Trimethylamine-N-oxide (TMAO) is the main diet-induced metabolite produced by the gut microbiota, and it is mainly eliminated through renal excretion. TMAO has been correlated with an increased risk of atherosclerotic cardiovascular disease (ASCVD) and related complications, such as cardiovascular mortality or major adverse cardiovascular events (MACE). Meta-analyses have postulated that high circulating TMAO levels are associated with an increased risk of cardiovascular events and all-cause mortality, but the link between TMAO and CVD remains not fully consistent. The results of prospective studies vary depending on the target population and the outcome studied, and the adjustment for renal function tends to decrease or reverse the significant association between TMAO and the outcome studied, strongly suggesting that the association is substantially mediated by renal function. Importantly, one Mendelian randomization study did not find a significant association between genetically predicted higher TMAO levels and cardiometabolic disease, but another found a positive causal relationship between TMAO levels and systolic blood pressure, which—at least in part—could explain the link with renal function. The mechanisms by which TMAO can increase this risk are not clearly elucidated, but current evidence indicates that TMAO induces cholesterol metabolism alterations, inflammation, endothelial dysfunction, and platelet activation. Overall, there is no fully conclusive evidence that TMAO is a causal factor of ASCVD, and, especially, whether TMAO induces or just is a marker of hypertension and renal dysfunction requires further study.

Background: Recently developed blood markers for Alzheimer's disease (AD) detection have high accuracy but usually require ultra-sensitive analytic tools not commonly available in clinical laboratories, and their performance in clinical practice is unknown. Methods: We analyzed plasma samples from 290 consecutive participants that underwent lumbar puncture in routine clinical practice in a specialized memory clinic (66 cognitively unimpaired, 130 participants with mild cognitive impairment, and 94 with dementia). Participants were classified as amyloid positive (A +) or negative (A-) according to CSF Aβ_1–42/Aβ_1–40 ratio. Plasma pTau₂₁₇, pTau₁₈₁, Aβ_1–42 and Aβ_1–40 were measured in the fully-automated LUMIPULSE platform. We used linear regression to compare plasma biomarkers concentrations between A + and A- groups, evaluated Spearman’s correlation between plasma and CSF and performed ROC analyses to assess their diagnostic accuracy to detect brain amyloidosis as determined by CSF Aβ_1–42/Aβ_1–40 ratio. We analyzed the concordance of pTau₂₁₇ with CSF amyloidosis. Results: Plasma pTau₂₁₇ and pTau₁₈₁ concentration were higher in A + than A- while the plasma Aβ_1–42/Aβ_1–40 ratio was lower in A + compared to A-. pTau₁₈₁ and the Aβ_1–42/Aβ_1–40 ratio showed moderate correlation between plasma and CSF (Rho = 0.66 and 0.69, respectively). The areas under the ROC curve to discriminate A + from A- participants were 0.94 (95% CI 0.92–0.97) for pTau₂₁₇, and 0.88 (95% CI 0.84–0.92) for both pTau₁₈₁ and Aβ_1–42/Aβ_1–40. Chronic kidney disease (CKD) was related to increased plasma biomarker concentrations, but ratios were less affected. Plasma pTau₂₁₇ had the highest fold change (× 3.2) and showed high predictive capability in discriminating A + from A-, having 4–7% misclassification rate. The global accuracy of plasma pTau₂₁₇ using a two-threshold approach was robust in symptomatic groups, exceeding 90%. Conclusion: The evaluation of blood biomarkers on an automated platform exhibited high diagnostic accuracy for AD pathophysiology, and pTau₂₁₇ showed excellent diagnostic accuracy to identify participants with AD in a consecutive sample representing the routine clinical practice in a specialized memory unit.

Recent evidence, including massive gene-expression analysis and a wide-variety of other multi-omics approaches, demonstrates an interplay between gut microbiota and the regulation of plasma lipids. Gut microbial metabolism of choline and l-carnitine results in the formation of trimethylamine (TMA) and concomitant conversion into trimethylamine-N-oxide (TMAO) by liver flavin monooxygenase 3 (FMO3). The plasma level of TMAO is determined by the genetic variation, diet and composition of gut microbiota. Multiple studies have demonstrated an association between TMAO plasma levels and the risk of atherothrombotic cardiovascular disease (CVD). We aimed to review the molecular pathways by which TMAO production and FMO3 exert their proatherogenic effects. TMAO may promote foam cell formation by upregulating macrophage scavenger receptors, deregulating enterohepatic cholesterol and bile acid metabolism and impairing macrophage reverse cholesterol transport (RCT). Furthermore, FMO3 may promote dyslipidemia by regulating multiple genes involved in hepatic lipogenesis and gluconeogenesis. FMO3 also impairs multiple aspects of cholesterol homeostasis, including transintestinal cholesterol export and macrophage-specific RCT. At least part of these FMO3-mediated effects on lipid metabolism and atherogenesis seem to be independent of the TMA/TMAO formation. Overall, these findings have the potential to open a new era for the therapeutic manipulation of the gut microbiota to improve CVD risk.

There is extensive information of the beneficial effects of virgin olive oil (VOO), especially on cardiovascular diseases. Some VOO healthy properties have been attributed to their phenolic-compounds (PCs). The aim of this review is to present updated data on the effects of olive oil (OO) PCs on the gut microbiota, lipid metabolism, immune system, and obesity, as well as on the crosstalk among them. We summarize experiments and clinical trials which assessed the specific effects of the olive oil phenolic-compounds (OOPCs) without the synergy with OO-fats. Several studies have demonstrated that OOPC consumption increases Bacteroidetes and/or reduces the Firmicutes/Bacteroidetes ratio, which have both been related to atheroprotection. OOPCs also increase certain beneficial bacteria and gut-bacteria diversity which can be therapeutic for lipid-immune disorders and obesity. Furthermore, some of the mechanisms implicated in the crosstalk between OOPCs and these disorders include antimicrobial-activity, cholesterol microbial metabolism, and metabolites produced by bacteria. Specifically, OOPCs modulate short-chain fatty-acids produced by gut-microbiota, which can affect cholesterol metabolism and the immune system, and may play a role in weight gain through promoting satiety. Since data in humans are scarce, there is a necessity for more clinical trials designed to assess the specific role of the OOPCs in this crosstalk.

Rationale: The HDL (high-density lipoprotein)-mediated stimulation of cellular cholesterol efflux initiates macrophage-specific reverse cholesterol transport (m-RCT), which ends in the fecal excretion of macrophage-derived unesterified cholesterol (UC). Early studies established that LDL (low-density lipoprotein) particles could act as efficient intermediate acceptors of cellular-derived UC, thereby preventing the saturation of HDL particles and facilitating their cholesterol efflux capacity. However, the capacity of LDL to act as a plasma cholesterol reservoir and its potential impact in supporting the m-RCT pathway in vivo both remain unknown. Objective: We investigated LDL contributions to the m-RCT pathway in hypercholesterolemic mice. Methods and Results: Macrophage cholesterol efflux induced in vitro by LDL added to the culture media either alone or together with HDL or ex vivo by plasma derived from subjects with familial hypercholesterolemia was assessed. In vivo, m-RCT was evaluated in mouse models of hypercholesterolemia that were naturally deficient in CETP (cholesteryl ester transfer protein) and fed a Western-type diet. LDL induced the efflux of radiolabeled UC from cultured macrophages, and, in the simultaneous presence of HDL, a rapid transfer of the radiolabeled UC from HDL to LDL occurred. However, LDL did not exert a synergistic effect on HDL cholesterol efflux capacity in the familial hypercholesterolemia plasma. The m-RCT rates of the LDLr (LDL receptor)-KO (knockout), LDLr-KO/APOB100, and PCSK9 (proprotein convertase subtilisin/kexin type 9)-overexpressing mice were all significantly reduced relative to the wild-type mice. In contrast, m-RCT remained unchanged in HAPOB100 Tg (human APOB100 transgenic) mice with fully functional LDLr, despite increased levels of plasma APO (apolipoprotein)-B–containing lipoproteins. Conclusions: Hepatic LDLr plays a critical role in the flow of macrophage-derived UC to feces, while the plasma increase of APOB-containing lipoproteins is unable to stimulate m-RCT. The results indicate that, besides the major HDL-dependent m-RCT pathway via SR-BI (scavenger receptor class B type 1) to the liver, a CETP-independent m-RCT path exists, in which LDL mediates the transfer of cholesterol from macrophages to feces. Graphical A graphical abstract is available for this article.