Association of the Chronotype Score with Circulating Trimethylamine N-Oxide (TMAO) Concentrations

Individual differences in the chronotype, an attitude that best expresses the individual circadian preference in behavioral and biological rhythms, have been associated with cardiometabolic risk and gut dysbiosis. Up to now, there are no studies evaluating the association between chronotypes and circulating TMAO concentrations, a predictor of cardiometabolic risk and a useful marker of gut dysbiosis. In this study population (147 females and 100 males), subjects with the morning chronotype had the lowest BMI and waist circumference (p < 0.001), and a better metabolic profile compared to the other chronotypes. In addition, the morning chronotype had the highest adherence to the Mediterranean diet (p < 0.001) and the lowest circulating TMAO concentrations (p < 0.001). After adjusting for BMI and adherence to the Mediterranean diet, the correlation between circulating TMAO concentrations and chronotype score was still kept (r = −0.627, p < 0.001). Using a linear regression analysis, higher chronotype scores were mostly associated with lower circulating TMAO concentrations (β = −0.479, t = −12.08, and p < 0.001). Using a restricted cubic spline analysis, we found that a chronotype score ≥59 (p < 0.001, R² = −0.824) demonstrated a more significant inverse linear relationship with circulating TMAO concentrations compared with knots <59 (neither chronotype) and <41 (evening chronotype). The current study reported the first evidence that higher circulating TMAO concentrations were associated with the evening chronotype that, in turn, is usually linked to an unhealthy lifestyle mostly characterized by low adherence to the MD.     

Egg n-3 Fatty Acid Composition Modulates Biomarkers of Choline Metabolism in Free-Living Lacto-Ovo-Vegetarian Women of Reproductive Age

The lacto-ovo-vegetarian (LOV) dietary regimen allows eggs, which are a rich source of choline. Consumption of eggs by LOV women may be especially important during pregnancy and lactation when demand for choline is high. The aim of this single blind, randomized, crossover-feeding study was to determine how near-daily egg consumption influenced biomarkers of choline metabolism in healthy LOV women of reproductive age (n=15). Because long-chain n-3 fatty acids could influence choline metabolism, the effect of n-3–enriched vs nonenriched eggs on choline metabolites was also investigated. Three 8-week dietary treatments consisting of six n-3–enriched eggs per week, six nonenriched eggs per week, and an egg-free control phase were separated by 4-week washout periods. Choline metabolites were quantified in fasted plasma collected before and after each treatment and differences in posttreatment choline metabolite concentrations were determined with linear mixed models. The n-3–enriched and nonenriched egg treatments produced different choline metabolite profiles compared with the egg-free control; however, response to the eggs did not differ (P>0.1). Consumption of the n-3–enriched egg treatment yielded higher plasma free choline (P=0.02) and betaine (P<0.01) (vs egg-free control) concentrations, whereas consumption of the nonenriched egg treatment yielded borderline higher (P=0.06) plasma phosphatidylcholine (vs egg-free control) levels. Neither egg treatment increased levels of plasma trimethylamine oxide, a gut-flora–dependent oxidative choline metabolite implicated as a possible risk factor for cardiovascular disease. Overall these data suggest that egg fatty-acid composition modulates the metabolic use of choline.     

Toxic trace elements at gastrointestinal level

Many trace elements are considered essential [iron (Fe), zinc (Zn), copper (Cu)], whereas others may be harmful [lead (Pb), cadmium (Cd), mercury (Hg), arsenic (As)], depending on their concentration and chemical form. In most cases, the diet is the main pathway by which they enter our organism. The presence of toxic trace elements in food has been known for a long time, and many of the food matrices that carry them have been identified. This has led to the appearance of legislation and recommendations concerning consumption. Given that the main route of exposure is oral, passage through the gastrointestinal tract plays a fundamental role in their entry into the organism, where they exert their toxic effect. Although the digestive system can be considered to be of crucial importance in their toxicity, in most cases we do not know the events that occur during the passage of these elements through the gastrointestinal tract and of ascertaining whether they may have some kind of toxic effect on it. The aim of this review is to summarize available information on this subject, concentrating on the toxic trace elements that are of greatest interest for organizations concerned with food safety and health: Pb, Cd, Hg and As.     

Intestinal microbial metabolism of phosphatidylcholine: a novel insight in the cardiovascular risk scenario

Intestinal microbiota is a “dynamic organ” influencing host metabolism, nutrition, physiology and immune system. Among its several interactions, the role of a phosphatidylcholine metabolite derived by gut flora activity, i.e., trimethylamine-N-oxide (TMAO), allows perceiving a novel insight in the cardiovascular risk scenario, being a strong predictor of this condition. Based on current reports, including the paper of Tang et al., we describe here: the possible role of intestinal microbiota in cardiovascular risk as well as potential interventions to reduce gut flora TMAO production by diet, probiotics and antibiotics. Finally, we highlight the possibility of evaluating, monitoring and modulating TMAO in order to use its serum levels as a marker of cardiovascular risk in the next future, when the need of controlled studies on large series will be satisfied.     

Archaebiotics

Trimethylamine (TMA) is produced by gut bacteria from dietary ingredients. In individuals with a hereditary defect in flavin-containing monooxygenase 3, bacterial TMA production is believed to contribute to the symptoms of trimethylaminuria (TMAU; fish-odor syndrome). Intestinal microbiota TMA metabolism may also modulate atherosclerosis risk by affecting trimethylamine oxide (TMAO) production levels. We propose that reducing TMA formation in the gut by converting it to an inert molecule could be used to prevent or limit these human diseases, while avoiding the major drawbacks of other clinical interventions. Reducing TMA levels by microbiological interventions could also be helpful in some vaginoses. Particular members of a recently discovered group of methanogens, that are variably present in the human gut, are unusual in being apparently restricted to utilizing only methyl compounds including TMA as substrates. We confirmed experimentally that one of these strains tested, Methanomassiliicoccus luminyensis B10, is able to deplete TMA, by reducing it with H₂ for methanogenesis. We therefore suggest that members of this archaeal lineage could be used as treatments for metabolic disorders.     

肠道菌群代谢物TMAO对糖尿病冠状动脉钙化的预测价值

目的探讨肠道菌群代谢物氧化三甲胺(TMAO)对糖尿病冠状动脉钙化的预测价值。方法选取行冠状动脉造影(CTA)的2型糖尿病患者为研究对象,根据Agatston钙化积分评分将其分为无钙化组、轻度钙化组、中度钙化组、重度钙化组。检测各组患者血清空腹血糖(FPG)、糖化血红蛋白(HbA1c)、总胆固醇(TC)、低密度脂蛋白(LDL)、TMAO水平。采用多元线性回归模型分析冠状动脉钙化的影响因素,通过受试者工作特征(ROC)曲线分析TMAO对冠状动脉钙化的预测价值。结果各组患者糖尿病病程、LDL、TMAO水平比较,差异有显著性(P＜0.05)。糖尿病病程、LDL、TMAO是冠状动脉钙化的影响因素;糖尿病患者冠状动脉钙化程度与血清TMAO浓度呈正相关(P＜0.05);ROC曲线下面积为0.80。结论糖尿病患者血清TMAO与冠状动脉钙化程度有关,可作为预测冠状动脉钙化的指标。     

Gut Microbial Signatures of Distinct Trimethylamine N-Oxide Response to Raspberry Consumption

The aim of this exploratory study was to evaluate the gut microbial signatures of distinct trimethylamine N-oxide (TMAO) responses following raspberry consumption. Investigations were carried out in 24 subjects at risk of developing metabolic syndrome who received 280 g/day of frozen raspberries for 8 weeks. Blood and stool samples were collected at weeks 0 and 8. Inter-individual variability in plasma TMAO levels was analyzed, 7 subjects were excluded due to noninformative signals and 17 subjects were kept for analysis and further stratified according to their TMAO response. Whole-metagenome shotgun sequencing analysis was used to determine the impact of raspberry consumption on gut microbial composition. Before the intervention, the relative abundance of Actinobacteriota was significantly higher in participants whose TMAO levels increased after the intervention (p = 0.03). The delta TMAO (absolute differences of baseline and week 8 levels) was positively associated with the abundance of gut bacteria such as Bilophila wadsworthia (p = 0.02; r² = 0.37), from the genus Granulicatella (p = 0.03; r² = 0.48) or the Erysipelotrichia class (p = 0.03; r² = 0.45). Changes in the gut microbial ecology induced by raspberry consumption over an 8-week period presumably impacted quaternary amines-utilizing activity and thus plasma TMAO levels.     

Metabolic profiling studies on the toxicological effects of realgar in rats by H NMR spectroscopy

The toxicological effects of realgar after intragastrical administration (1 g/kg body weight) were investigated over a 21 day period in male Wistar rats using metabonomic analysis of ¹H NMR spectra of urine, serum and liver tissue aqueous extracts. Liver and kidney histopathology examination and serum clinical chemistry analyses were also performed. ¹H NMR spectra and pattern recognition analyses from realgar treated animals showed increased excretion of urinary Kreb's cycle intermediates, increased levels of ketone bodies in urine and serum, and decreased levels of hepatic glucose and glycogen, as well as hypoglycemia and hyperlipoidemia, suggesting the perturbation of energy metabolism. Elevated levels of choline containing metabolites and betaine in serum and liver tissue aqueous extracts and increased serum creatine indicated altered transmethylation. Decreased urinary levels of trimethylamine-N-oxide, phenylacetylglycine and hippurate suggested the effects on the gut microflora environment by realgar. Signs of impairment of amino acid metabolism were supported by increased hepatic glutamate levels, increased methionine and decreased alanine levels in serum, and hypertaurinuria. The observed increase in glutathione in liver tissue aqueous extracts could be a biomarker of realgar induced oxidative injury. Serum clinical chemistry analyses showed increased levels of lactate dehydrogenase, aspartate aminotransferase, and alkaline phosphatase as well as increased levels of blood urea nitrogen and creatinine, indicating slight liver and kidney injury. The time-dependent biochemical variations induced by realgar were achieved using pattern recognition methods. This work illustrated the high reliability of NMR-based metabonomic approach on the study of the biochemical effects induced by traditional Chinese medicine.     

Metabolomic analysis of prostate cancer risk in a prospective cohort: The alpha‐tocopherol,beta‐carotene cancer prevention (ATBC) study

Despite decades of concerted epidemiological research, relatively little is known about the etiology of prostate cancer. As genome‐wide association studies have identified numerous genetic variants, so metabolomic profiling of blood and other tissues represents an agnostic, “broad‐spectrum” approach for examining potential metabolic biomarkers of prostate cancer risk. To this end, we conducted a prospective analysis of prostate cancer within the Alpha‐Tocopherol, Beta‐Carotene Cancer Prevention Study cohort based on 200 cases (100 aggressive) and 200 controls (age‐ and blood collection date‐matched) with fasting serum collected up to 20 years prior to case diagnoses. Ultrahigh performance liquid chromatography/mass spectroscopy and gas chromatography/mass spectroscopy identified 626 compounds detected in >95% of the men and the odds ratio per 1‐standard deviation increase in log‐metabolite levels and risk were estimated using conditional logistic regression. We observed strong inverse associations between energy and lipid metabolites and aggressive cancer (p = 0.018 and p = 0.041, respectively, for chemical class over‐representation). Inositol‐1‐phosphate showed the strongest association (OR = 0.56, 95% CI = 0.39–0.81, p = 0.002) and glycerophospholipids and fatty acids were heavily represented; e.g., oleoyl‐linoleoyl‐glycerophosphoinositol (OR = 0.64, p = 0.004), 1‐stearoylglycerophosphoglycerol (OR=0.65, p = 0.025), stearate (OR=0.65, p = 0.010) and docosadienoate (OR = 0.66, p = 0.014). Both alpha‐ketoglutarate and citrate were associated with aggressive disease risk (OR = 0.69, 95% CI = 0.51–0.94, p = 0.02; OR = 0.69, 95% CI = 0.50–0.95, p = 0.02), as were elevated thyroxine and trimethylamine oxide (OR = 1.65, 95% CI = 1.08–2.54, p = 0.021; and OR = 1.36, 95% CI = 1.02–1.81, p = 0.039). Serum PSA adjustment did not alter the findings. Our data reveal several metabolomic leads that may have pathophysiological relevance to prostate carcinogenesis and should be examined through additional research.