Gut microbiota has increasingly been shown to exert effects beyond the gastrointestinal tract, some of which are mediated through its metabolites, such as trimethylamine N-oxide (TMAO)—a compound converted by gut bacteria from dietary choline found predominantly in animal products that is associated with cardiovascular disease (CVD). However, a significant gap persists in human clinical trials assessing its potential causal role. This narrative review aims to present the current understanding of the gut microbiome, TMAO, and their relationship with CVD, while proposing future directions that may support the use of TMAO as a biomarker and guide potential interventions to reduce its harmful impact. Both animal and human studies have demonstrated a link between TMAO and CVD, with animal studies also indicating a causal effect—showing increased cardiovascular risk following TMAO administration and reduced risk when TMAO is eliminated. While direct extrapolation from animal models to humans is limited due to biological differences, these findings offer a foundation for the development of well-designed clinical trials in human populations. Although direct approaches to target TMAO—such as trimethylamine (TMA) lyase inhibitors and antisense oligonucleotide (ASO) therapy—have shown promising results in animal studies, they have yet to be investigated in human trials, leaving indirect strategies such as dietary changes and probiotics as the only currently available options.

Probiotics and postbiotics have gained increasing attention in microbiome research due to their potential roles in maintaining gut homeostasis and supporting human health. While probiotics are defined as live microorganisms that confer health benefits when administered in adequate amounts, postbiotics represent preparations of inanimate microorganisms and/or their components that also exert biological effects on the host. This narrative review provides an updated overview of the current knowledge on probiotics and postbiotics, with a particular focus on their mechanisms of action, production strategies, and emerging applications in human health. The review discusses key mechanisms through which probiotics and postbiotics interact with the host, including modulation of the gut microbiota, enhancement of epithelial barrier integrity, immune system regulation, metabolic modulation, and systemic signaling pathways. Advances in production technologies, ranging from conventional fermentation to innovative inactivation and stabilization approaches, are also examined, alongside challenges related to yield optimization, stability, safety, and standardization. Although a growing body of evidence suggests potential benefits of probiotics and postbiotics in metabolic, inflammatory, gastrointestinal, and immune-related conditions, much of the available data is derived from preclinical studies or small-scale clinical trials. Consequently, their clinical efficacy, optimal dosing, and long-term safety require further validation. By integrating current findings and highlighting existing gaps in the literature, this review aims to clarify the therapeutic potential of probiotics and postbiotics and to support the development of more robust, evidence-based strategies for their application in functional foods, supplements, and future biotherapeutic interventions.

The root of metabolic disease lies in the gastrointestinal tract, where nutrient absorption occurs. Within this environment, a diverse community of microorganisms exerts effects that extend beyond the intestinal barrier. Akkermansia muciniphila (A. muciniphila), one such bacterium, has been associated with enhanced intestinal integrity, reduced intestinal inflammation, weight loss, and improved insulin sensitivity, mediated through mucus fermentation, production of short-chain fatty acids (SCFAs), bacterial proteins, and extracellular vesicles (EVs). Research in this field is promising, yet far from perfect. Its clinical applicability remains limited by factors such as strain variability, scarcity of human intervention studies, and the lack of established causality. While associations have been consistently observed in both rodent and human studies, causality has thus far been demonstrated only in animal models. This issue is of critical importance, as metabolic disease remains highly prevalent, carries systemic consequences, and imposes a substantial burden on healthcare systems, underscoring the urgent need for alternative therapeutic strategies. The aim of this narrative review is to synthesize current knowledge on A. muciniphila and to highlight the key limitations consistently reported in the literature. By addressing these factors, the review seeks to provide realistic perspectives on its therapeutic potential and to outline directions for future research.

Atherosclerotic cardiovascular disease (ASCVD) has long been screened using the traditional lipid profile, mainly focusing on LDL cholesterol. However, despite growing evidence supporting lipoprotein(a) [Lp(a)] as an independent risk factor involved in atherosclerosis, its clinical use remains limited. This review examines the reasons behind the limited use of Lp(a) screening in clinical practice, assessing its role in cardiovascular risk, comparing it to traditional lipid markers and evaluating current assessment methods. It also explores existing and emerging treatments, including gene-silencing therapies, for managing elevated Lp(a) levels. One in four clinicians does not routinely check Lp(a) levels, which proves a lack of awareness amongst them. The reasons for that are implied to be that the cost is too high and that available treatments are scarce. The traditional lipid profile, including LDL, high-density lipoprotein (HDL) and triglycerides, continues to be the gold standard for CV risk assessment. One limitation of using Lp(a) in clinical practice is the significant variability in apo(a) sizes, which results from the presence of multiple isoforms determined by the number of kringle domains. This structural diversity poses challenges in standardizing measurement methods, affecting the accuracy and comparability of results. While statins have a minimal impact on Lp(a), PCSK9-i lowers its levels by 20–25%, although this class is not prescribed primarily for this reason. Lastly, gene-silencing therapies, which achieve the greatest reduction in Lp(a) levels, are still in phase III trials, and there is still a need to examine whether this reduction translates into CV benefits. These limitations should not discourage further research, because ASCVD’s complexity requires a more tailored approach. Current lipid-lowering therapy still fails in a minority of cases, as evidenced by new-onset cardiovascular events in patients with well-controlled LDL levels. There is a need for future interventional studies to assess whether a reduction in Lp(a) by PCSK9-i really translates into CV benefits, independent of LDL.

Gut microbiota has increasingly been shown to exert effects beyond the gastrointestinal tract, some of which are mediated through its metabolites, such as trimethylamine N-oxide (TMAO)—a compound converted by gut bacteria from dietary choline found predominantly in animal products that is strongly associated with cardiovascular disease (CVD). However, a significant gap persists in human clinical trials assessing its potential causal role. This narrative review aims to present the current understanding of the gut microbiome, TMAO, and their relationship with CVD, while proposing future directions that may support the use of TMAO as a biomarker and guide potential interventions to reduce its harmful impact. Both animal and human studies have demonstrated a link between TMAO and CVD, with animal studies also indicating a causal effect—showing increased cardiovascular risk following TMAO administration and reduced risk when TMAO is eliminated. While direct extrapolation from animal models to humans is limited due to biological differences, these findings offer a foundation for the development of well-designed clinical trials in human populations. Although direct approaches to target TMAO—such as trimethylamine (TMA) lyase inhibitors and antisense oligonucleotide (ASO) therapy—have shown promising results in animal studies, they have yet to be investigated in human trials, leaving indirect strategies such as dietary changes and probiotics as the only currently available options.