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Production of trimethylamine-N-oxide (TMAO), a biomarker of CVD risk, is dependent on intestinal microbiota, but little is known of dietary conditions promoting changes in gut microbial communities. Resistant starches (RS) alter the human microbiota. We sought to determine whether diets varying in RS and carbohydrate (CHO) content affect plasma TMAO levels. We also assessed postprandial glucose and insulin responses and plasma lipid changes to diets high and low in RS. In a cross-over trial, fifty-two men and women consumed a 2-week baseline diet (41 percentage of energy (%E) CHO, 40 % fat, 19 % protein), followed by 2-week high- and low-RS diets separated by 2-week washouts. RS diets were assigned at random within the context of higher (51–53 %E) v. lower CHO (39–40 %E) intake. Measurements were obtained in the fasting state and, for glucose and insulin, during a meal test matching the composition of the assigned diet. With lower CHO intake, plasma TMAO, carnitine, betaine and γ-butyrobetaine concentrations were higher after the high- v. low-RS diet (P<0·01 each). These metabolites were not differentially affected by high v. low RS when CHO intake was high. Although the high-RS meal reduced postprandial insulin and glucose responses when CHO intake was low (P<0·01 each), RS did not affect fasting lipids, lipoproteins, glucose or insulin irrespective of dietary CHO content. In conclusion, a lower-CHO diet high in RS was associated with higher plasma TMAO levels. These findings, together with the absence of change in fasting lipids, suggest that short-term high-RS diets do not improve markers of cardiometabolic health.

Background: Trimethylamine-N-oxide (TMAO), a choline-derived gut microbiota-dependent metabolite, is a newly recognized risk marker for cardiovascular disease. We sought to determine: (1) TMAO response to meals containing free versus lipid-soluble choline and (2) effects of gut microbiome on TMAO response. Methods: In a randomized, controlled, double-blinded, crossover study, healthy men (n = 37) were provided meals containing 600 mg choline either as choline bitartrate or phosphatidylcholine, or no choline control. Results: Choline bitartrate yielded three-times greater plasma TMAO AUC (p = 0.01) and 2.5-times greater urinary TMAO change from baseline (p = 0.01) compared to no choline and phosphatidylcholine. Gut microbiota composition differed (permutational multivariate analysis of variance, PERMANOVA; p = 0.01) between high-TMAO producers (with ≥40% increase in urinary TMAO response to choline bitartrate) and low-TMAO producers (with <40% increase in TMAO response). High-TMAO producers had more abundant lineages of Clostridium from Ruminococcaceae and Lachnospiraceae compared to low-TMAO producers (analysis of composition of microbiomes, ANCOM; p < 0.05). Conclusion: Given that phosphatidylcholine is the major form of choline in food, the absence of TMAO elevation with phosphatidylcholine counters arguments that phosphatidylcholine should be avoided due to TMAO-producing characteristics. Further, development of individualized dietary recommendations based on the gut microbiome may be effective in reducing disease risk

Background/Objectives: Trimethylamine N-oxide (TMAO), a gut microbiota-derived metabolite from L-carnitine and choline (abundant in meat and eggs), is linked to CVD and T2D. This study investigated whether TMAO responses to animal-based foods differ between individuals with and without metabolic syndrome (MetS), in relation to their gut microbiota composition. Subjects/Methods: In a randomized crossover trial, 12 MetS (≥3 criteria according to the Adult Treatment Panel III: elevated waist circumference, fasting glucose, triglycerides, and blood pressure or reduced HDL cholesterol) and 21 non-MetS subjects consumed two test meals (3 hard-boiled eggs or 170 g meat balls) after overnight fasting, with ≥1-week washout. Blood was collected at baseline and 0.5, 1, 2, 4, and 6 h postprandially; urine was collected over 6 h. Fecal samples (collected pre-first day of intervention) underwent 16S rRNA sequencing. Plasma and urinary TMAO, TMA, choline, and carnitine were quantified using UPLC-MS/MS. Results: MetS subjects exhibited a non-significant trend towards higher incremental AUCs for plasma TMA, TMAO, choline, and carnitine after consuming both foods, with a 30–50% higher urinary TMAO excretion (but similar for TMA) versus non-MetS subjects. This exploratory analysis also indicated that MetS subjects had reduced gut microbial diversity, featuring decreased Blautia glucerasea (butyrate producer) and increased Ruminococcus torques (pro-inflammatory), a profile associated with inflammation but not TMA production. Conclusion: No significant increase in plasma methylamines after choline and carnitine challenge was observed in subjects with MetS compared with non-MetS. In MetS subjects (without CVD and T2D), gut microbiota composition was characterized by increased pro-inflammatory bacteria rather than TMAO-generating bacteria. The lack of statistical significance with regard to plasma TMAO response could be due to an insufficient sample size rather than the absence of an effect. Nevertheless, the observed elevation might still be clinically relevant, supported by concurrent differences in microbiota composition. These preliminary findings warrant validation in larger cohorts due to sample size limitations.

Background The microbiota-gut-brain (MGB) axis is implicated in Alzheimer’s disease (AD), but evidence for interventional strategies targeting this axis remains limited. Methods In a 24-week, single-blind, randomized controlled trial, 84 individuals with mild cognitive impairment (MCI) or mild AD received either computerized cognitive training (CCT) or treatment as usual (TAU). Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) was the primary outcome. We also assessed functional connectivity (fNIRS), plasma trimethylamine N-oxide (TMAO) levels, and gut microbiota at baseline and 24 weeks. Results Seventy-four participants completed the study. The CCT group showed significant improvement in ADAS-cog scores compared to controls ( Cohen’s d  = 1.57 by week 24). Notably, CCT also induced a distinct reorganization of prefrontal functional connectivity and significantly reduced plasma TMAO levels. Microbiome analysis revealed that CCT mitigated the expansion of Ruminococcus torques group ( R.torques ), which was observed in the control group. Crucially, R.torques was the only genus significantly correlated with improvements in cognition (ADAS-cog, r  = 0.407), neuropsychiatric symptoms (NPI, r  = 0.395), TMAO reduction ( r  = 0.443), and functional connectivity changes ( r  = 0.449). Conclusion A 24-week CCT program improves cognitive function in MCI and mild AD, potentially through downregulating the R.torques -TMAO pathway within the MGB axis. This pathway represents a promising novel target for multi-domain intervention in AD.

Trimethylamine N-oxide (TMAO) is considered a novel risk factor for cardiovascular diseases. Several studies demonstrated that polyphenols are able to inhibit the growth of TMA-producing bacterial strains, and resveratrol (RSV) reduced TMAO levels in mice. In the present study, we evaluated the TMAO-reducing effect of a novel nutraceutical formulation containing grape pomace extract in humans (Taurisolo®). The Taurisolo® polyphenol content was evaluated by a High Performance Liquid Chromatography-diode-array detector (HPLC-DAD) method, and RSV was monitored as an indicative marker. After in vitro GI digestion, intestinal bioaccessibility of RSV was 92.3%. A randomized, placebo-controlled, cross-over trial was carried out to evaluate the TMAO-reducing effect of Taurisolo®. In acute, the maximum levels of RSV were detected both in serum and whole blood 60 min after the administration of Taurisolo®; in chronic, a significant increase of RSV was detected in serum after the 4-week treatment. After 4 weeks, the levels of TMAO were significantly decreased in the treatment group compared to placebo (63.6% vs. 0.54%, respectively, P < 0.0001). In conclusion, our data show that Taurisolo® may represent a novel and useful natural remedy to reduce prognostic markers for incident cardiovascular events. Undoubtedly, further in vitro and in vivo studies need to be performed in order to elucidate possible mechanisms of action and corroborate our preliminary results.

Objectives: This study aimed to evaluate the association between adherence to the Mediterranean diet and blood trimethylamine-N-oxide (TMAO) levels. Methods: This randomized clinical trial enrolled 53 healthy adults with normal or overweight body mass index (BMI) who were recruited from a cardiology outpatient clinic in Istanbul, Turkey. Dietary patterns and Mediterranean diet adherence (assessed using the MEDAS) were evaluated alongside anthropometric and biochemical parameters, including fasting glucose, total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides, alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Twenty individuals with low adherence underwent a 4-week Mediterranean dietary intervention with daily dietary monitoring. To assess changes, pre- and postintervention data were compared. Results: The results revealed that individuals adhering to the Mediterranean diet exhibited significantly lower blood TMAO levels (p < 0.001). In males, total cholesterol, LDL, triglyceride, and ALT levels significantly decreased compared with those at baseline (p < 0.05), whereas fasting blood glucose, HDL, and AST levels showed no significant changes (p > 0.05). In females, only blood TMAO levels exhibited significant reduction, with no other biochemical parameters indicating significant differences (p > 0.05). Additionally, males demonstrated significant improvements in anthropometric measures, including weight, BMI, fat mass, muscle mass, waist, and hip circumference, compared with pre-intervention values (p < 0.05), whereas females exhibited no significant changes in these measures (p > 0.05). Conclusions: Our findings demonstrate that implementing the Mediterranean diet in individuals with initially low adherence causes significantly reduced blood TMAO levels even within a short intervention period of 4 weeks.

Accumulating evidence linking trimethylamine N-oxide (TMAO) to cardiovascular disease (CVD) risk has prompted interest in developing therapeutic strategies to reduce its production. We compared two lifestyle intervention approaches: hypocaloric versus eucaloric diet, combined with exercise, on TMAO levels in relation to CVD risk factors. Sixteen obese adults (66.1 ± 4.4 years, BMI (body mass index): 35.9 ± 5.3 kg/m2, fasting glucose: 106 ± 16 mg/dL, 2-h PPG (postprandial glucose): 168 ± 37 mg/dL) were randomly assigned to 12 weeks of exercise (5 days/week, 80–85% HRmax (maximal heart rate)) plus either a hypocaloric (HYPO) (−500 kcal) or a eucaloric (EU) diet. Outcomes included plasma TMAO, glucose metabolism (oral glucose tolerance test (OGTT) and euglycemic-hyperinsulinemic clamps for glucose disposal rates (GDR)), exercise capacity (VO2max, maximal oxygen consumption), abdominal adiposity (computed tomography scans), cholesterol, and triglycerides. Results showed that body composition (body weight, subcutaneous adiposity), insulin sensitivity, VO2max, and cholesterol all improved (p < 0.05). HYPO decreased the percentage change in TMAO compared to an increase after EU (HYPO: −31 ± 0.4% vs. EU: 32 ± 0.6%, p = 0.04). Absolute TMAO levels were not impacted (HYPO: p = 0.09 or EU: p = 0.53 group). The change in TMAO after intervention was inversely correlated with baseline visceral adipose tissue (r = −0.63, p = 0.009) and GDR (r = 0.58, p = 0.002). A hypocaloric diet and exercise approach appears to be effective in reducing TMAO. Larger trials are needed to support this observation.

Components present in the diet, l -carnitine, choline, and betaine are metabolized by gut microbiota to produce metabolites such as trimethylamine- N -oxide (TMAO) that appear to promote cardiovascular disease in chronic kidney disease (CKD) patients. The objective of this pilot study was to evaluate the effects of probiotic supplementation for 3 months on plasma TMAO levels in CKD patients on hemodialysis (HD). A randomized, double-blind trial was performed in 21 patients [54.8 ± 10.4 years, nine men, BMI 26.1 ± 4.8 kg/m 2 , dialysis vintage 68.5 (34.2–120.7) months]. Ten patients were randomly allocated to the placebo group and 11 to the probiotic group [three capsules, totaling 9 × 10 13 colony-forming units per day of Streptococcus thermophilus ( KB19 ), Lactobacillus acidophilus ( KB27 ), and Bifidobacteria longum ( KB31 ). Plasma TMAO, choline, and betaine levels were measured by LC-MS/MS at baseline and after 3 months. While TMAO did not change after probiotic supplementation, there was a significant increase in betaine plasma levels. In contrast, the placebo group showed a significant decrease in plasma choline levels. Short-term probiotic supplementation does not appear to influence plasma TMAO levels in HD patients. Long-term studies are needed to determine whether probiotics may affect TMAO production in CKD patients.

The gut, microflora-dependent metabolite trimethylamine-N-oxide (TMAO) has emerged as a dietary-associated risk factor for incident cardiovascular events. Chronic obstructive pulmonary disease (COPD) is a prevalent disease worldwide with a high associated risk for cardiovascular disease and death due to an infectious cause. To study whether TMAO is predictive for adverse clinical outcomes in patients with exacerbated COPD. A total of 189 patients with COPD exacerbation were prospectively followed for a median of 6.1 y. TMAO plasma levels at the time of emergency department admission were measured by liquid chromatography coupled with tandem mass spectrometry. Cox and linear regression models were used to investigate associations of TMAO with all-cause mortality and different comorbidities. All-cause mortality was 55.6% after 6 y. The deceased patients showed significantly higher median admission TMAO (μmol/L) levels compared with survivors (3.9 [interquartile range: 2.3–7.1] versus 2.9 [interquartile range: 1.8–4.7]; P = 0.01), which resulted in an unadjusted hazard ratio of 1.8 ([95% confidence interval: 1.2–3.0], P = 0.01). This association was no longer significant after multivariate adjustment. Median TMAO levels were similar in nonpneumonic and pneumonic COPD exacerbation. Higher age, higher body mass index, diabetes mellitus, and chronic kidney disease were predictors for increased plasma TMAO levels in linear regression analysis. Increased circulating TMAO levels per se were associated with long-term all-cause mortality in patients with COPD independent of type of exacerbation. However, this association was largely explained by comorbidities and age. Whether TMAO levels can additionally be influenced by nutritional interventions should be addressed in future studies. •The gut, microflora-dependent metabolite trimethylamine-N-oxide (TMAO) is associated with mortality in patients with chronic obstructive pulmonary disease.•The prognostic value of TMAO was independent of type of exacerbation.•Comorbidities and age had a strong influence on TMAO levels.•Whether nutritional interventions influence TMAO warrants further investigation.

Higher dietary protein intake is increasingly recommended for the elderly; however, high protein diets have also been linked to increased cardiovascular disease (CVD) risk. Trimethylamine-N-oxide (TMAO) is a bacterial metabolite derived from choline and carnitine abundant from animal protein-rich foods. TMAO may be a novel biomarker for heightened CVD risk. The purpose of this study was to assess the impact of a high protein diet on TMAO. Healthy men (74.2 ± 3.6 years, n = 29) were randomised to consume the recommended dietary allowance of protein (RDA: 0.8 g protein/kg bodyweight/day) or twice the RDA (2RDA) as part of a supplied diet for 10 weeks. Fasting blood samples were collected pre- and post-intervention for measurement of TMAO, blood lipids, glucose tolerance, insulin sensitivity, and inflammatory biomarkers. An oral glucose tolerance test was also performed. In comparison with RDA, the 2RDA diet increased circulatory TMAO (p = 0.002) but unexpectedly decreased renal excretion of TMAO (p = 0.003). LDL cholesterol was increased in 2RDA compared to RDA (p = 0.049), but no differences in other biomarkers of CVD risk and insulin sensitivity were evident between groups. In conclusion, circulatory TMAO is responsive to changes in dietary protein intake in older healthy males.