Obesity is a recognized and independent risk factor for chronic kidney disease. Accumulation of visceral fat within the abdominal cavity is a defining characteristic of metabolic syndrome and is associated with an increased risk of kidney disease (Stasi et al., 2022). This process involves multiple mechanisms, including hemodynamic alterations, lipid metabolism disturbances, and hormonal dysregulation. Elevated visceral fat, resulting from increased leptin production, stimulates adipocytes to overproduce aldosterone and modifies mineralocorticoid receptor activation (Vecchiola et al., 2016). Activation of the renin-angiotensin-aldosterone system (RAAS) and heightened sympathetic activity in individuals with obesity further elevates aldosterone levels (Sharma and Engeli, 2006). Aldosterone enhances sodium reabsorption in renal tubules, leading to sodium and water retention. Additionally, RAAS activation contributes to glomerular hyperfiltration by exerting a greater effect on efferent arterioles compared to afferent arterioles (Navar, 2014). To compensate for the increased glomerular filtration rate (GFR) observed in obesity, glomerular hypertrophy (glomerulomegaly) develops, followed by mechanical stretching of podocytes, which are unable to accommodate the increased glomerular volume (Chagnac et al., 2019). When podocytes reach their stretching limit, their foot processes detach from the glomerular basement membrane. This event leads to the development of focal sclerotic changes, termed obesity-associated glomerulopathy in the context of obesity (Zhang and Lerman, 2017). At this stage, obesity-related kidney damage becomes clinically evident, presenting as proteinuria and/or reduced GFR in laboratory assessments (Salvatore et al., 2017). Weight gain also increases perirenal adipose tissue, which may compress the thin segment of the loop of Henle and the vasa recta vessels in the renal medulla, thereby reducing renal tubular flow. Reduced tubular flow, combined with RAAS activation, decreases sodium excretion and leads to secondary glomerular hyperfiltration (Parvanova et al., 2023). Compression of the kidney further stimulates juxtaglomerular apparatus cells in the macula densa to release renin, amplifying RAAS activation. Concurrently, increased perirenal adipose tissue increases intrarenal pressure, leading to oedema and renal tissue inflammation (Kanbay et al., 2025). In obesity, fat also accumulates in the renal interstitium, a condition known as fatty kidney, which contributes to compression of renal vessels, increased intrarenal pressure, and further RAAS activation, ultimately causing kidney damage (Parvanova et al., 2023). Adipokines released by renal fat cells promote renal parenchymal inflammation and fibrosis, primarily by upregulating transforming growth factor beta (TGF-β1) expression (Abdullah et al., 2025). Increased fatty acid availability also leads to greater uptake by podocytes and tubular cells, potentially inducing apoptosis when the cellular capacity for lipid oxidation or storage is exceeded (Schelling, 2022).

Diabetes represents the primary cause of chronic kidney disease in numerous countries. Kidney damage may occur as early as the development of insulin resistance, preceding the onset of overt diabetic symptoms. Similar to obesity, insulin resistance induces sodium retention and vascular endothelial contraction, which in turn activates the RAAS (Sarafidis and Ruilope, 2006). Insulin resistance also promotes lipid droplet accumulation in renal tubular cells by increasing the activity of sterol regulatory element-binding protein 1c (SREBP-1c), ultimately leading to tubular atrophy and renal interstitial fibrosis (Li et al., 2024). In the initial stages DKD, glomerular hyperfiltration develops due to impaired regulation of afferent and efferent arteriolar tone, a consequence of increased glucose uptake in proximal tubular cells (Vallon and Thomson, 2020). Prolonged dilatation of the afferent arteriole in the context of elevated glucose uptake may lead to glomerular enlargement and proliferation of mesangial cells and the glomerular basement membrane (Chagnac et al., 2019). Hyperglycemia is a critical factor in the pathogenesis of diabetic kidney damage. Hyperglycemia increases endothelin-1 production, a potent vasoconstrictor (Park et al., 2000). Elevated blood glucose and endothelin-1 levels contribute to podocyte cytoskeletal breakdown and subsequent apoptosis (Hu et al., 2024). In hyperglycemic states, proximal tubular cells increase glucose uptake, a process that is energetically demanding. These cells rely exclusively on fatty acids as an energy source. Increased ATP consumption for glucose transport leads to hypoxia in proximal tubular cells, activating the hypoxia-inducible factor (HIF) and AMP-activated protein kinase (AMPK) pathways and resulting in hypertrophy of these cells (Mohandes et al., 2023). Persistent hyperglycemia induces a metabolic shift to the glycolytic pathway in these cells (Zhang et al., 2018). Inefficient fatty acid oxidation in the proximal tubules, due to abnormal energy expenditure and metabolic alterations, is considered the primary cause of renal tubular damage and fibrosis in diabetes (Lv et al., 2025).

Elevated blood pressure, similar to the aforementioned metabolic changes, contributes to kidney damage and the progression of chronic kidney disease (Lin et al., 2024). Furthermore, metabolic disorders such as obesity and diabetes promote the onset of hypertension, primarily through excessive sympathetic nervous system activity and activation of the RAAS (Kalil and Haynes, 2012). Glomerular hyperfiltration is the principal factor accelerating kidney damage in hypertension. Mechanisms underlying this process include reduced nephron number, increased sodium retention and subsequent extracellular volume expansion, vascular endothelial dysfunction, and activation of both the RAAS and the sympathetic nervous system (Bansal and Chonchol, 2025). As hypertension advances, renal blood flow diminishes, predominantly affecting the renal tubules. Resulting ischemia further enhances angiotensin II synthesis, which exerts vasoconstrictive effects and stimulates renal parenchymal cell proliferation, thereby worsening both hemodynamic and extravascular injury, including fibrosis (Basile et al., 2012).

Subsequent sections examine the associations between gut microbiota and obesity, T2D, and CVD, with particular emphasis on the mediating role of microbiota-derived metabolites in the potential development of these conditions.

Studies in mice have shown that obesity-associated alterations in gut microbiota composition may increase energy harvest from ingested food (Turnbaugh et al., 2006). Proposed mechanisms include expansion of specific bacterial taxa, such as Thomasclavelia ramosa (formerly Clostridium ramosum), which has been associated with increased intestinal expression of nutrient transporters including glucose transporter 2 (GLUT2) and CD36 (a fatty acid translocase) (Woting et al., 2014). Obesity-related microbiota has also been linked to an increased abundance of microbial enzymes involved in polysaccharide degradation, potentially enhancing fermentation and production of short-chain fatty acids (SCFAs) (Turnbaugh et al., 2006). In addition, interactions between hydrogen-producing bacteria and methanogenic archaea may increase fermentation efficiency and SCFA generation (Zhang et al., 2009). In experimental animal models, increased energy harvest is not necessarily accompanied by a proportional increase in energy expenditure. Proposed explanations include alterations in bile acid metabolism and SCFA signaling. In obese mice, changes in gut microbiota composition have been associated with reduced production of secondary bile acids and altered activation of TGR5- and FXR-dependent pathways, potentially leading to impaired thermogenesis and reduced browning of white adipose tissue (Gao et al., 2025). Early studies in mice suggested that the gut microbiota may promote energy storage by suppressing intestinal fasting-induced adipose factor (FIAF/ANGPTL4) expression, thereby facilitating lipid accumulation (Bäckhed et al., 2004). However, subsequent studies in human intestinal cell models demonstrated that SCFAs can induce ANGPTL4/FIAF expression via PPARγ activation (Alex et al., 2013), suggesting that the relationship among SCFAs, FIAF and energy metabolism is more complex than initially proposed. In addition, butyrate has been shown to increase PGC-1α and UCP1 expression and enhance thermogenesis in mice (Gao et al., 2009). Overall, the effects of SCFAs on energy expenditure remain incompletely understood. Taken together, evidence from rodent studies suggests that obesity-associated alterations in gut microbial composition may influence energy balance through effects on nutrient harvest, bile acid metabolism and SCFA signaling. However, these mechanisms have been demonstrated predominantly in animal models, and direct evidence that they make a substantial contribution to obesity development in humans remains limited.

Alterations in bile acid metabolism have been associated with obesity and obesity-related changes in gut microbiota composition. In murine models, obesity-associated dysbiosis has been linked to changed microbial conversion of primary to secondary bile acids, resulting in shifts in bile acid composition (Sayin et al., 2013). These compositional changes can influence bile acid–receptor signaling, including FXR pathways, since FXR activity is differentially regulated by specific bile acid species, thereby affecting hepatic lipid and glucose metabolism, as demonstrated in mouse studies (Trauner et al., 2010). In experimental mouse models, alterations in FXR signaling have been associated with changes in intestinal FGF15/19 production and downstream effects on hepatic lipid metabolism. Disruption of this signaling axis may contribute to increased lipogenic pathways, although the underlying mechanisms are complex and involve multiple regulatory steps (Bhatnagar et al., 2009). The relevance of these pathways to human obesity remains uncertain. SCFAs can contribute to gluconeogenesis and serve as substrates for lipid synthesis, acting as precursors for the synthesis of fatty acids and cholesterol (Amabebe et al., 2020). In contrast, studies in mice have identified an association between butyric acid and reduced lipogenesis, mediated by inhibition of peroxisome proliferator-activated receptor γ (PPAR-γ) activity and stimulation of β-oxidation (Zheng et al., 2023). Collectively, findings from experimental animal studies underscore the complexity of SCFA-mediated regulation of lipid metabolism. Although these pathways may influence fat accumulation under experimental conditions, their quantitative contribution to obesity development in humans remains unclear.

Alterations in the gut microbiota can also affect appetite regulation. Evidence from rat models indicates that the production of gut hormones, including peptide YY (PYY) and glucagon-like peptide 1 (GLP-1), is closely associated with the presence of bile acids and SCFAs (Sun et al., 2018; Christiansen et al., 2018). Mouse studies demonstrate that increased SCFA production promotes satiety and reduces appetite, potentially through activation of G protein-coupled receptors 41 (GPR41) and 43 (GPR43). In mouse studies, activation of these receptors enhances the production and secretion of appetite-suppressing gut hormones, specifically GLP-1 and PYY (Cunningham et al., 2021). Notably, concentrations of these hormones are often reduced or dysregulated in obese individuals. SCFAs may also exert central effects by acting directly in the hypothalamus. In mouse models, SCFAs induce the expression of α-melanocyte-stimulating hormone, which has an anorexigenic effect, while simultaneously inhibiting the expression of agouti-related protein (AGRP), which has an orexigenic effect (Frost et al., 2014). The gut microbiota may modulate host neurochemical pathways implicated in appetite regulation, such as γ-aminobutyric acid (GABA) signaling and serotonin metabolism. Specific intestinal microorganisms can produce GABA, and the gut microbiota can influence host serotonin synthesis and tryptophan metabolism (Yano et al., 2015; Strandwitz et al., 2019). Nevertheless, neither peripheral serotonin nor microbiota-derived serotonin crosses the blood-brain barrier to a significant degree under normal physiological conditions (Berger et al., 2009). Likewise, direct transport of microbiota-derived GABA into the central nervous system has not been established. Consequently, the influence of the gut microbiota on central appetite regulation is thought to act indirectly, for example, by modulating tryptophan availability, vagal signaling, immune pathways, or gut hormone secretion (Morais et al., 2021; Cryan et al., 2019). Most evidence supporting these mechanisms derives from animal studies, and direct evidence that microbiota-induced neurochemical changes substantially influence appetite regulation in humans remains limited.

Although numerous studies have reported associations between obesity and gut microbiota composition, caution is warranted regarding the immediate practical application of these findings. This is particularly important because much of the mechanistic evidence discussed in the literature originates from experimental animal models rather than human intervention studies. This caution is necessary due to persistent challenges in interpreting microbiota research. For example, identification of microbiota components is typically conducted at various taxonomic levels, often resulting in conclusions based on higher taxa rather than specific species. The widely reported imbalance in the Bacteroidetes/Firmicutes (now Bacteroidota/Bacillota) ratio involves two broad bacterial groups, each encompassing multiple species. Additionally, studies investigating specific bacterial species as potential therapeutic agents frequently lack mechanistic explanations. Moreover, even rigorous animal experiments may not adequately distinguish the bidirectional interactions between diet and microbiota (Cani et al., 2021; Arrieta et al., 2016).

The mechanisms outlined above have been demonstrated predominantly in rodent models and should therefore be interpreted with caution. Although associations between obesity and gut microbiota composition have been reported in humans, causal pathways remain poorly established. Furthermore, randomized clinical studies, including fecal microbiota transplantation trials, have generally failed to demonstrate meaningful effects on body weight. Consequently, the translational relevance of many experimentally described mechanisms remains uncertain and requires confirmation in well-controlled human studies.

Patients with T2D often exhibit a reduced abundance of SCFA-producing bacteria, particularly butyrate-producing taxa such as Faecalibacterium, Roseburia, and Eubacterium (Qin et al., 2012). Butyric acid is responsible, amongst other things, for stabilizing the intestinal barrier by promoting the expression of tight junction proteins such as claudin-3 and zonula occludens-1, and by increasing mucin production. Reduced butyric acid production, as observed in individuals with T2D or impaired glucose tolerance, can compromise intestinal barrier integrity, as demonstrated in studies using human intestinal epithelial cell model (Gaudier et al., 2004). SCFAs also contribute to the regulation of insulin sensitivity and the regulation of carbohydrate homeostasis partly by activating G protein-coupled receptors in the gut, including GPR41, GPR43, and GPR109a (Cunningham et al., 2021). Activation of these receptors enhances the release of GLP-1 and PYY, as shown in mouse models (Christiansen et al., 2018). GLP-1 stimulates insulin secretion, inhibits gastric emptying, increases hepatic glycogen storage, and reduces de novo glucose production in hepatocytes, primarily through insulin-mediated mechanisms. PYY primarily inhibits intestinal motility, gastric emptying, and pancreatic secretion, and decreases food intake. Additionally, SCFAs may reduce fat accumulation by lowering PPAR-γ receptor expression and modulating the immune system to decrease inflammation, as demonstrated in mouse studies (den Besten et al., 2015).

Significant attention is given to the role of SCFAs in this article. SCFAs reach physiologically relevant concentrations in the large intestine, where acetate, propionate, and butyrate are present at millimolar levels and directly influence epithelial metabolism and immune regulation. In contrast, SCFA concentrations in peripheral blood are substantially lower, typically remaining in the low micromolar range, particularly for butyrate and propionate, due to extensive intestinal and hepatic metabolism. SCFAs achieve concentrations sufficient to locally activate GPR41 and GPR43 receptors in the intestine and portal circulation. Reported EC50 values for SCFA-mediated activation of GPR41 and GPR43 generally lie within the high micromolar to low millimolar range (approximately 0.1–1 mM, depending on the receptor subtype, ligand, and assay system). However, systemic peripheral concentrations may often remain near or below reported EC50 (half maximal effective concentration) ranges for receptor activation in experimental systems, potentially limiting robust receptor engagement under physiological conditions. This discrepancy is a frequently overlooked limitation when extrapolating the mechanisms of SCFA receptor activation from cell culture studies to human systemic physiology (Sankarganesh et al., 2025; Martin-Gallausiaux et al., 2021).

Dysbiosis of the gut microbiota disrupts bile acid metabolism, notably by promoting the conversion of primary to secondary bile acids via bacterial enzymes, primarily dehydroxylases (Ridlon et al., 2016). Beyond facilitating lipid digestion, bile acids function as signaling molecules that regulate metabolic processes by activating specific receptors, including FXR and TGR5. FXR activation modulates lipid metabolism, including reduced triglyceride levels, enhanced fatty acid β-oxidation, and improved glucose tolerance and insulin sensitivity. Alterations in gut microbiota composition can impair FXR-dependent signaling, thereby contributing to metabolic disorders associated with insulin resistance and T2D (Mori et al., 2022). Experimental studies indicate that secondary bile acids also serve as ligands for the TGR5 receptor, whose activation supports intestinal barrier integrity and stimulates secretion of GLP-1, thereby enhancing insulin release (Gao et al., 2022). In dysbiotic conditions, altered secondary bile acid profiles may reduce TGR5 activation, thereby exacerbating insulin resistance and hyperglycemia (Gurung et al., 2020).

The gut microbiota contributes to amino acids metabolism, particularly branched-chain amino acids (BCAA) and aromatic amino acids (AAA) metabolism. Human studies indicate that elevated concentrations of BCAA and AAA may predict the future development of T2D (Najafi et al., 2023). Increased levels of BCAA, including leucine, isoleucine and valine, have been observed in patients with T2D (Mosley et al., 2024). These amino acids can activate the mammalian target of rapamycin (mTOR)/p70 S6 kinase (p70S6K) pathway, which inhibits phosphorylation of the insulin receptor substrate and impairs insulin signalling, as demonstrated in skeletal muscle cell lines (Tremblay and Marette, 2001). Elevated blood BCAA levels may inhibit AMPK activation, leading to increased hepatic gluconeogenesis and decreased glucose uptake by peripheral tissues, ultimately increasing blood glucose levels, as shown in rat models (Saha et al., 2010). In cases of gut dysbiosis, altered activity of BCAA-degrading enzymes may lead to excessive BCAA accumulation in the bloodstream. Mouse model studies have identified certain bacterial strains, such as Prevotella copri and Bacteroides vulgatus, as contributors to increased BCAA biosynthesis (Gojda and Cahova, 2021). In individuals with insulin resistance or T2D, elevated BCAA concentrations may also result from impaired metabolism. Rodent studies have shown that increased plasma BCAA concentrations are associated with reduced activity and dysregulation of enzymes involved in BCAA catabolism, such as branched-chain amino acid transaminase and the branched-chain α-ketoacid dehydrogenase complex (She et al., 2007). Deficiencies in these enzymes impair lipid and glucose oxidation by contributing to mitochondrial dysfunction (Lerin et al., 2016). Similarly, concentrations of AAA, including tyrosine, tryptophan and phenylalanine, are often elevated in patients with T2D (Li et al., 2023). Indole propionate (IPA), a specific metabolite of tryptophan produced primarily by the gut microbiota, is closely linked to dietary fibre intake. Higher blood concentrations of IPA are associated with a lower risk of developing T2D and improved insulin secretion in humans (Tuomainen et al., 2018).

Elevated BCAA levels are consistently observed in insulin-resistant individuals and are strongly associated with metabolic dysfunction. However, current evidence does not support a direct causal relationship whereby physiological concentrations of BCAA alone are sufficient to induce insulin resistance in humans. Instead, elevated circulating BCAA are best interpreted as biomarkers of impaired amino acid metabolism, while potentially contributing to the modulation and progression of metabolic disease in a context-dependent manner (Neinast et al., 2019).

Although several mechanistic pathways linking microbiota-derived metabolites to insulin resistance have been identified, much of the supporting evidence comes from animal models and cell culture systems, with direct confirmation in humans limited.

Multiple factors contribute to the development of atherosclerosis, notably chronic inflammation driven by lipopolysaccharide (LPS) derived from a dysbiotic gut microbiota. The presence of LPS in the bloodstream promotes inflammation and foam cell formation by activating the Toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88) pathway. Additionally, bacterial DNA of possible intestinal origin has been detected in human atherosclerotic plaques (Nicolaou et al., 2012). Comparative analyses of the microbiota in patients with atherosclerosis have revealed significant differences from healthy individuals. Specifically, individuals with atherosclerosis exhibit increased abundance of Streptococcus and Enterobacteriaceae species (Zhu et al., 2023). In patients with coronary artery disease (CAD), elevated levels of Lactobacillales and Clostridium subcluster XIVa colonies have been observed in the gut microbiota (Emoto et al., 2017). Trimethylamine N-oxide (TMAO) represents a principal link between gut microbiota and atherosclerosis. Gut bacteria metabolize choline, phosphatidylcholine, and carnitine from dietary sources into trimethylamine, which is subsequently oxidized to TMAO in the liver (Bennett et al., 2013). Elevated plasma TMAO levels are associated with an increased risk of coronary plaque rupture (Tan et al., 2019). Several mechanisms have been identified through which elevated TMAO levels may promote pro-atherosclerotic effects. TMAO can upregulate macrophage scavenger receptors including CD36, destabilizing cholesterol metabolism and leading to foam cell formation, as demonstrated in mouse studies (Wang et al., 2011). Inhibition of CYP7A1 by TMAO limits bile acid synthesis, thereby reducing cholesterol excretion and reabsorption, as shown in mouse models (Koeth et al., 2013). Destabilization of the vascular endothelium, induced by TMAO-mediated activation of NF-κB (nuclear factor kappa B) and the inflammasome, increases expression of endothelial inflammatory factors in mice (Ma et al., 2017). In addition to upregulating inflammatory factors, TMAO may disrupt intercellular junction regulation and alter endothelial permeability by activating High Mobility Group Box 1 (HMGB1). The resulting endothelial dysfunction contributes to the initiation and progression of atherosclerotic changes, as demonstrated in mouse endothelial cell lines (Singh et al., 2019). TMAO may also enhance platelet hyperreactivity, promoting platelet aggregation and intravascular clot formation. This effect is partly mediated by increased intracellular calcium release, as observed in mouse models (Zhu et al., 2016). In contrast, SCFAs, another group of gut microbiota metabolites, exert anti-atherosclerotic effects by inhibiting inflammation, lowering cholesterol levels, and reducing lipid deposition (Tonch-Cerbu et al., 2025). Secondary bile acids may also confer protection against atherosclerosis, primarily by regulating cholesterol excretion through bile salt hydrolase activity and the FXR/CYP7A1 pathway (Lau et al., 2017).

Hypertension is among the most prevalent medical conditions globally. Research has established an association between the gut microbiota and blood pressure regulation. Although studies involving patients with hypertension remain limited, evidence indicates that these individuals exhibit reduced microbial diversity compared to those with normal blood pressure (Yang et al., 2015). In addition, individuals with elevated blood pressure display a decreased abundance of butyrate-producing bacteria, such as Butyricimonas and Fusobacterium (Kim et al., 2018). Positive correlations have also been identified between the abundance of Ruminococcaceae, Streptococcus, and Turicibacter and blood pressure. Moreover, a higher Bacillota/Bacteroidota ratio has been reported in individuals with hypertension (Yang et al., 2015). Recognition of gut dysbiosis as a potential contributor to hypertension has prompted the development of experimental gut microbiota transplantation. Transferring microbiota from hypertensive individuals to healthy mice increases blood pressure in the recipients (Li et al., 2017). Among gut microbiota metabolites, SCFAs are implicated in blood pressure regulation. Animal studies have demonstrated that SCFAs influence blood pressure through interactions with G protein-coupled receptors, including GPR41 and olfactory receptor 78 (Olfr78). Activation of GPR41 by SCFAs is generally associated with lower blood pressure, whereas stimulation of Olfr78 may increase it. Notably, the EC50 values of SCFAs, representing the concentrations required to achieve 50% of the maximum effect, differ substantially between Olfr78 and GPR41 (Pluznick, 2014). This difference partly accounts for the simultaneous action of SCFAs on both receptors despite their opposing effects on blood pressure. High salt intake is a recognized risk factor for hypertension. Sodium absorption primarily occurs in the intestine, where the gut microbiota likely plays a significant role. Rodent studies have shown that a high-sodium diet (HSD) alters the composition of the gut microbiota (Hamad et al., 2022). Specifically, diet-induced hypertensive rats exhibit increased populations of Erwinia and Corynobacteriaceae, along with a reduction in Anaerostipes (Bier et al., 2018). The HSD is also associated with decreased Lactobacillus murinus populations and increased induction of type 17 T helper cells, both of which are correlated with hypertension development in mouse models (Wilck et al., 2017).

Heart failure, the most common end-stage manifestation of various cardiovascular diseases, has recently been associated with alterations in the gut microbiota. Intestinal ischaemia resulting from reduced cardiac output may cause intestinal wall oedema, compromise the intestinal barrier, promote bacterial translocation and inflammation, and alter microbiota composition, potentially accelerating heart failure progression (Sandek et al., 2007). In patients with chronic heart failure, increased proliferation of pathogenic microorganisms, such as Shigella, Salmonella, Campylobacter, and Yersinia enterocolitica, has been documented. A positive correlation exists between heart failure severity and elevated colony counts of Campylobacter, Shigella and Candida (Pasini et al., 2016). Elevated TMAO concentrations have been observed in patients with heart failure, with higher TMAO levels associated with increased mortality and a greater need for heart transplantation (Kanitsoraphan et al., 2018). In murine models of heart failure induced by aortic stenosis, supplementation with choline (a TMAO precursor) and TMAO itself led to increased circulating TMAO, greater myocardial fibrosis, and worsened cardiac function (Organ et al., 2016). Studies in rat models indicate that TMAO exacerbates myocardial fibrosis and ventricular remodelling, thereby contributing to heart failure development (Li X. et al., 2019). Although the precise mechanisms remain unclear, TMAO may influence the heart through pathways such as activation of the NLRP3 inflammasome and the TGF-β/SMAD3 axis, which can promote myocardial fibrosis, as shown in mouse studies (Li Z. et al., 2019). Individuals with heart failure also exhibit reduced abundance of butyrate-producing bacteria, particularly from the Lachnospiraceae and Ruminococcaceae families (Trøseid et al., 2020). Another short-chain fatty acid, propionate, may attenuate cardiac hypertrophy and fibrosis, primarily by modulating regulatory T cells, as demonstrated in mouse studies (Bartolomaeus et al., 2019). In congestive heart failure, both the quantity and composition of microbiota-derived bile acids are altered, with studies reporting decreased concentrations of primary bile acids and increased levels of certain secondary bile acids (Trøseid et al., 2020). Additionally, the microbiota metabolite indoxyl sulfate is linked to myocardial fibrosis and cardiac remodelling, as evidenced in rat models (Lekawanvijit et al., 2010).

This chapter has frequently discussed the potential role of TMAO in the development of CVD. Current evidence indicates that circulating TMAO levels in patients with CVD are associated with adverse metabolic and cardiovascular outcomes, and elevated plasma concentrations have been consistently reported in individuals with atherosclerosis, heart failure, and other cardiovascular conditions. Higher TMAO levels are correlated with an increased risk of major adverse cardiovascular events and mortality (Schiattarella et al., 2017). However, it remains uncertain whether the concentrations of TMAO observed in humans are independently sufficient to directly induce cardiovascular or metabolic dysfunction. Renal function, dietary patterns, gut microbiota composition, and overall cardiometabolic health significantly influence circulating TMAO levels, complicating the establishment of direct causality. Consequently, TMAO is generally regarded as both a biomarker and a potential modulator of CVD progression, rather than a definitively established primary causal factor (Canyelles et al., 2023).

Several mechanisms linking microbiota-derived metabolites to the development of CVD have been identified. However, most mechanistic evidence originates from animal models and in vitro studies. Therefore, these pathways should currently be considered biologically plausible rather than fully established cause-and-effect processes in humans. Additional human studies are required to confirm their clinical significance.