The Gut Microbiota–Metabolite–Vascular Wall Axis in Abdominal Aortic Aneurysm: Mechanisms, Biomarkers, and Translational Opportunities

Abstract

Abdominal aortic aneurysm (AAA) is a progressive degenerative vascular disorder associated with substantial rupture-related mortality and persistent lack of effective pharmacological therapy. Traditionally regarded as a localized structural disease, AAA is now recognized as a systemic inflammatory and remodeling disorder. Key processes include inflammation, oxidative stress, endothelial dysfunction, vascular smooth muscle cell apoptosis and switching, extracellular matrix degradation, and thrombo-inflammatory remodeling. The gut microbiota–metabolite–vascular wall axis has emerged as a candidate upstream regulator of these processes. In this review, this axis refers to the biological continuum through which intestinal microbial dysbiosis and microbial or host–microbial metabolites influence immune activation, endothelial injury, thrombosis, and matrix remodeling in aneurysmal wall. This review synthesizes advances in understanding gut microbiota dysbiosis and microbiota-derived metabolites in AAA, with emphasis on mechanistic, translational, and clinically relevant developments. Current evidence suggests that gut microbial imbalance may promote aneurysm progression through immune and inflammatory pathways. One important mechanism is enhanced neutrophil extracellular trap formation. Among microbial mediators, trimethylamine N-oxide has become the most intensively studied candidate, with growing evidence linking elevated circulating levels to AAA occurrence, growth rate, and progression-related events, alongside experimental data supporting inflammatory and apoptotic mechanisms. In contrast, short-chain fatty acids may exert protective immunometabolic and barrier-supportive effects, whereas lipopolysaccharide may function as a key inflammatory amplifier linking intestinal barrier dysfunction to vascular injury. Insights from related disorders, including atherosclerosis, hypertension, metabolic syndrome, and inflammatory bowel disease, further strengthen the biological plausibility of microbiota-mediated aneurysmal remodeling. Despite this progress, major challenges remain, including taxonomic inconsistency, cohort heterogeneity, analytical standardization, and unresolved causality. Future studies should prioritize function-oriented microbiome analysis, integrated multi-omics, imaging-linked phenotyping, and mechanism-based intervention trials. Collectively, emerging evidence supports a conceptual shift in which AAA is viewed within a broader microbiome–metabolite–immune–matrix framework, opening new possibilities for biomarker development and non-surgical disease modification.

Graphical abstract

Keywords

Abdominal aortic aneurysm / Gut microbiome / Trimethylamine N-oxide (TMAO) / Microbial metabolites / Neutrophil extracellular traps (NETs) / Biomarker / Vascular inflammation / Microbiota-targeted therapy

Introduction

Abdominal aortic aneurysm (AAA) is a progressive degenerative disorder of the infrarenal aorta that carries substantial rupture-related mortality and continues to lack an effective disease-modifying medical therapy[1]. In current practice, management remains largely anchored to anatomical surveillance and diameter-based procedural thresholds, reflecting a persistent therapeutic gap between early biological activity and late structural intervention[2]. This gap has driven increasing interest in upstream mechanisms that shape aneurysm progression before repair becomes necessary[3].

AAA is no longer adequately explained as a purely localized mechanical failure of the aortic wall[1]. Instead, it is increasingly recognized as a chronic inflammatory and tissue-remodeling disease sustained by immune activation, oxidative stress, endothelial dysfunction, vascular smooth muscle cell (VSMC) loss, extracellular matrix (ECM) degradation, and thrombo-inflammatory interactions[4,5]. These processes form a self-reinforcing network rather than a set of isolated lesions, suggesting that aneurysm progression may be influenced by systemic signals that condition vascular inflammation and remodeling[6,7].

The gut microbiota has emerged as one such candidate regulatory layer[8]. Across cardiovascular and metabolic disease, gut microbial dysbiosis and microbiota-derived metabolites have been linked to inflammatory tone, endothelial injury, thrombosis, and host immunometabolic balance[9,10]. In AAA, this framework is particularly compelling because many of the canonical processes that drive aneurysm growth are also known to be modulated by microbial products and host–microbe metabolic interactions[11,12]. This review therefore examines AAA through the lens of this axis, with emphasis on three questions: how gut dysbiosis may amplify aneurysm-relevant host pathways, which microbial metabolites are most mechanistically and translationally relevant, and how microbiota-centered biology might be evaluated as clinically informative biomarkers or testable intervention strategies.

Throughout the review, evidence directly demonstrated in AAA models or AAA patient cohorts is distinguished from mechanistic inference derived from adjacent cardiovascular, metabolic, and inflammatory diseases. This distinction is important because cross-disease evidence strengthens biological plausibility but should not be treated as equivalent to AAA-specific causal proof.

Core pathobiology of AAA: host processes susceptible to microbial regulation

This section briefly summarizes classical AAA mechanisms only to identify host nodes that are susceptible to gut-derived regulation. AAA develops through the convergence of chronic vascular wall injury and maladaptive remodeling[1,6]. Although aneurysm is clinically defined by abnormal aortic dilatation, its biological basis lies in a destructive network of inflammation, oxidative stress, endothelial dysfunction, VSMC apoptosis and phenotypic switching, ECM degradation, and thrombo-inflammatory crosstalk[1,13]. These processes are tightly interconnected and together determine whether the abdominal aorta maintains structural integrity or progresses toward irreversible expansion[6,14].

A persistent inflammatory microenvironment is central to AAA[4]. Aneurysmal tissues are characterized by infiltration of macrophages, lymphocytes, and neutrophils, accompanied by activation of cytokine and chemokine networks that sustain wall injury[15]. Inflammation in AAA is not merely reactive; it actively drives protease expression, oxidative damage, and cellular dysfunction, thereby functioning as a core engine of aneurysmal degeneration[16].

Oxidative stress and endothelial dysfunction further amplify vascular injury[17]. Excess reactive oxygen species, coupled with reduced nitric oxide bioavailability, impair endothelial homeostasis and facilitate leukocyte recruitment, vascular permeability, and local inflammatory persistence[18,19]. Because the endothelium forms the interface between circulating systemic signals and the aortic wall, endothelial dysfunction may represent a critical checkpoint through which extra-aortic factors shape aneurysm biology[19,20].

Loss of VSMC integrity is another defining feature of AAA[1,21]. In healthy vessels, VSMCs preserve medial architecture and matrix homeostasis[21,22]. In aneurysmal tissue, however, apoptosis reduces the cellular backbone of the aortic wall, while phenotypic switching promotes a more inflammatory and matrix-remodeling state[23,24]. This transition weakens the vessel’s ability to withstand hemodynamic stress and contributes directly to structural instability[25,26].

At the tissue level, progressive ECM degradation provides the immediate structural basis for aneurysm expansion[14,27]. Protease activation, particularly involving matrix metalloproteinases, disrupts elastin and collagen organization, undermining tensile strength and elastic recoil[28]. Microbial signals do not need to degrade matrix directly to be relevant; they may act upstream by intensifying macrophage and neutrophil activation, protease-rich microenvironments, and danger-signal amplification[4,14].

Finally, intraluminal thrombus and neutrophil-driven thrombo-inflammation add a critical luminal dimension to AAA pathogenesis[13,29]. The thrombus is increasingly understood as a biologically active compartment enriched in inflammatory mediators, proteases, and oxidative signals[13,30]. Neutrophil extracellular traps (NETs), in particular, link innate immunity to thrombosis and matrix injury, making them especially relevant to aneurysm progression[29,31].

Gut dysbiosis as an upstream amplifier of aneurysm progression

The relevance of the gut microbiota to AAA lies not in the identification of a single disease-specific organism, but in the capacity of a dysbiotic microbial ecosystem to amplify host pathways already central to aneurysm progression[32,33]. Under physiological conditions, the gut microbiota supports epithelial barrier integrity, regulates mucosal and systemic immunity, and generates metabolites that help maintain immunometabolic balance[33–35]. When this ecosystem becomes dysregulated, these homeostatic functions may be replaced by a systemic state favoring inflammation, endothelial dysfunction, and tissue-destructive remodeling[36,37].

One of the most plausible routes linking dysbiosis to AAA is intestinal barrier dysfunction[38,39]. Loss of barrier integrity increases host exposure to microbial-associated molecular patterns, including lipopolysaccharide (LPS), thereby promoting chronic low-grade endotoxemia[39,40]. In a disease already shaped by persistent immune activation, even modest increases in circulating inflammatory microbial ligands may enhance vascular inflammation, oxidative stress, endothelial dysfunction, and protease induction[12,14,41,42]. This barrier-centered model is particularly useful because it explains how gut microbiota can affect a remote vascular lesion without requiring a simplistic pathogen-centered interpretation[43,44].

Innate immune signaling provides the next mechanistic bridge[15]. Microbial products can engage Toll-like receptors and related pattern-recognition pathways, thereby inducing cytokine production, macrophage activation, oxidative stress, and matrix-remodeling programs[45,46]. In the aneurysmal context, these pathways are especially important because they do not operate in isolation: endothelial activation facilitates immune-cell recruitment, inflammatory macrophages intensify proteolysis, and neutrophils become primed for exaggerated effector responses[15,47].

Among recent developments, the gut dysbiosis–neutrophil–NET axis represents one of the most important mechanistic advances[48]. NETs integrate inflammation, thrombosis, and tissue injury, making them particularly relevant to AAA, where intraluminal thrombus and mural degeneration are closely linked[13,49]. A dysbiotic microbiota may bias the host toward enhanced neutrophil activation and NET release, thereby converting distal microbial imbalance into localized vascular damage[32,50]. This framework is valuable because it moves the field beyond loose association and toward a more specific immune effector mechanism capable of explaining how gut-derived signals aggravate aneurysmal remodeling[8,48] (Figure 1).

Human studies also increasingly support the presence of microbial ecological disturbances in AAA[51,52]. However, interpretation remains challenging because microbiome composition is highly sensitive to diet, age, smoking, renal function, medications, and metabolic comorbidity—all of which are also relevant to aneurysm risk[8,53]. For this reason, the most robust reading of the current literature is not that AAA is defined by one fixed microbial signature, but that dysbiosis may converge on a limited set of host pathways, including barrier disruption, innate immune activation, and thrombo-inflammatory amplification[32,38].

Microbial metabolites as effectors and biomarkers in AAA

If dysbiosis provides the ecological context for microbiota-mediated AAA progression, microbial metabolites represent the more immediate molecular effectors through which these signals are translated into host biology[54]. This level of analysis is especially attractive because metabolites are measurable, mechanistically interpretable, and potentially actionable[11,55]. In AAA, the most relevant framework is not single-molecule determinism, but a broader imbalance between harmful and protective microbial outputs[38,54] (Figure 2).

TMAO as the leading risk-associated metabolite

Among microbiota-derived metabolites implicated in AAA, trimethylamine N-oxide (TMAO) is currently the best-characterized candidate from both mechanistic and translational perspectives[54,55]. Generated through microbial metabolism of dietary choline, phosphatidylcholine, and carnitine followed by host hepatic oxidation, TMAO has already been widely studied in atherosclerotic cardiovascular disease[56,57]. Its relevance to AAA is strengthened by the fact that many of the vascular processes linked to TMAO—including inflammation, thrombosis, endothelial dysfunction, and adverse remodeling—overlap with canonical aneurysm biology[11,56].

Recent evidence suggests that elevated circulating TMAO is associated not only with AAA presence, but also with biologically relevant disease dynamics such as aneurysm growth and progression-related events[11,55]. This distinction matters. A metabolite associated only with disease prevalence may still function as a passive marker, whereas one linked to longitudinal progression is more likely to capture active pathogenic processes[55]. TMAO is therefore emerging as more than a biomarker of vascular risk; it may reflect the inflammatory and remodeling-prone state that drives aneurysm enlargement[11,55].

Mechanistically, TMAO is attractive because it intersects with several host pathways already established in AAA[11,12]. It has been linked to inflammatory amplification, apoptosis-related signaling, and platelet hyperreactivity, thereby connecting microbial metabolism with immune activation, wall cellular instability, and thrombo-inflammatory crosstalk[11,56]. In this sense, TMAO serves as a useful molecular centerpiece of the microbiota–metabolite–vascular wall axis, translating systemic microbial dysregulation into the local language of aneurysmal remodeling[55,56].

At the same time, the translational maturation of TMAO in AAA requires caution[55,56]. Analytical standardization, especially for LC-MS/MS-based quantification, remains essential[58,59]. Interpretation also requires rigorous handling of confounders such as renal function, diet, medication exposure, and metabolic comorbidity[60]. Most importantly, association and mechanistic plausibility do not yet establish therapeutic actionability[11,56]. The key next step is to determine whether lowering TMAO can favorably alter inflammatory, thrombotic, or structural aneurysm endpoints[11,55].

SCFAs as candidate protective mediators

Short-chain fatty acids (SCFAs), particularly acetate, propionate, and butyrate, represent a mechanistically important counterpoint to TMAO[11,61]. Produced through microbial fermentation of dietary fiber, SCFAs are widely regarded as immunoregulatory and barrier-supportive metabolites[61,62]. Although direct AAA-specific evidence remains limited, their established functions make them highly relevant to aneurysm biology[54,63].

SCFAs can strengthen epithelial barrier integrity, modulate immune-cell differentiation, support regulatory immune pathways, and attenuate excessive inflammatory signaling[62,64]. These properties map closely onto vulnerabilities that appear central to microbiota-mediated vascular injury in AAA[12,54]. A disease state characterized by chronic inflammation, endothelial dysfunction, and possible barrier disruption is inherently one in which loss of SCFA-dependent homeostatic signaling may be biologically meaningful[65,66].

The importance of SCFAs in AAA is therefore conceptual as well as mechanistic[54,67]. They reinforce the idea that aneurysm progression may reflect not only enrichment of harmful microbial outputs but also depletion of protective ones[11,54]. This shift from a gain-of-harm model to a loss-of-balance model provides a more realistic framework for understanding microbiota-driven vascular remodeling[38,61]. It also creates a natural bridge to translational strategies centered on dietary fiber, prebiotics, and ecological restoration rather than single-pathway inhibition alone[62,66].

LPS and endotoxemia as inflammatory amplifiers

Unlike TMAO, which represents a defined microbial–host co-metabolite, LPS functions as a prototypic inflammatory amplifier emerging from dysbiosis and barrier failure[39,54]. Its significance in AAA lies less in biomarker specificity than in mechanistic positioning[38,54]. LPS provides a direct bridge between intestinal permeability and vascular injury by linking the gut lumen to innate immune activation in the circulation and vessel wall[39,68].

Increased systemic exposure to LPS can promote endothelial activation, leukocyte recruitment, cytokine production, and oxidative stress, all of which are highly relevant to aneurysm progression[15,68]. Within the broader microbiota–vascular framework, LPS should therefore be viewed as a signal of failed compartmentalization: once barrier integrity is compromised, inflammatory microbial products gain access to host pathways already primed to sustain vascular remodeling and wall destruction[38,39].

The biological importance of LPS in AAA is also interpretive. It helps explain why taxonomic heterogeneity across microbiome studies may still converge on common host phenotypes[54,69]. Even if different cohorts exhibit different microbial compositions, they may still produce a similar pro-inflammatory output if dysbiosis consistently promotes barrier dysfunction and low-grade endotoxemia[39]. This makes LPS and endotoxemia conceptually central, even in the absence of a single reproducible microbial signature[38,39].

Translational opportunities for microbiota-centered AAA management

The translational significance of the microbiota field in AAA lies not simply in adding another layer of disease description, but in opening new routes toward biomarker-guided surveillance and non-surgical disease modification[38,55]. Because AAA still lacks an established pharmacological therapy that reliably slows growth, any biologically grounded upstream pathway with measurable intermediates and modifiable targets is of substantial clinical interest[1,2].

Biomarker integration and risk stratification

Among currently available translational avenues, circulating microbial metabolites are the most immediately relevant for clinical development[38,55]. TMAO is the leading candidate because it can be measured in peripheral blood, is mechanistically linked to vascular injury, and may capture progression-relevant biology beyond conventional risk factors[11,55]. However, a clinically informative biomarker must do more than show statistical association[1,70]. It must provide reproducible and interpretable information that improves risk stratification over existing clinical and imaging frameworks[55,71].

In AAA, this likely means that microbial metabolites will be most useful when integrated with aneurysm diameter, expansion rate, thrombo-inflammatory features, and broader inflammatory context rather than assessed in isolation[1,55]. The future of biomarker translation is therefore multidimensional[70,71]. Serial rather than single-time-point measurements may prove particularly informative, especially if metabolite dynamics track biological activity before structural progression becomes radiologically apparent[1,55].

Diet-, prebiotic-, and probiotic-based modulation

Dietary and microbiota-modulating interventions are attractive because they are comparatively accessible and potentially suitable for long-term use in patients with small aneurysms under surveillance[1,38]. High-fiber dietary strategies may enhance SCFA production and support barrier integrity, while reduction of trimethylamine (TMA)-generating dietary substrates could, in principle, attenuate pro-inflammatory microbial metabolism[11,62]. Similarly, prebiotics and probiotics may help shift microbial ecology toward a more favorable immunometabolic state[54,69].

Yet these approaches should not be framed as generic gut-health interventions[1,38]. In AAA, their scientific credibility will depend on mechanism-linked study design[1,29]. Trials should ideally demonstrate not only ecological change, but also downstream modulation of metabolites, inflammatory mediators, NET-related signals, or imaging-relevant aneurysm phenotypes[11,54]. Without this chain of evidence, positive findings will be difficult to interpret and negative findings will remain mechanistically ambiguous[1,70].

Targeting the TMA/TMAO pathway

The TMA/TMAO axis represents the most direct pathway-targeted strategy currently available within the microbiota field[11,55]. Inhibition of microbial TMA-lyase activity is especially appealing because it targets a defined injurious metabolic pathway without requiring wholesale disruption of the microbial ecosystem[11,72]. Preclinical work has examined small-molecule inhibitors such as 3,3-dimethyl-1-butanol (DMB), iodomethylcholine, and fluoromethylcholine, but these approaches have not yet been validated as AAA therapies. Human translational studies have begun to examine TMAO biology in defined settings, including studies of TMAO production and metabolism (NCT02558673), Mediterranean diet/TMAO modulation in healthy adults (NCT03060811), and cardiovascular health in liver-transplant recipients with TMAO as a target pathway (NCT06043531). This pathway-focused approach offers an important conceptual advantage over broad-spectrum microbiota manipulation and may provide a cleaner bridge from mechanism to intervention[11,73].

Host-directed modulation of TMA oxidation also remains of interest, although this approach is biologically more complex because host metabolic enzymes participate in pathways beyond aneurysm biology[11,74]. Accordingly, pathway-targeted intervention in AAA should currently be framed as biologically plausible but preliminary[11,75]. The critical translational test will be whether pathway inhibition can influence not only circulating metabolite levels but also downstream inflammatory and structural indicators of aneurysm progression[11,12].

Early-phase mechanistic trial design

Because structural endpoints in AAA evolve slowly, microbiota-centered intervention studies should initially be designed around layered mechanistic endpoints rather than definitive clinical outcomes alone[1,71]. A rational early-phase trial would first assess pathway engagement, such as changes in TMAO, SCFAs, or endotoxemia-related markers[11,39,62]. It would then test whether such changes alter biologically relevant downstream mediators, including inflammatory cytokines, endothelial markers, thrombotic indicators, or NET-associated signals[11,54]. Only in a third step would it examine aneurysm-relevant structural outcomes such as expansion rate, thrombus burden, or progression toward repair thresholds[1,55].

This layered design is essential because it makes negative trials interpretable[1,70]. If an intervention fails to influence aneurysm growth, investigators need to know whether the pathway was not engaged, whether biological response was incomplete, or whether the targeted pathway is not in fact a major driver of aneurysm progression[11,54]. In a field that remains early and mechanistically complex, this distinction is critical[1,38].

Cross-disease evidence supporting microbiota-mediated aneurysmal remodeling

Direct evidence linking the gut microbiota to AAA is still accumulating, but the biological plausibility of this field is strengthened by adjacent literatures in atherosclerosis, hypertension, metabolic syndrome, and inflammatory bowel disease[38,76]. These disorders repeatedly implicate dysbiosis, microbial metabolites, barrier dysfunction, and systemic immune activation in vascular or inflammatory injury[37,39].

Atherosclerosis offers the most informative comparator because it provides a mature framework for understanding how TMAO and related microbial metabolites influence vascular inflammation, thrombosis, and risk stratification[39,56]. Hypertension reinforces the idea that the microbiota can shape chronic vascular homeostasis and remodeling, rather than acting only in overt inflammatory disease[76,77]. Metabolic syndrome and obesity highlight the importance of host immunometabolic context, suggesting that microbiota-dependent mechanisms in AAA may be especially relevant in biologically susceptible subgroups[78,79]. Intestinal barrier disorders, particularly inflammatory bowel disease, provide a useful model for understanding how gut leak and microbial translocation can translate local dysbiosis into distant tissue injury[44,80].

These comparisons should not be used to collapse AAA into other disease entities[1,38]. Rather, they serve to show that microbiota-mediated vascular remodeling is not a speculative concept in isolation, but part of a broader and increasingly coherent pattern across cardiovascular and inflammatory biology[11,39,54,76].

Challenges, knowledge gaps, and future directions

Despite rapid conceptual progress, the microbiota field in AAA remains limited by several major challenges. First, much of the available literature remains taxonomic rather than functional. Descriptive differences in microbial composition are useful for ecological mapping but insufficient for mechanistic inference. Future studies must move toward function-oriented profiling, including shotgun metagenomics, targeted pathway analysis, and integrated metabolomics (Figure 3).

Second, cohort heterogeneity remains a major obstacle. AAA populations are typically older and medically complex, and microbiome readouts are highly sensitive to diet, antibiotics, renal function, medications, smoking, and metabolic status. Without stricter cohort design and phenotypic standardization, it will remain difficult to distinguish aneurysm-related microbial signals from broader host variation.

Third, the field still lacks adequately integrated study architectures. Microbiome data alone rarely support strong mechanistic inference. The most informative next-generation studies will combine microbial profiling with targeted metabolite quantification, inflammatory and thrombo-inflammatory mediators, and imaging-based aneurysm phenotypes. This type of layered design is essential for reconstructing the biological chain from dysbiosis to structural disease activity.

Finally, causality remains the central unresolved question. Observational association and mechanistic plausibility are both necessary but insufficient. Mendelian randomization and other causal inference tools may strengthen the evidence base, but decisive progress will require intervention-linked studies showing that microbial pathway modulation changes downstream biology and meaningfully alters aneurysm-relevant outcomes. The field must therefore move from association-rich to intervention-ready science.

Conclusion

AAA remains a major unmet clinical challenge because effective non-surgical therapies capable of slowing aneurysm progression are still lacking. The emerging gut microbiota–metabolite–vascular wall framework offers a timely reappraisal of aneurysm biology by positioning AAA not merely as a localized structural lesion, but as a disease potentially influenced by microbiota-conditioned immunometabolic remodeling. Within this model, gut dysbiosis, barrier dysfunction, microbial metabolites, innate immune activation, NET formation, and matrix-destructive vascular remodeling can be understood as connected components of a pathogenic axis, while the strength of evidence differs across individual links.

Among candidate effectors, TMAO currently represents the most mature bridge between mechanism and translation, while SCFAs and LPS help define the broader balance between protective and injurious microbial outputs. Yet the field will only reach clinical maturity if future studies prioritize functional microbiome analysis, standardized metabolite assessment, rigorous phenotyping, integrated multi-omics, and mechanistically anchored intervention trials. A central question is how microbiota relevance in AAA can be measured, stratified, and tested therapeutically without overstating current causal evidence. If that challenge can be met, microbiota-centered research could eventually contribute to biomarker-informed and non-surgical disease-modification strategies in AAA.

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