Autophagy as a Proposed Regulatory Interface in the Gut Microbiota–Cardiovascular Axis

Abstract

The gut–cardiovascular axis is increasingly recognized as a contributor to cardiovascular disease (CVD) risk; however, most available evidence remains associative, and the mechanistic links between gut dysbiosis, autophagy, and cardiovascular pathology require further validation. This review proposes a conceptual framework in which autophagy may serve as a regulatory interface linking gut microbiota-derived signals with vascular and cardiac dysfunction. We summarize evidence that microbial metabolites, including trimethylamine N-oxide (TMAO), short-chain fatty acids (SCFAs), bile acids, and dysbiosis-associated products such as lipopolysaccharide (LPS), may influence autophagic flux in intestinal epithelial cells, endothelial cells, macrophages, and myocardium through pathways involving TLR–MyD88–NF-κB/NLRP3 signaling, AMPK–mTOR–ULK1–Beclin-1 regulation, and FXR/TGR5-associated mechanisms. These pathways may contribute to oxidative stress, lipid dysregulation, gut barrier dysfunction, endothelial activation, foam cell formation, and cardiovascular inflammation. We also discuss selected inflammatory and metabolic biomarkers, including PCSK9, MPO, Lp-PLA2, TMAO, and CRP, while emphasizing that their relationships with autophagy are context-dependent and, in several cases, indirect. Emerging therapeutic opportunities, including microbiome remodeling, prebiotics, probiotics, postbiotic SCFAs, high-purity eicosapentaenoic acid, PCSK9 inhibition, and autophagy-targeted nanocarriers, are evaluated with attention to their current evidence level. As many of these approaches remain supported mainly by preclinical, mechanistic, or indirect clinical evidence, future translation will require longitudinal human studies, standardized autophagy-flux assessment, multi-omics integration, and well-designed clinical trials using clinically relevant cardiovascular endpoints. Overall, this review positions the gut microbiota–autophagy–cardiovascular axis as a testable conceptual model to guide future mechanistic and translational research in CVD.

Graphical Abstract

Introduction

Recent evidence has highlighted the key role played by the human gut microbiota in modulating cardiovascular health and disease.^1–4 The human gut microbiome is a complex and dynamic ecosystem of bacteria, viruses, fungi, and archaea that interacts with the host to influence both health and disease.^5,6 Gut microbiome composition varies considerably between individuals and over time, shaped by factors such as diet, genetics, medications, and environmental exposures. Dysbiosis, marked by reduced microbial diversity and altered taxonomic composition, has been repeatedly associated with cardiovascular disease (CVD) and its risk factors.^3,4

CVD is the leading cause of death worldwide, and the global burden is increasing.^7,8 CVD describes a broad spectrum of disorders of the heart and blood vessels including coronary artery disease, stroke, atherosclerosis, hypertension, and heart failure, which share common underlying mechanisms such as chronic inflammation, metabolic dysregulation, and endothelial dysfunction.^9,10

In terms of microbiome composition, individuals with CVD often have less microbial diversity and a disrupted Firmicutes-to-Bacteroidetes (F/B) ratio, a dysbiosis pattern shared by people with obesity, insulin resistance, and inflammation, suggesting a common microbiome-associated metabolic and inflammatory signature contributing to disease onset and progression.^2,4,11 In this context, the gut microbiota can act as both a biomarker of disease and a pathophysiological modulator of systemic inflammation, lipid metabolism, endothelial function, and immune homeostasis modifying metabolic and inflammatory pathways accelerating the CVD onset.^12–14

Dysbiosis is characterized by impaired metabolic regulation, leading to disrupted nutrient handling and energy production that represent an intermediate stage between health and disease.¹⁵ Dysbiosis-driven metabolic alterations link the gut microbiota to host cellular pathways, with autophagy emerging as a potential mediator of downstream inflammatory and cardiovascular outcomes.

There is growing evidence that autophagy plays a vital role in the gut-cardiovascular axis. Gut-derived metabolites including trimethylamine N-oxide (TMAO), short-chain fatty acids (SCFAs), and bile acids (BAs) have been shown to modulate autophagic flux, while autophagy, in turn, influences gut barrier integrity, microbial composition, and inflammatory signaling.^16–20 Autophagy is also considered an important regulator of cardiovascular physiology and pathology, as it is involved in myocardial remodeling, plaque stability, endothelial integrity, and immune modulation.^18,19 These observations support a bidirectional relationship between gut microbiota-derived signals and host autophagic processes.

Evidence from inflammatory bowel disease (IBD), a condition characterized by severe gut dysbiosis, further supports this link. Patients with IBD exhibit an increased risk of CVD, including coronary artery disease, stroke, and heart failure (HF).²¹ Dysbiosis in IBD is associated with increased intestinal permeability, facilitating the translocation of microbial proteins and toxins into the circulation to promote systemic inflammation and endothelial dysfunction, thereby contributing to cardiovascular pathology.²¹ Notably, a genetic variant affecting the autophagy-related gene ATG16L1 is strongly associated with IBD susceptibility, suggesting that impaired autophagic regulation may influence host–microbiome interactions,²² although its direct contribution to cardiovascular disease remains incompletely defined.

Previous studies on the gut–cardiovascular axis have largely focused on metabolic or inflammatory pathways.^5,23–29 This review, however, combines the available data into a unified conceptual framework that highlights autophagy as a regulatory interface connecting microbial dysbiosis to cardiovascular outcomes. Rather than considering microbial metabolites just as biomarkers or independent effectors, we propose that dysbiosis-driven alterations in metabolite profiles directly engage host autophagic machinery, thereby influencing inflammatory signaling, mitochondrial homeostasis, and endothelial function. Within this model, metabolic alterations caused by dysbiosis are proposed to drive disease progression through autophagy-dependent mechanisms, although this framework requires further clinical validation.

Given these emerging but complex interactions, this review therefore explores the interplay between gut microbiota, autophagy, and cardiovascular disease. Specifically, we (i) summarize patterns of dysbiosis associated with CVD; (ii) examine the roles of key microbial metabolites, including TMAO, SCFAs, and BAs, in regulating metabolic and inflammatory pathways; (iii) discuss autophagy-centered mechanisms linking microbial signals to cardiovascular outcomes; and (iv) highlight therapeutic opportunities that target the microbiota–autophagy axis while identifying key gaps for future investigation.

Unlike previous reviews that typically examine gut microbiota-derived metabolites and inflammatory pathways separately, here we propose a cohesive mechanistic framework in which autophagy is proposed to function as an integrative regulatory interface linking microbial-derived signals to cardiovascular outcomes. In this framework, gut dysbiosis alters the production of key metabolites, including TMAO, SCFAs, and BAs, which engage host cellular sensors such as AMPK, mTOR, and pattern recognition receptors. These signals converge on autophagy pathways, thereby modulating mitochondrial function, inflammatory signaling, and endothelial integrity.^30,31 Through this integrative axis, autophagy may act as a bidirectional mediator translating microbial and metabolic inputs into cardiovascular responses that influence both disease initiation and progression.

The Gut Microbiota and CVD

Numerous observational studies have shown that reduced gut microbial diversity is associated with CVD severity.^4,12,32,33 Choroszy et al reported that patients with coronary artery disease (CAD) had significantly lower gut microbiome alpha-diversity scores than healthy controls,³⁴ with lower levels of beneficial, anti-inflammatory, and SCFA-producing bacteria such as Faecalibacterium prausnitzii, Roseburia, and Akkermansia muciniphila.³⁴ Other atherosclerosis-associated alterations in the gut microbiota include increased numbers of pathogenic bacteria including Lachnospiraceae, Clostridiaceae, Enterobacteriaceae, and Proteobacteria, while beneficial bacteria such as Bacteroides and Roseburia are reduced.^13,27 Similarly, Sayols-Baixeras et al identified an inverse correlation between the Shannon diversity index and coronary artery calcium score, suggesting an association between reduced microbial richness and an increased risk of subclinical atherosclerosis.³⁵ The observed patterns suggest that gut microbial diversity may play a role in atherosclerosis.^34,35

Microbial dysbiosis is also a feature of other important CVDs like hypertension, which is characterized by lower diversity and an increased prevalence of proinflammatory bacteria such as Prevotella and Klebsiella, along with a reduction in beneficial SCFA-producing bacteria like Faecalibacterium prausnitzii and Roseburia.^13,27,36 Similarly, patients with HF have dysbiotic guts, including increased abundance of pathogenic bacteria such as Escherichia coli and Enterococcus and associated increases in gut-derived metabolites linked to disease severity.³⁶ Specific bacterial species exert differential effects in CVD; for example, Akkermansia muciniphila is associated with protective effects, while Collinsella has been linked to inflammatory responses in atherosclerosis.^27,37 Alterations in the gut microbiota associated with various cardiovascular conditions are illustrated in Figure 1.

Figure 1.

Alterations in the gut microbiota associated with CVD. Alterations in microbial diversity and taxonomic abundance are associated with hypertension, atherosclerosis, and heart failure. These conditions are characterized by gut dysbiosis, including reduced microbial diversity, enrichment of selected dysbiosis-associated taxa, and depletion of beneficial short-chain fatty acid (SCFA)-producing bacteria.

Taken together, these observations suggest that shifts in gut microbiota composition are not merely correlative but may exert direct effects on cardiovascular disease through metabolite-driven signaling and barrier-mediated regulation of host cellular pathways. Dysbiosis-induced disruption of intestinal barrier integrity facilitates microbial translocation and systemic inflammation, ultimately contributing to cardiac dysfunction and remodeling.³⁸ These mechanisms converge on intracellular regulatory networks, particularly autophagy, suggesting that autophagy may serve as a key interface linking microbial imbalance to cardiovascular disease.

Metabolic Regulation of Autophagy by the Gut Microbiota in Cardiovascular Disease

A key mechanism linking gut dysbiosis to cardiovascular homeostasis involves microbiota-derived metabolites that modulate host cellular pathways. These metabolites influence interconnected processes, including inflammation, oxidative stress, and metabolic signaling, and are increasingly recognized to regulate autophagic activity.^16,23–25 Metabolites associated with dysbiosis, including TMAO and LPS, have been implicated in promoting pro-inflammatory and oxidative signaling, whereas others, such as SCFAs and BAs, exert context-dependent protective or regulatory effects.^23–25

Although LPS is not discussed as a separate metabolite pathway, it is incorporated throughout this review as a dysbiosis-associated microbial product that triggers gut barrier dysfunction by activating TLR4–NF-κB/NLRP3 and dysregulating autophagic flux, thereby contributing to cardiovascular inflammation.^39,40 These metabolites interact with important intracellular pathways, such as mechanistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK), to regulate autophagic activity and subsequent inflammatory reactions.^16,41,42 To clarify these interactions, we first describe key microbiota-derived metabolic pathways with strong mechanistic and experimental support in cardiovascular disease, specifically TMAO, SCFAs, and BA signaling.^{16,23–25,41–48}

The Trimethylamine N-Oxide (TMAO) Pathway

TMAO is a metabolite produced by gut microbiota during digestion of dietary components rich in choline, phosphatidylcholine, and L-carnitine.⁴⁹ Increased plasma levels of TMAO have emerged not only as an important aspect of CVD pathogenesis but also as a risk factor for adverse cardiovascular outcomes.^50,51

The latest evidence suggests that TMAO may act as an important mediator linking gut microbiota-derived metabolic signals to systemic cardiovascular pathology by disrupting autophagic flux in intestinal epithelial cells, endothelial cells, and vascular smooth muscle cells, thereby inducing cellular stress responses. This provides a unifying autophagy-dependent mechanism linking impaired gut barrier integrity with vascular injury and the inflammation underlying both local and systemic effects.⁵²

Several mechanisms are thought to explain TMAO-mediated effects, including the generation of oxidative stress and deregulation of inflammatory signaling pathways that limit autophagic function.^42–46 TMAO activates NF-κB signaling, promoting the transcription of NLRP3 inflammasome components and pro-IL-1β, while ROS further facilitate inflammasome assembly, leading to increased cytokine production and vascular inflammation.^53,54 Notably, defective autophagy intensifies inflammasome activation, creating a feedback cycle that worsens vascular inflammation and endothelial dysfunction.

In parallel, TMAO contributes to CVD through activation of the renin–angiotensin–aldosterone system (RAAS), prolonging angiotensin II signaling, increasing norepinephrine synthesis, and promoting aldosterone secretion, thereby driving vasoconstriction and sodium retention.^51,55 In addition, TMAO influences osmotic homeostasis via the TMAO–AVP–AQP2 axis, enhancing water reabsorption via the translocation of aquaporin-2 (AQP2) channels, contributing to hypertensive responses.⁵¹

In atherosclerosis, TMAO promotes foam cell formation by activating scavenger receptors (CD36, SRA1), thereby enhancing cholesterol uptake and lipid deposition in arterial walls.⁵⁶ Notably, these processes further exacerbate autophagic impairment by preventing lysosomal breakdown, promoting oxidative stress, platelet hyperreactivity, and an increased risk of thrombosis.^42–46

Clinical observations further support these findings, with elevated TMAO levels reported in patients with acute coronary syndrome (ACS) and chronic stable angina (CSA).²⁶ Beyond its mechanistic role, TMAO has been proposed as a potential biomarker and therapeutic target in cardiovascular disease, although further clinical validation is required.⁵⁷

Overall, these findings indicate that TMAO appears to function as an important mediator linking microbial dysbiosis to cardiovascular disease, in part through pathways that converge on autophagic regulation.

Short-Chain Fatty Acid (SCFA) Pathway

SCFAs, including acetate, propionate, and butyrate, are gut microbiota-derived metabolites produced through the fermentation of dietary fiber.⁵⁸ These metabolites are beneficial to cardiovascular health as they regulate lipid metabolism and inflammation through activation of G-protein-coupled receptors GPR41, GPR43, and GPR109A.⁵⁹ SCFAs promote nitric oxide (NO) release, reduce oxidative stress, and inhibit pro-inflammatory mediators, leading to improvements in vascular function and elasticity.⁶⁰

Additionally, SCFAs influence lipid metabolism by suppressing hepatic lipogenesis and increasing fatty acid oxidation, improving lipid profiles and reducing the risk of atherosclerosis.⁶⁰ Moreover, SCFAs inhibit foam cell formation by downregulating scavenger receptors, promoting atherosclerotic plaque stabilization by modulating macrophage polarization toward an anti-inflammatory phenotype that reduces thrombotic risk.⁶⁰

Conversely, SCFA-producing bacteria, including Roseburia and Faecalibacterium prausnitzii, are consistently reduced in patients with CVD, accompanied by decreased circulating levels of propionate and butyrate, increased inflammation, and impaired barrier integrity.^13,26

At the mechanistic level, the protective effects of SCFAs are partly mediated by activating AMPK and inhibiting mTOR, thereby supporting cellular homeostasis, reducing inflammation, and improving intestinal barrier integrity, which prevents the translocation of pro-inflammatory microbial products associated with endothelial dysfunction and CVDs.^16,41,42 Notably, SCFAs may counteract the autophagy-disrupting effects of metabolites such as TMAO, further highlighting the role of microbiota-derived metabolites in modulating autophagy within the gut–cardiovascular axis.^16,41,42

The mechanistic link between gut-derived SCFAs and cardiovascular health is further supported by clinical intervention data. Human dietary trials have consistently shown that prebiotic fibers and modified starches (such as HAMSAB) that enrich SCFA-producing microbial communities effectively reduce blood pressure and improve arterial stiffness, validating the physiological relevance of the gut-cardiovascular axis.^61,62

Overall, these findings indicate that SCFAs exert protective cardiovascular effects, in part through pathways that converge on autophagic regulation.

Bile Acids

Bile acids (BAs) are cholesterol-derived metabolites synthesised in the liver and then changed by gut microbiota into secondary BAs, thus changing the BA pool and its signalling properties.⁶³

Beyond their classical role in lipid digestion, BAs function as signaling molecules that regulate host metabolic and inflammatory pathways through receptors such as the nuclear receptor farnesoid X receptor (FXR) and the G protein–coupled receptor TGR5.^63,64 Through these receptors, BAs influence lipid metabolism, glucose homeostasis, and energy balance, processes closely linked to cardiovascular health.^65,66

Experiments have shown that activation of both FXR and TGR5 is atheroprotective, whereas disruption of their signaling intensifies atherosclerotic lesion formation. FXR activation inhibits hepatic lipogenesis, increases cholesterol efflux, and reduces circulating atherogenic lipoproteins, whereas TGR5 stimulation improves insulin sensitivity and energy metabolism.^65,66 In addition to metabolic homeostasis, FXR and TGR5 are expressed in innate and adaptive immune cells, linking BAs to immune cell balance and function.⁶⁷

Beyond systemic metabolic effects, emerging evidence further implicates BAs in the regulation of autophagic processes. FXR directly interacts with promoters of autophagy-related genes, indicating transcriptional control of autophagy pathways.^68,69 In addition, BAs regulate selective autophagy, including mitophagy, lipophagy, and pexophagy, thereby influencing mitochondrial quality control, lipid metabolism, and oxidative stress responses.^70,71

At the signaling level, activation of FXR can also activate AKT/ERK1 signaling, which in turn activates mTORC1, a central inhibitor of autophagy via ULK1/2 suppression at the autophagosome formation level, highlighting the context-dependent role of BA signaling in fine-tuning autophagic flux.^72,73

BA-mediated signaling intersects with inflammatory pathways that further modulate autophagy. FXR activation has been shown to suppress NF-κB signaling and downstream IL-6–STAT3 activation, thereby attenuating inflammatory responses.⁷⁴ Conversely, gut dysbiosis induces alterations in BA composition that contribute to metabolic disorders by increasing pro-inflammatory secondary BAs,^63,75 which in turn compromises intestinal barrier integrity and activates inflammatory pathways, collectively exacerbating endothelial dysfunction and atherogenesis.^28,76–78

Disruption of BA homeostasis is increasingly recognized as a key driver of cardiometabolic disease. High-fat diets and gut dysbiosis alter BA composition, leading to accumulation of primary BAs and expansion of pro-inflammatory microbial communities, which collectively promote dyslipidemia, macrophage activation, and foam cell formation through pathways including CD36 upregulation.⁷⁹

While early clinical interventions targeting the BA pool, such as BA sequestrants, have definitively proven successful in lowering LDL cholesterol and reducing cardiovascular events, modern receptor-specific therapies face translational hurdles. For instance, despite the atheroprotective mechanisms of FXR activation in animal models, human clinical trials using the FXR agonist obeticholic acid have revealed paradoxical increases in LDL cholesterol, highlighting the complex, species-specific nature of BA signaling in cardiovascular pathophysiology.^80–82

Together, these pathways converge into an integrated regulatory network linking microbial metabolites to autophagic signaling.^83,84 Within this network, autophagy works as a primary integrative hub combining metabolic, inflammatory, and cellular stress responses, therefore linking microbial dysbiosis to cardiovascular disease progression.

Gut Barrier Dysfunction

Gut barrier dysfunction and systemic inflammation have emerged as critical contributors to the pathogenesis and progression of CVD.^39,85 Dysbiosis, high-fat and low-fiber diets, chronic stress, and metabolic disorders such as obesity and insulin resistance all alter epithelial tight junction (TJ) integrity, leading to increased intestinal permeability.⁸⁵ Consequently, bacterial components such as LPS enter the circulation, causing metabolic endotoxemia and promoting systemic inflammation.⁸⁵

Circulating LPS interacts with toll-like receptor 4 (TLR4) on immune and endothelial cells, activating the NF-κB and MAPK signaling pathways.^85,86 This promotes production of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), IL-6, and IL-1β, producing a state of chronic, low-grade inflammation.^40,86–88 Chronic systemic inflammation causes further endothelial dysfunction by reducing NO bioavailability, increasing oxidative stress, and upregulating adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), promoting monocyte infiltration and progression of atherosclerosis.^89–91 Prolonged LPS exposure worsens CVD by promoting hepatic overproduction of very low-density lipoproteins (VLDL), enhancing foam cell formation, and exacerbating dyslipidemia.⁹²

In addition to innate immunity, the gut microbiota also modulates adaptive immunity,⁹³ creating an imbalance favoring Th17 over Treg responses to promote vascular inflammation and plaque instability.⁹⁴ Microbial metabolites modulate these processes; TMAO has been linked to oxidative stress, endothelial dysfunction, and atherosclerosis, whereas SCFAs exert immunoregulatory effects by affecting Tregs and inflammatory cytokine production, potentially counteracting chronic inflammation.⁹³

At the molecular level, LPS-induced endotoxemia, particularly through NLRP3 inflammasome activation^39,85,95 (NLRP3 is a cytosolic pattern recognition receptor that responds to microbial metabolites, mitochondrial stress, and reactive oxygen species (ROS)⁹⁶), leads to caspase-1 activation and maturation and release of IL-1β and IL-18, thereby promoting systemic inflammation, vascular calcification, and cardiac fibrosis.⁹⁶

Prospective clinical cohort studies have consistently shown that markers of increased intestinal permeability are associated with adverse cardiovascular outcomes. Functional indicators of endotoxemia, such as circulating LBP, and structural markers of tight junction breakdown, such as zonulin, independently predict incident cardiovascular disease, highlighting gut barrier integrity as a key determinant of cardiovascular health.^97–99

Collectively, these mechanisms are supported by clinical evidence showing that circulating endotoxin levels correlate with inflammation severity and are elevated when beneficial microbial populations such as Bacteroides are reduced.^100–102 Similarly, septic cardiomyopathy has also been linked to gut microbiota dysbiosis, where microbial imbalance promotes inflammatory pathways contributing to myocardial dysfunction, highlighting gut–heart interaction during acute conditions.¹⁰³

Molecular Machinery of Autophagy

Autophagy is an evolutionarily conserved catabolic process that, guided by autophagy-related genes (ATGs), degrades and recycles damaged organelles and misfolded proteins or pathogenic cytosolic bacteria, enabling cells to maintain homeostasis under stress conditions.^18,104–106 This process is upregulated as a protective mechanism to preserve cellular health.¹⁰⁶

In eukaryotic cells, autophagy is classified into three major types: macroautophagy, microautophagy, and chaperone-mediated autophagy.^19,104 Macroautophagy (hereafter referred to as autophagy) is the most prevalent pathway.^19,107 Macroautophagy starts with the development of a distinct, cup-shaped double membrane known as the phagophore. This structure grows and matures, eventually surrounding and encapsulating damaged molecules within a double-membrane vesicle referred to as an autophagosome, that passes through the cytoplasm to fuse with lysosomes for degradation by acidic hydrolases. This generates macromolecules that are transported to the cytosol for recycling, supplying cells with amino acids and FAs.^18,19,107

At the molecular level, autophagy is regulated by key pathways including mTORC/AMPK signaling, which integrates cellular energy and nutrient status. Activation of AMPK under conditions of energy stress promotes autophagy through activation of the ULK1 complex, whereas mTORC1 acts as a central inhibitor by suppressing ULK1 activity.^82–85 In addition to this core regulatory pathway, autophagy is further modulated by other signaling mechanisms, including PI3K/AKT signaling, NF-κB–mediated inflammatory pathways, oxidative stress–responsive mechanisms, and epigenetic regulation, which influence autophagic activity in a context-dependent manner.^19,108–112

Following initiation, autophagosome formation proceeds through a coordinated sequence of steps, including phagophore nucleation, membrane elongation, and vesicle closure. The nucleation phase is controlled by the Beclin-1–VPS34 class III PI3K complex, which generates phosphatidylinositol 3-phosphate (PI3P), a key lipid signal that recruits downstream autophagy machinery.^113–116 Membrane elongation is mediated by ubiquitin-like conjugation systems, including the ATG12–ATG5–ATG16L1 complex and LC3 lipidation (conversion of LC3-I to LC3-II), which are essential for autophagosome expansion and cargo sequestration.^115–118 Autophagic flux is a major component of this process, including the full pathway from autophagosome production to lysosomal breakdown. This is frequently assessed by LC3-II accumulation and degradation of p62/SQSTM1, which represent autophagosome formation and cargo clearance, respectively.¹¹⁹

Importantly, dysregulation of autophagic flux, rather than simple activation or inhibition, is now widely recognized as a critical mechanism generating cellular dysfunction.¹²⁰ Autophagy can also be subdivided according to its target into selective autophagy and non-selective autophagy depending on cargo specificity; non-selective autophagy involves bulk degradation of cytoplasmic components, whereas selective autophagy targets specific substrates.^19,105

Autophagy as a Central Regulator of the Gut Microbiota–Cardiovascular Axis

Building on the molecular mechanisms outlined above, autophagy combines metabolic and inflammatory signals to coordinate cellular responses to gut dysbiosis, linking gut microbiota–derived signals to systemic cardiovascular outcomes.

In the gut–cardiovascular context, dysbiosis-associated microbial metabolites modulate autophagic activity through these pathways. These mechanisms suggest that autophagy may function as an integrative regulatory interface within the gut microbiota–cardiovascular axis, coordinating responses to metabolic stress, particularly via AMPK activation and mTOR inhibition, to limit inflammatory signaling and preserve cellular function.^18,104–106 Disturbances in this regulatory pathway, driven by dysbiosis, impair autophagic flux, thereby triggering mitochondrial dysfunction, amplifying inflammation,^121,122 and contributing to cardiovascular disease.³⁸ The proposed role of autophagy as an integrative regulatory interface linking gut dysbiosis, microbiota-derived metabolites, cellular stress responses, and cardiovascular outcomes is summarized in Figure 2.

Figure 2.

Autophagy as a central regulator of the gut microbiota–cardiovascular axis. Gut dysbiosis is associated with representative alterations in microbiota-derived signals, including increased trimethylamine N-oxide (TMAO), reduced short-chain fatty acids (SCFAs), altered bile-acid signaling, and increased lipopolysaccharide (LPS) exposure. These signals may modulate autophagic flux through AMPK, mTORC1, and TLR4–NF-κB/NLRP3 signaling pathways. Intact autophagic flux supports intestinal barrier integrity and microbial homeostasis, whereas impaired autophagic flux may contribute to mitochondrial dysfunction, impaired mitophagy, oxidative stress, and inflammation. These alterations may contribute to cardiovascular outcomes, including hypertension, atherosclerosis, and heart failure. Dashed arrows indicate proposed or context-dependent mechanistic links.

Pathophysiological and Clinical Implications in CVD

The functional consequences of microbiota–autophagy interactions are evident in multiple cardiovascular conditions. In the heart, mitophagy maintains mitochondrial quality control and supports the high metabolic demands of cardiomyocytes by removing damaged mitochondria, while autophagy preserves cellular energy balance and limits oxidative stress, thereby contributing to myocardial remodeling and overall cardiac function.^{18,19,104,123} Autophagy is essential for maintaining cardiomyocyte structure and function, and dysregulation of autophagy has been implicated in the pathogenesis of atherosclerosis, ischemic injury, and HF.¹⁹

Beyond its metabolic role, autophagy is a key regulator of inflammation. Under physiological conditions, it suppresses inflammatory signaling by reducing NF-κB activity, limiting ROS accumulation and degrading inflammasome components such as NLRP3.^124,125 Through these mechanisms, autophagy constrains excessive innate immune activation, including Toll-like receptor (TLR) signaling, and preserves immune homeostasis.¹²⁶ Impairment of autophagic flux disrupts this control, promoting endothelial dysfunction and chronic inflammation, central features of cardiovascular disease.^19,120

In the gut, autophagy maintains intestinal barrier integrity by regulating tight junction proteins, mucin secretion, and antimicrobial defenses, thereby restricting the translocation of microbial products such as LPS.^95,101 Disruption of autophagy compromises these protective mechanisms, resulting in increased intestinal permeability and systemic dissemination of pro-inflammatory signals.^121,127

Genetic and epigenetic alterations further highlight the importance of autophagy in intestinal homeostasis. Variants in autophagy-related genes including ATG16L1, NOD2, VDR, MTMR3, and PTPN2, as well as microRNA-mediated regulation, impair autophagic processes at multiple levels, including initiation, autophagosome formation, and transcriptional control.^22,121,122 These alterations compromise microbial clearance, weaken barrier integrity, and amplify inflammatory pathways, ultimately driving gut microbiota imbalance and systemic immune activation.¹²²

At the compositional level, autophagy also shapes the gut microbial ecosystem. Experimental models of autophagy deficiency (eg, Atg5^−/−) showed a reduction in microbial diversity, with depletion of butyrate-producing taxa such as Lachnospiraceae and Ruminococcaceae, alongside enrichment of LPS-producing bacteria. This shift is associated with reduced SCFA availability and impaired Treg differentiation, which may promote a pro-inflammatory milieu.¹²⁸ Together, these alterations establish a self-reinforcing feedback loop in which dysbiosis impairs autophagic flux, while defective autophagy further exacerbates microbial imbalance, sustaining inflammation and tissue injury.^17,38,121

Clinically, inflammatory bowel disease (IBD) provides a relevant model of the gut–cardiovascular connection. Cohort studies indicate that IBD independently increases the risk of cardiovascular complications, including heart failure, myocardial infarction, and thromboembolic events.³⁸ Elevated levels of pro-inflammatory cytokines (including TNF-α, IL-1β, and IL-6), oxidative stress, and aberrant microRNA activity collectively foster endothelial dysfunction, vascular remodeling, and a predisposition to thrombosis.³⁸ These processes intersect with autophagy-dependent mechanisms, as chronic dysbiosis and inflammation impair autophagic regulation, leading to mitochondrial dysfunction, ROS accumulation, and enhanced inflammation, supporting a role for defective autophagy as a mechanistic link between intestinal inflammation and cardiovascular pathology.

These mechanisms are reflected across major cardiovascular diseases. In HF, increased gut permeability due to intestinal hypoperfusion facilitates bacterial translocation of endotoxins like LPS into the circulation, triggering systemic inflammation and dysregulated cardiac autophagy, evidenced by altered expression of autophagy-related proteins such as LC3 and ATG7 and contributing to myocardial remodeling and HF progression.^47,48 In atherosclerosis, microbial metabolites including TMAO influence autophagy in vascular cells, enhancing foam cell formation, endoplasmic reticulum stress, and plaque development.¹²⁹ Similarly, in hypertension, dysbiosis-associated alterations in microbial composition influence autophagic signaling within cardiovascular tissues, with potential implications for blood pressure regulation.^130,131 Conversely, beneficial microbial metabolites such as the SCFA propionate triggers autophagy, for example in hepatocytes, via uncoupling protein 2 (UCP2), emphasizing the metabolic and cardiovascular implications of microbiota-autophagy interactions.¹³²

However, the current evidence linking gut microbiota, autophagy, and cardiovascular disease remains largely observational and experimental, limiting causal inference. Key confounders including diet, medications, renal function, and metabolic status independently influence both microbiota composition and cardiovascular risk.^133,134 In addition, the dynamic and heterogeneous nature of the gut microbiota constrains generalizability.¹³⁵ Finally, the context-dependent regulation of autophagy across tissues and disease states complicates its interpretation as a therapeutic target.¹³⁶

Biomarkers Related to the Gut Microbiota

Recent evidence suggests that inflammatory biomarkers function as active mediators rather than passive indicators in the intricate interactions between gut microbiota, autophagy, and CVD.^16,137 Below we highlight five clinically-relevant biomarkers that exemplify this interconnected axis.

C-Reactive Protein (CRP)

CRP is a hepatic acute phase marker produced by hepatocytes and endothelial cells in response to IL-6 and IL-1β during systemic inflammation. Elevated CRP levels are strongly associated with the risk of atherothrombosis and CVD.^138,139 CRP exerts a dual role in inflammation, acting as both a pro- and anti-inflammatory factor.¹⁴⁰ CRP reduces the production of endothelial nitric oxide synthase (eNOS) in human aortic endothelial cells, resulting in vasoconstriction, enhancing inflammatory signaling, and exacerbating endothelial dysfunction.¹⁴¹ Oxidative stress and diminished NO availability interact with the effects of CRP, thereby connecting redox imbalance to increased plaque instability and cardiovascular risk.^142–144 In a murine model, CRP overexpression downregulated autophagy and increased vulnerability to ischemic kidney injury, where the intensified damage was associated with a decrease in autophagic flux.¹⁴⁵

Lipoprotein-Associated Phospholipase-A2 (Lp-PLA2)

Lipoprotein-associated phospholipase-A2 (Lp-PLA2) is a circulating enzyme secreted by macrophages and monocytes. It primarily circulates in complex with LDL and, to a lesser extent, with HDL, hydrolyzing oxidized phospholipids on lipoproteins.^146,147 The products of these reactions are proinflammatory molecules such as oxidized non-esterified fatty acids (oxNEFAs) and lysophosphatidylcholine (lysoPC),¹⁴⁸ which activate endothelial cells to trigger inflammation to produce adhesion molecules and cytokines, attracting leukocytes and facilitating their migration into the arterial wall.^149–151 oxNEFAs and lysoPC accumulate in the plaque lipid core, while macrophage uptake of these lipids encourages the development of foam cells, linking lipid metabolism to vascular inflammation.¹⁵²

Gut dysbiosis modifies lipid metabolism, which in turn affects Lp-PLA2 activity and indirectly connects microbial signals to vascular inflammation.¹⁵³ Lp-PLA2 does not directly regulate autophagy; however, its oxidative lipid products may impair autophagic flux in vascular cells, thereby promoting a pro-atherogenic environment.⁴⁶

Trimethylamine-N-Oxide (TMAO)

As noted above, TMAO is a metabolite of gut bacteria that is associated with an increased risk of cardiovascular events and mortality.^102,154,155 Increased plasma TMAO is associated with increased death rates and cardiovascular risk.¹⁵⁴ TMAO promotes vascular inflammation by stimulating ROS and activating the inflammasome and NF-κB signaling pathways.^156–159 TMAO also modulates cholesterol metabolism, which contributes to plaque formation in atherosclerosis.^56,160 Moreover, TMAO influences autophagic flux, for example through PI3K/AKT/mTOR signaling, in cardiovascular tissues, potentially exacerbating metabolic stress and oxidative damage, which can promote the progression of CVD.^121,161

Myeloperoxidase (MPO)

Myeloperoxidase (MPO) is a pro-oxidant heme peroxidase released by neutrophils and monocytes.¹⁶² MPO produces hypochlorous acid (HOCl), part of the microbicidal system of phagocytes, through catalysis of MPO at physiological chloride concentrations.^162,163 MPO and its oxidative products play a critical role in immunological defense against pathogens, and they also react with lipids, proteins, and nucleic acids to cause adverse reactions in host tissues, modifying lipoproteins and damaging vascular tissue.^164,165 MPO is a known component of human atherosclerotic tissues, contributing to plaque destabilization through oxidation of LDL, impairment of HDL function, reducing NO availability, promoting endothelial dysfunction, and facilitating thrombosis.¹⁶⁶ It has been proposed that oxidative stress induced by MPO activity can disrupt autophagy, leading to the accumulation of damaged cellular debris and worsening inflammation.^165,167 However, MPO is not directly derived from the gut; instead, dysbiosis of the gut microbiota promotes systemic inflammation, which in turn modulates MPO activity and contributes to the progression of CVD.^2,154,165

Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9)

Beyond its canonical role in degrading LDL receptors, PCSK9 acts as a crucial intermediate connecting gut dysbiosis to cardiovascular inflammation.¹⁶⁸ In the context of the gut–heart axis, gut-derived microbial products and metabolites LPS and TMAO have been shown to directly upregulate PCSK9 expression in hepatic and vascular tissues.¹⁶⁸ In vascular lesions, this elevated PCSK9 acts as a potent pro-inflammatory and pro-atherogenic mediator.¹⁶⁹ It enhances vascular inflammation by activating TLR4/NF-κB signaling and collaborates with LOX-1 to increase oxLDL absorption and foam cell production.^169,170 Furthermore, circulating PCSK9 binds to platelet-bound CD36, enhancing platelet activation and thrombosis.¹⁷¹ Crucially, while recent evidence implicates PCSK9 in myocardial remodeling and autophagy/mitophagy dysregulation in cardiometabolic diseases, this interaction appears to be predominantly indirect.^172,173 Rather than directly modulating the core autophagic machinery, the severe metabolic and inflammatory stress driven by the gut-PCSK9 axis disrupts cellular homeostasis, which subsequently overwhelms and impairs autophagic flux. For instance, in mice, Pcsk9 knockout decreases hepatic apoB production and alleviates systemic lipid and inflammatory burdens; this reduction in metabolic stress indirectly restores and increases autophagic flow, thereby reducing the risk of atherosclerosis.¹⁷⁴ Thus, within the gut-heart axis, PCSK9 may function as an upstream disruptor, creating a toxic inflammatory microenvironment that secondarily compromises cardioprotective autophagy.

Future Research Priorities

While the gut-heart axis presents a rich landscape of therapeutic targets, the translation of novel interventions like miRNA modulators and nanomedicines from preclinical models to clinical reality is fraught with significant, well-defined challenges. Future research must pivot from demonstrating potential to systematically overcoming these specific hurdles to realize their therapeutic promise.

MicroRNAs: From Promising Signals to Clinically Actionable Tools

MicroRNAs (miRNAs) function as active, bidirectional regulators of the gut–heart axis rather than passive biomarkers. In the gastrointestinal tract, miRNAs modulate barrier integrity, innate immune responses, and autophagy-related pathways by targeting key adaptors, transcription factors, and autophagy-related (ATG) genes.¹⁷⁵ Because these mucosal regulatory circuits are closely connected with vascular and cardiac tissues, gut-associated miRNAs may influence systemic endothelial activation and cardiometabolic inflammation.¹⁷⁵ In HF, dysregulated miRNAs have been implicated in TLR–NF-κB signaling, NLRP3 inflammasome activation, and impaired cardioprotective autophagy programs.¹⁶⁸ Therefore, therapeutic modulation using miRNA mimics or antagomirs may represent a promising strategy to restore barrier integrity and reduce downstream cardiovascular inflammation. However, clinical translation remains limited by diagnostic and therapeutic barriers, including pre-analytical variability, hemolysis, inconsistent normalization strategies, nuclease degradation, renal clearance, poor target-tissue delivery, off-target effects, and innate immune activation.^176–179 These limitations reduce reproducibility across studies and currently restrict miRNA-based approaches to investigational use. Therefore, improved tissue-targeted delivery systems, safety validation, standardized detection workflows, and disease-specific clinical testing are required before routine cardiovascular application.

Nanomedicine: Biological, Manufacturing, and Regulatory Challenges in Cardiovascular Translation

Nanomedicine may improve the delivery of autophagy- and inflammation-modulating agents within the gut–heart axis. Engineered nanoparticles can enhance cargo stability, tissue distribution, and cellular uptake of small molecules, siRNAs, or miRNAs.¹⁸⁰ In CVD, targeted or stimulus-responsive systems may be useful for delivering therapeutics to dysfunctional endothelium, lesional macrophages, or inflamed vascular tissues.¹⁸⁰ These platforms may allow more localized modulation of autophagy- and inflammation-related pathways, including AMPK–mTOR–ULK1, Beclin-1, TFEB, and NLRP3 signaling. This strategy may be relevant to atherosclerosis, hypertension, and HF, where dysregulated autophagy and inflammatory activation contribute to disease progression.^180,181 However, these approaches remain clinically immature and require disease-specific validation.

Several biological barriers limit cardiovascular translation. After systemic administration, nanoparticles rapidly interact with plasma proteins, forming a protein corona that can alter targeting, biodistribution, and clearance by the mononuclear phagocyte system.¹⁸² This issue may be particularly relevant in CVD, where systemic inflammation, complement activation, and altered plasma protein profiles can modify nanoparticle behavior.¹⁸³ PEGylation can prolong circulation, but it does not fully prevent opsonization, immune recognition, or accelerated clearance after repeated exposure.¹⁸⁴ Intracellular delivery is also inefficient because endocytosed cargo may be degraded in lysosomes unless effective endosomal escape is achieved.¹⁸⁵ These limitations are especially important for nucleic acid nanomedicines. The MRX34 trial, which used a liposomal miR-34a mimic, illustrates that both RNA cargo and delivery vehicles can contribute to immune-related toxicity.¹⁸⁶ In contrast, the clinical use of ligand-directed siRNA delivery, such as GalNAc-conjugated inclisiran targeting hepatic PCSK9, shows that tissue-specific delivery design can improve translational feasibility.¹⁸⁷ However, this success does not eliminate the need for cardiovascular-specific delivery validation, since targeting hepatocytes differs substantially from targeting myocardium, vascular endothelium, or atherosclerotic plaques.¹⁸⁸

Cardiovascular delivery presents additional disease-specific challenges. In atherosclerosis, nanoparticles must tolerate arterial flow, bind dysfunctional endothelium, avoid nonspecific immune clearance, and penetrate complex plaque structures.¹⁸⁹ In HF, fibrosis, impaired perfusion, and microvascular dysfunction may restrict biodistribution. Clinical translation also requires strict control of critical quality attributes, including particle size, size distribution, surface charge, drug loading, release kinetics, sterility, stability, and batch-to-batch reproducibility.¹⁹⁰ Therefore, future studies involving nucleic acid or gene-modulating nanomedicines should integrate biodistribution, immunogenicity, cardiotoxicity, manufacturability, and regulatory assessment early in development.¹⁹¹

Omega-3 Fatty Acids

Eicosapentaenoic acid (EPA) is an omega-3 polyunsaturated fatty acid found in phospholipid bilayers.¹⁹² High purity eicosapentaenoic acid (icosapent ethyl) cardioprotects beyond the effects of lipid reduction alone. Patients with elevated triglyceride levels treated with statins have a reduced risk of major adverse cardiovascular events, decreased blood triglyceride levels, and measurable anti-inflammatory and pro-resolving effects that improve endothelial function and plaque stability, as evidenced by trials such as REDUCE-IT.¹⁹³ EPA-derived specialized pro-resolving mediators inhibit TLR/NF-κB–NLRP3 signaling and may restore autophagy in response to stress. Additionally, omega-3 FAs positively affect gut-barrier integrity and microbial inflammation, suggesting EPA as a complementary factor alongside microbiota and autophagy-targeted strategies within the gut–heart axis.¹⁹³ The immunoresolving activities of EPA likely interact with miRNA circuits that govern inflammatory and autophagy pathways in HF and vascular disease, supporting the incorporation of circulating and extracellular vesicle miRNA panels as indicators of autophagy-inflammation interplay.¹⁹⁴ One approach could be to combine EPA with microbiome-targeted fiber/prebiotics and monitor autophagy/mitophagy flux (LC3-II, p62, PINK1/Parkin) alongside vascular outcomes.^195,196

Microbiome Remodeling

Dietary fiber, targeted pre/probiotics, and postbiotic SCFAs such as butyrate increase SCFA levels, strengthen epithelial junctions, and reduce endotoxemia.^197,198 Additionally, SCFAs influence autophagy and inflammasome activity, thereby collectively reducing vascular inflammation along the gut-heart axis.^16,60 Autophagy has been shown to be crucial to this interaction: in periodontitis-induced dysbiosis, Porphyromonas gingivalis disrupts SCFA metabolism through autophagy, identifying it as a viable therapeutic target.¹⁹⁹ SCFAs function systemically as immunometabolic mediators that enhance barrier integrity and inhibit inflammatory signaling.²⁰⁰ Simultaneously, precision probiotics and metabolite-guided consortia originating in oncology could influence BA and SCFA pathways and provide a transportable basis for individualized cardiometabolic therapies.²⁰¹ A cohesive framework to exploit these findings could: (i) employ shotgun metagenomics to determine gut microbial taxa and roles associated with cardiovascular risk;²⁰² (ii) use multi-omics (transcriptomics, proteomics, and metabolomics) to identify targeted pathways in patients with HF;²⁰³ and (iii) link the resulting molecular readouts with autophagy readouts such as LC3-II, p62, flux assays, and vascular phenotyping (flow-mediated dilation, plaque imaging) within advanced diagnostic frameworks²⁰⁴ (Table 1).

Table 1.

Potential Gut-Focused Interventions Targeting Autophagy-, Inflammasome-, and PCSK9-Related Pathways in CVD

Intervention	Primary Gut Mechanism	Key Molecular Associations	Expected Vascular Endpoints	References
Dietary Fiber	↑ SCFA production and microbial diversity	May ↑ SCFA-mediated AMPK/HDAC-related autophagy regulation and ↓ inflammatory signaling	● Improved gut barrier integrity ● Reduced systemic inflammation and endotoxemia	[16,205,206]
Prebiotics eg, resistant starch, inulin-type fructans, FOS/GOS	↑ Selective growth of SCFA-producing bacteria	● ↑ SCFA–AMPK/metabolic signaling; ↓ inflammatory activation; autophagy/NLRP3 links mainly mechanistic	● Potential ↓ blood pressure; ↑ endothelial/vascular function ● Reduced systemic inflammation	[16,207–209]
Targeted probiotics/engineered strains	Modulates SCFA & bile acid pathways	● May indirectly ↓inflammatory signaling, including NF-κB/NLRP3-related pathways; autophagy-specific CVD evidence remains limited	● Potential ↓ systemic inflammation, ↓ oxLDL-driven foam-cell formation, and improved plaque biology; clinical validation remains insufficient	[1,16,37,60,210,211]
Postbiotics eg, SCFAs/butyrate	Directly supplies butyrate and other SCFAs	● ↑ AMPK/mTOR-related autophagy signaling ● Inflammasome: ↓ (NLRP3)	● Reduced vascular inflammation ● Enhanced endothelial function	[16,41,60,207,212]
Bile acid modulators, eg, FXR/TGR5-related approaches, UDCA/TUDCA	Rebalances BA pool and signaling (FXR/TGR5)	● Context-dependent effects on autophagy/lysosomal flux; ↓ ER stress/inflammatory signaling; NLRP3 links mainly mechanistic	● ↑ lipid metabolism/endothelial function; potential plaque stabilization, mostly preclinical/context-dependent	[65,66,68,69,71,80–82]
EPA (Icosapent Ethyl)	↑ EPA-derived pro-resolving lipid mediators	● ↓ inflammatory signaling ● Possible ↓ NLRP3 activity mainly from mechanistic PUFA studies	● ↓ MACE when added to statins ● Potential ↓ coronary plaque progression/stabilization	[196,213,214]
PCSK9 inhibitors, mAbs/siRNA	↓ PCSK9 activity; ↑ LDLR recycling; ↓ LDL-C/apoB	● ↓ inflammatory signaling ● Autophagy/mitophagy links mainly mechanistic	● potential ↓ thrombo-inflammation/plaque risk ● Strong reduction in MACE & atherogenesis	[76,171,215–218]
Nanomedicine Carriers	Targeted/stimuli-responsive cargo delivery	● Potential delivery of autophagy/NLRP3/PCSK9-modulating cargos; CVD use remains investigational	● ↑ on-target delivery ● ↓ systemic/off-target toxicity; clinical validation limited	[219–222]

Note: Reference numbers correspond to the main manuscript reference list.

Limitations of Current Evidence and Need for Clinical Validation

Despite accumulating mechanistic evidence, current investigations into the interplay between gut microbiota, autophagy, and cardiovascular disease are hampered by several critical limitations. Much of the existing data are derived from observational human studies or experimental models, thereby restricting causal inference and hindering direct clinical translation.^133–137 Moreover, the composition of the microbiome is also modulated by factors such as diet, pharmacological interventions, age, renal function, metabolic status, and disease stage, thereby complicating efforts to distinguish causal mechanisms from disease-associated signatures.^133,134 Autophagy exhibits pronounced context-dependency, exerting either cytoprotective or deleterious effects contingent upon tissue type, disease stage, and the duration of cellular stress.¹³⁶ Accordingly, future investigations should go beyond association-based analyses by incorporating longitudinal cohort designs, multi-omics integration, standardized assessments of autophagy flux, and rigorously controlled interventional studies.^202–204 Well-designed clinical trials are imperative to determine whether modulation of the microbiota–autophagy axis can yield improvements in cardiovascular outcomes, delineate patient subgroups most likely to benefit, establish optimal therapeutic timing, and rigorously evaluate long-term safety. Such trials should incorporate clinically relevant endpoints, including vascular function, plaque stability, progression of HF, inflammatory biomarkers, metabolite profiling, and standardized assessments of autophagy and mitophagy.^{193–196,204}

Potential Translational Strategies and Future Directions for Targeting Autophagy in CVDs

We propose that autophagy may represent an integrative regulatory hub that integrates metabolism, inflammation, and the microbiota,^16,223 with its dysregulation accelerating endothelial dysfunction, vascular remodeling, foam cell accumulation, and maladaptive stress responses contributing to the progression of CVD. Precise modulation of autophagy may offer future therapeutic opportunities for CVD,^115,124 but direct clinical validation remains limited.

Atherosclerosis

Gut-derived metabolites, lipid regulators, and autophagy intersect to contribute to plaque formation and instability.²²⁴ TMAO activates the NLRP3 inflammasome and inhibits autophagic flux, contributing to foam cell formation and expanding the necrotic core.^56,224 Emerging targeted therapeutic approaches aim to address this imbalance. PCSK9 inhibitors reduce LDL receptor degradation, mitigate vascular inflammation, and restore macrophage autophagy.^225,226 SCFAs, including butyrate and propionate, stimulate AMPK and inhibit mTOR pathways, thereby promoting endothelial and macrophage homeostasis, resulting in beneficial downstream effects on vascular inflammation and metabolism.²²⁷ Simultaneously, the regulation of BA signaling via FXR and TGR5 agonists improves cholesterol metabolism and promotes cytoprotective autophagy, indicating an alternative translational approach for plaque stabilization.⁶⁶ Importantly, the clinical viability of PCSK9 inhibition is firmly proven by major randomized trials like FOURIER and ODYSSEY OUTCOMES, which demonstrated a substantial 15% reduction in cardiovascular death, myocardial infarction, and stroke, highlighting the translational significance of pathways regulating PCSK9.^215,216

These findings suggest that autophagy modulation may represent a potential therapeutic direction for plaque stabilization, although direct clinical validation remains limited.

Hypertension

Autophagy contributes to blood pressure regulation by mediating interactions between gut-derived metabolites and vascular remodeling pathways.^55,131 TMAO exacerbates hypertension via a multifaceted mechanism that involves RAAS stimulation, amplifying angiotensin II–AT1R–NF-κB/NLRP3 inflammasome signaling, and disrupting endothelial autophagic processes, hence increasing oxidative stress and vascular stiffness.⁵⁵ In contrast, SCFAs such as propionate are vasoprotective by activating GPR41/43 receptors, leading to vasodilation, and by amplifying the AMPK–mTOR–ULK1 autophagy pathway.²²⁸ Recent data from atherosclerosis models corroborate the gut–autophagy–inflammasome axis, with a traditional medicine formula, Buyang Huanwu decoction, stabilizing vulnerable plaques by modifying the intestinal microbiota, inhibiting TLR4–NF-κB–NLRP3 signaling, and reinstating mitophagy.²²⁹ Disulfiram reduces atherosclerosis by enhancing efferocytosis, autophagy, and an atheroprotective (SCFA-producing) microbiome.²³⁰ Translational therapeutic strategies could concentrate on propionate supplementation and microbiome modification with dietary fiber and probiotics, with the aim of altering the metabolite balance from TMAO-induced RAAS activation to SCFA-facilitated vascular protection.⁶⁰ Overall, therapies targeting microbiome and autophagy for hypertension would aim to enhance SCFAs through fiber, probiotics, and propionate, thereby reducing TMAO and RAAS activation. Outcomes could be monitored with metabolites (TMAO, SCFAs), autophagy flux (LC3-II, p62), inflammasome cytokines (IL-1β, IL-18), and vascular function (blood pressure, flow-mediated dilation, pulse wave velocity).^{26,55,96,131,132,231}

Heart Failure

In HF, disruption of the gut barrier facilitates the translocation of LPS into the bloodstream, activating TLR4–NF-κB signaling and enhancing cytokine production and chronic inflammation.⁴⁰ This inflammatory environment further inhibits autophagic flow by disrupting LC3 processing and ATG7 signaling, exacerbating proteotoxic stress and the loss of cardiomyocytes.²³² Impaired PINK1/Parkin-mediated mitophagy promotes mitochondrial ROS generation and fibrosis, a characteristic of maladaptive remodeling.^233,234 Furthermore, TMAO induces cardiomyocyte stress by initiating the autophagic degradation of SERCA2a (a calcium reuptake pump) and facilitating hypertrophy, connecting dysbiosis to autophagy-mediated cardiac damage.²⁰ Conversely, the SCFA-producing commensal Faecalibacterium prausnitzii alleviates age-related HF through butyrate-mediated modulation of LCN2 (an iron-handling inflammatory protein) and inhibition of cardiomyocyte ferroptosis.²³⁵ However, the exact HF phenotype matters; for instance, in HF with reduced ejection fraction (HFrEF), autophagy is initially activated as an adaptive mechanism but subsequently diminishes with chronic overload, whereas in HF with preserved ejection fraction (HFpEF), autophagy appears to be impaired or repressed due to metabolic stress and systemic inflammation.²³⁶ The therapeutic control of autophagy specific to HF phenotypes could have translational potential. Hydrophilic BAs, including ursodeoxycholic acid (UDCA) and tauroursodeoxycholic acid (TUDCA), reduce endoplasmic reticulum stress and enhance autophagic flux through the CHOP-linked pathway.^68,71,237 EPA promotes mitochondrial and inflammatory equilibrium to improve cardiovascular outcomes.²³⁸ As noted above, nanomedicine carriers that target autophagic pathways, delivering targeted siRNA treatment or small compounds to restore flux, could minimize systemic adverse effects.^180,219 Furthermore, the clinical benefit of SGLT2 inhibitors in HF, demonstrated in DAPA-HF and EMPEROR-Reduced, supports the therapeutic relevance of metabolic modulation; however, their proposed effects on autophagic flux remain mechanistic and require further validation.^239–241

These strategies highlight the importance of customizing autophagy modulation according to the HF phenotype, increasing autophagic flux in the early stages of HFrEF to alleviate maladaptive effects while reinstating chronically reduced autophagy in HFpEF caused by metabolic stress.^{232–234,236}

Conclusion

The current evidence suggests that the gut–heart axis may contribute to cardiovascular risk through microbiota-driven metabolic and inflammatory signals. Dysbiosis can disrupt the intestinal metabolite balance, increasing levels of pro-atherogenic factors such as TMAO, reducing protective SCFAs, and altering BA signaling, all of which affect endothelial, immune, and lipid pathways. Within this context, autophagy may act as a key regulator, linking barrier integrity, mitochondrial quality control, inflammasome activity, and vascular inflammation. Still, this model should be interpreted with caution, as most supporting evidence remains associative or preclinical.

Promising therapeutic options include microbiome remodeling with fiber, pre- and probiotics, postbiotic SCFAs, high-purity EPA, modulation of BA signaling, inhibition of inflammasome and PCSK9 pathways, and nanocarrier delivery of autophagy-targeting agents, though all require further validation.

Future research should focus on longitudinal human studies, standardized measures of autophagy flux, multi-omics integration, and well-designed clinical trials to test whether targeting the microbiota–autophagy axis can improve cardiovascular outcomes. For now, this axis is best regarded as a testable framework rather than an established clinical strategy.

Funding Statement

The authors declare that financial support was received for the research and/or publication of this article. This publication was supported by Qatar University, internal grants no. QUCG-CHS-25/26–716 and QUCG-CHS-25/26–736. The findings achieved herein are solely the responsibility of the authors.

Data Sharing Statement

Data sharing is not applicable to this article as no data were created or analysed in this study.

Author Contributions

Salam Almoghrabi Ramirez: Conceptualization, Investigation, Project administration, Visualization, Writing – original draft, and Writing – review & editing. Mai Mohamed Karousa: Investigation, Visualization, and Writing – original draft. Esraa Yassin: Investigation, Visualization, and Writing – original draft. Anas AlOrjan: Investigation and Writing – original draft. Salima Shebbo: Visualization and Writing – review & editing. Amal Al-Haidose: Funding acquisition, Supervision, Visualization, Writing – review & editing. Asad Zeidan: Methodology, Project administration, Writing – review & editing. Atiyeh M Abdallah: Conceptualization, Project administration, Supervision, Writing – review & editing. All authors gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors declare that they have no competing interests.