ClinicalTrials.gov on 2015-08-01 with Identifier NCT02528864.

Pro-atherogenic medical conditions are associated with widespread regional brain metabolite abnormalities in those with alcohol use disorder.

AIMS: Widespread brain metabolite abnormalities in those with alcohol use disorder (AUD) were reported in numerous studies, but the effects of the pro-atherogenic conditions of hypertension, type 2 diabetes mellitus, hepatitis C seropositivity, and hyperlipidemia on metabolite levels were not considered. These conditions were associated with brain metabolite abnormalities in those without AUD. We predicted treatment-seeking individuals with AUD and pro-atherogenic conditions (Atherogenic+) demonstrate lower regional metabolite markers of neuronal viability [N-acetylaspartate (NAA)] and cell membrane turnover/synthesis [choline-containing compounds (Cho)], compared with those with AUD without pro-atherogenic conditions (Atherogenic-) and healthy controls (CON). METHODS: Atherogenic+ (n = 59) and Atherogenic- (n = 51) and CON (n = 49) completed a 1.5 T proton magnetic resonance spectroscopic imaging study. Groups were compared on NAA, Cho, total creatine, and myoinositol in cortical gray matter (GM), white matter (WM), and select subcortical regions. RESULTS: Atherogenic+ had lower frontal GM and temporal WM NAA than CON. Atherogenic+ showed lower parietal GM, frontal, parietal and occipital WM and lenticular nuclei NAA level than Atherogenic- and CON. Atherogenic- showed lower frontal GM and WM NAA than CON. Atherogenic+ had lower Cho level than CON in the frontal GM, parietal WM, and thalamus. Atherogenic+ showed lower frontal WM and cerebellar vermis Cho than Atherogenic- and CON. CONCLUSIONS: Findings suggest proatherogenic conditions in those with AUD were associated with increased compromise of neuronal integrity and cell membrane turnover/synthesis. The greater metabolite abnormalities observed in Atherogenic+ may relate to increased oxidative stress-related compromise of neuronal and glial cell structure and/or impaired arterial vasoreactivity/lumen viability.

Influence of terahertz waves on the binding of choline to choline acetyltransferase: insights from molecular dynamics simulations.

Acetylcholine (Ach) is a common neurotransmitter in the central nervous system (CNS) and peripheral nervous system (PNS). It is one of the neurotransmitters in the autonomic nervous system and the main neurotransmitter in all autonomic ganglia. Experiments have confirmed that electromagnetic waves can affect the synthesis of animal neurotransmitters, but the microscopic effects of electromagnetic waves in the terahertz (THz) frequency band are still unclear. Based on density functional theory (DFT) and molecular dynamics (MD) simulation methods, this paper studies the effect of THz electromagnetic waves on the binding of choline to choline acetyltransferase (ChAT). By emitting THz waves that resonate with the characteristic vibration mode of choline near the active site, it was found that THz waves with a frequency of 45.3 THz affected the binding of choline to ChAT, especially the binding of the active site histidine His324 to choline. The main evidence is that under the action of THz waves, the binding free energy of choline to histidine His324 and ChAT at the active site was significantly reduced compared to noE, which may have a potential impact on the enzymatic synthesis of Ach. It is expected to achieve the purpose of regulating the synthesis of the neurotransmitter Ach under the action of THz waves and treat certain nervous system diseases.

Optimisation of acid hydrolysis conditions of choline esters and mass spectrometric determination of total choline in various foods.

Determining the content of the nutrient choline in foods and obtaining the required amount from the diet are crucial. One way to measure choline in foods is by converting choline esters to free choline via acid hydrolysis, followed by quantifying the total choline, as adopted by the AOAC method (AOAC-Choline); however, certain choline esters are difficult to hydrolyse. Here, we investigated various acid hydrolysis conditions to establish a reliable method for determining the total choline in foods by detecting free choline using highly sensitive and selective mass spectrometry. Hydrolysis in 0.055 mol/L HCl for 8 h in an autoclave (121 °C) was found to be optimal for the hydrolysis of choline esters in various foods. Twenty-four foods, including grains, seed, vegetables, fruits, mushroom, algae, fish, meats, beverage, processed foods, and egg, were measured. The trends in the total choline content were consistent with previous reports; however, the choline content was 10-20% higher than that measured using AOAC-Choline. Therefore, re-evaluation of the total choline content in foods using our constructed method is recommended. This reassessment will allow for a more reliable determination of choline intake for maintaining health.

Effects of dietary fish to rapeseed oil ratio on steatosis symptoms in Atlantic salmon (Salmo salar L) of different sizes.

Choline is recognized as an essential nutrient for Atlantic salmon at all developmental stages. However, its dietary requirement is not well defined. Choline plays a critical role in lipid transport, and the clearest deficiency sign is intestinal steatosis. The present work, aiming to find whether lipid source and fish size may affect steatosis symptoms, was one of a series of studies conducted to identify which production-related conditions may influence choline requirement. Six choline-deficient diets were formulated varying in ratios of rapeseed oil to fish oil and fed to Atlantic salmon of 1.5 and 4.5 kg. After eight weeks, somatic characteristics were observed, and the severity of intestinal steatosis was assessed by histological, biochemical, and molecular analyses. Fatty acid composition in pyloric intestine, mesenteric tissue, and liver samples was also quantified. The increasing rapeseed oil level increased lipid digestibility markedly, enhancing lipid supply to the fish. Moreover, small fish consumed more feed, and consequently had a higher lipid intake. In conclusion, the results showed that choline requirement depends on dietary lipid load, which depends on the fatty acid profile as well as the fish size.

Acetylcholine and choline in honey bee (Apis mellifera) worker brood food are seasonal and age-dependent.

Nursing honeybees produce brood food with millimolar concentrations of acetylcholine (ACh), which is synthesized through head gland secretions mixed with honey stomach contents. While we previously demonstrated the necessity of ACh for proper larval development, the dynamics of ACh levels throughout ontogenesis and their seasonal variations have remained unclear until now. Our HPLC analysis reveals dependencies of choline and ACh levels on larval development days (LDDs), influenced by seasonal (April-September) variations. Median ACh concentrations peak on LDD 2, declining significantly toward cell capping, while choline levels are lowest during the initial LDDs, rising markedly toward cell capping. Seasonal patterns show peak ACh levels from April to June and a low in August, paralleling choline's peak in July and low in August. This seasonality holds consistently across multiple years (2020-2022) and colonies, despite potential variations in colony performance and environmental conditions. Our analysis found no correlation between temperature, sunshine, precipitation, or favourable foraging days and ACh/choline levels, suggesting the involvement of additional factors. These findings underscore the seasonal fluctuation of ACh levels and its potential implications for the genetic programs governing winter bee development.

Functional roles of pantothenic acid, riboflavin, thiamine, and choline in adipocyte browning in chemically induced human brown adipocytes.

Brown fat is a therapeutic target for the treatment of obesity-associated metabolic diseases. However, nutritional intervention strategies for increasing the mass and activity of human brown adipocytes have not yet been established. To identify vitamins required for brown adipogenesis and adipocyte browning, chemical compound-induced brown adipocytes (ciBAs) were converted from human dermal fibroblasts under serum-free and vitamin-free conditions. Choline was found to be essential for adipogenesis. Additional treatment with pantothenic acid (PA) provided choline-induced immature adipocytes with browning properties and metabolic maturation, including uncoupling protein 1 (UCP1) expression, lipolysis, and mitochondrial respiration. However, treatment with high PA concentrations attenuated these effects along with decreased glycolysis. Transcriptome analysis showed that a low PA concentration activated metabolic genes, including the futile creatine cycle-related thermogenic genes, which was reversed by a high PA concentration. Riboflavin treatment suppressed thermogenic gene expression and increased lipolysis, implying a metabolic pathway different from that of PA. Thiamine treatment slightly activated thermogenic genes along with decreased glycolysis. In summary, our results suggest that specific B vitamins and choline are uniquely involved in the regulation of adipocyte browning via cellular energy metabolism in a concentration-dependent manner.

A methionine-choline-deficient diet induces nonalcoholic steatohepatitis and alters the lipidome, metabolome, and gut microbiome profile in the C57BL/6J mouse.

The methionine-choline-deficient (MCD) diet-induced non-alcoholic steatohepatitis (NASH) in mice is a well-established model. Our study aims to elucidate the factors influencing liver pathology in the MCD mouse model by examining physiological, biochemical, and molecular changes using histology, molecular techniques, and OMICS approaches (lipidomics, metabolomics, and metagenomics). Male C57BL/6J mice were fed a standard chow diet, a methionine-choline-sufficient (MCS) diet, or an MCD diet for 10 weeks. The MCD diet resulted in reduced body weight and fat mass, along with decreased plasma triglyceride, cholesterol, glucose, and insulin levels. However, it notably induced steatosis, inflammation, and alterations in gene expression associated with lipogenesis, inflammation, fibrosis, and the synthesis of apolipoproteins, sphingolipids, ceramides, and carboxylesterases. Lipid analysis revealed significant changes in plasma and tissues: most ceramide non-hydroxy-sphingosine lipids significantly decreased in the liver and plasma but increased in the adipose tissue of MCD diet-fed animals. Oxidized glycerophospholipids mostly increased in the liver but decreased in the adipose tissue of the MCD diet-fed group. The gut microbiome of the MCD diet-fed group showed an increase in Firmicutes and a decrease in Bacteroidetes and Actinobacteria. Metabolomic profiling demonstrated that the MCD diet significantly altered amino acid biosynthesis, metabolism, and nucleic acid metabolism pathways in plasma, liver, fecal, and cecal samples. LC-MS data indicated higher total plasma bile acid intensity and reduced fecal glycohyodeoxycholic acid intensity in the MCD diet group. This study demonstrates that although the MCD diet induces hepatic steatosis, the mechanisms underlying NASH in this model differ from those in human NASH pathology.

Enzymes of sphingolipid metabolism as transducers of metabolic inputs.

Sphingolipids (SLs) constitute a discrete subdomain of metabolism, and they display both structural and signaling functions. Accumulating evidence also points to intimate connections between intermediary metabolism and SL metabolism. Given that many SLs exhibit bioactive properties (i.e. transduce signals), these raise the possibility that an important function of SLs is to relay information on metabolic changes into specific cell responses. This could occur at various levels. Some metabolites are incorporated into SLs, whereas others may initiate regulatory or signaling events that, in turn, modulate SL metabolism. In this review, we elaborate on the former as it represents a poorly appreciated aspect of SL metabolism, and we develop the hypothesis that the SL network is highly sensitive to several specific metabolic changes, focusing on amino acids (serine and alanine), various fatty acids, choline (and ethanolamine), and glucose.

Choline and geranate ionic liquid for subgingival biofilm control.

Periodontitis is a chronic inflammatory disease that causes destruction of the periodontium and eventual tooth loss. The priority in the periodontal treatment is to remove the subgingival biofilm. Chemical removal of biofilms using antimicrobial agents has been applied in clinical practice. However, their clinical effect is still limited because the agents must overcome biofilm's significant drug tolerance, which is primarily caused by the extracellular matrix, a physical barrier that attenuates drug diffusion. This study aimed to study the use of ionic liquids (ILs), a new class of biocompatible materials, for controlling subgingival biofilms because of their excellent permeability. Choline and geranate (CAGE) IL was tested for its highly potent antiseptic behavior and permeability. Antibacterial tests revealed that the significant efficacy of CAGE against periodontopathic microorganisms was derived from their ability to destroy cell membrane, as demonstrated by membrane permeability assay and transmission electron microscopy imaging. Antibiofilm tests using two pathogenic biofilm models revealed that CAGE exerted efficacy against the biofilm-embedded bacteria, conspicuously neutralized the biofilms, and eventually destroyed the biofilm structure. Furthermore, the penetration of CAGE into the biofilm was visually confirmed using confocal laser scanning microscopy. This study highlighted the potential of CAGE as a powerful antibiofilm therapeutic.

Homocysteine contributes to atherogenic transformation of the aorta in rabbits in the absence of hypercholesterolemia.

Atherosclerosis, the leading cause of cardiovascular disease, cannot be sufficiently explained by established risk factors, including cholesterol. Elevated plasma homocysteine (Hcy) is an independent risk factor for atherosclerosis and is closely linked to cardiovascular mortality. However, its role in atherosclerosis has not been fully clarified yet. We have previously shown that rabbits fed a diet deficient in B vitamins and choline (VCDD), which are required for Hcy degradation, exhibit an accumulation of macrophages and lipids in the aorta, aortic stiffening and disorganization of aortic collagen in the absence of hypercholesterolemia, and an aggravation of atherosclerosis in its presence. In the current study, plasma Hcy levels were increased by intravenous injections of Hcy into balloon-injured rabbits fed VCDD (VCDD+Hcy) in the absence of hypercholesterolemia. While this treatment did not lead to thickening of aortic wall, intravenous injections of Hcy into rabbits fed VCDD led to massive accumulation of VLDL-triglycerides as well as significant impairment of vascular reactivity of the aorta compared to VCDD alone. In the aorta intravenous Hcy injections into VCDD-fed rabbits led to fragmentation of aortic elastin, accumulation of elastin-specific electron-dense inclusions, collagen disorganization, lipid degradation, and autophagolysosome formation. Furthermore, rabbits from the VCDD+Hcy group exhibited a massive decrease of total protein methylated arginine in blood cells and decreased creatine in blood cells, serum and liver compared to rabbits from the VCDD group. Altogether, we conclude that Hcy contributes to atherogenic transformation of the aorta not only in the presence but also in the absence of hypercholesterolemia.

Diffusion magnetic resonance spectroscopy captures microglial reactivity related to gut-derived systemic lipopolysaccharide: A preliminary study.

Neuroinflammation is a key component underlying multiple neurological disorders, yet non-invasive and cost-effective assessment of in vivo neuroinflammatory processes in the central nervous system remains challenging. Diffusion weighted magnetic resonance spectroscopy (dMRS) has shown promise in addressing these challenges by measuring diffusivity properties of different neurometabolites, which can reflect cell-specific morphologies. Prior work has demonstrated dMRS utility in capturing microglial reactivity in the context of lipopolysaccharide (LPS) challenges and serious neurological disorders, detected as changes of microglial metabolite diffusivity properties. However, the extent to which such dMRS metrics are capable of detecting subtler and more nuanced levels of neuroinflammation in populations without overt neuropathology is unknown. Here we examined the relationship between intrinsic, gut-derived levels of systemic LPS and dMRS-based apparent diffusion coefficients (ADC) of choline, creatine, and N-acetylaspartate (NAA) in two brain regions: the thalamus and the corona radiata. Higher plasma LPS concentrations were significantly associated with increased ADC of choline and NAA in the thalamic region, with no such relationships observed in the corona radiata for any of the metabolites examined. As such, dMRS may have the sensitivity to measure microglial reactivity across populations with highly variable levels of neuroinflammation, and holds promising potential for widespread applications in both research and clinical settings.