Cardiorenal metabolic syndrome (CRMS) represents an integrative clinical and pathophysiological construct that acknowledges the bidirectional and progressive interaction among cardiovascular dysfunction, chronic kidney disease, and metabolic disorders—particularly obesity, insulin resistance, and type 2 diabetes mellitus. This syndrome accounts more comprehensively than single-organ models for the high burden of major cardiovascular events, renal disease progression, and mortality observed in these populations, even at early stages of subclinical dysfunction. From an epidemiological standpoint, CRMS has become one of the leading determinants of global morbidity and mortality, driven by shifts in dietary patterns, population aging, and nutritional transition.1–3

This integrative view has recently been formalized at the level of scientific societies. In 2023, the American Heart Association (AHA) defined cardiovascular–kidney–metabolic (CKM) syndrome as a systemic disorder attributable to the pathophysiological interconnections among metabolic risk factors, chronic kidney disease and the cardiovascular system, resulting in multiorgan dysfunction and a disproportionate burden of adverse cardiovascular outcomes. The advisory proposed a staged framework ranging from stage 0, defined by the absence of CKM risk factors, through stage 1, characterized by excess or dysfunctional adiposity; stage 2, defined by metabolic risk factors such as hypertriglyceridemia, hypertension, diabetes mellitus or metabolic syndrome and/or by established chronic kidney disease; stage 3, corresponding to subclinical cardiovascular disease within CKM syndrome or to risk equivalents such as very-high-risk chronic kidney disease; and stage 4, defined by clinical cardiovascular disease and subdivided according to the presence or absence of kidney failure.4 The term cardiorenal metabolic syndrome (CRMS) used throughout this review is conceptually equivalent to CKM syndrome and is retained here for consistency with the nephrology literature. Importantly, the AHA staging provides an operational framework onto which the microbiota-related mechanisms discussed below can be mapped, since intestinal dysbiosis is plausibly involved from the earliest stages—dysfunctional adiposity and insulin resistance—to the most advanced ones, namely heart failure and kidney failure.

The gut microbiota comprises the dynamic community of microorganisms—predominantly bacteria, but also viruses, fungi, and archaea—that inhabit the human gastrointestinal tract in a symbiotic relationship with the host. Under eubiotic conditions, this ecosystem is characterized by high diversity and functional stability, actively participating in the fermentation of non-digestible fibers, the production of short-chain fatty acids (SCFAs), the regulation of energy metabolism, the modulation of immune responses, and the maintenance of intestinal barrier integrity. Within this framework, prebiotics are defined as non-digestible substrates that selectively stimulate beneficial microorganisms; probiotics as live microorganisms that, when administered in adequate amounts, confer health benefits; postbiotics as bioactive microbial metabolites or components with demonstrable physiological effects; and synbiotics as rational combinations of prebiotics and probiotics designed to synergistically potentiate their effects.5–8

In recent years, the gut microbiota has emerged as a key systemic modulator within CRMS, functioning as a true “metabolic organ” capable of simultaneously influencing energy homeostasis, low-grade inflammation, endothelial function, and the progression of cardiorenal damage. Observational and mechanistic evidence has indicated that unfavorable dietary patterns are associated with intestinal dysbiosis, increased intestinal barrier permeability, and the production of microbial metabolites with deleterious systemic effects. In this context, dietary indices designed to reflect microbiota health have shown consistent associations with gastrointestinal disturbances and cardiometabolic markers, reinforcing the role of diet as an upstream determinant of the gut–heart–kidney axis.1,2

In patients with chronic kidney disease, dietary composition may influence intestinal microbial diversity and the production of bioactive metabolites, including short-chain fatty acids and compounds derived from protein metabolism. Clinical studies have shown that low-fiber, high animal-protein diets are associated with a pro-inflammatory microbial profile, with increased uremic toxin generation and activation of systemic inflammatory pathways, which may contribute to both renal progression and heightened cardiovascular risk. These findings are particularly relevant in CRMS, where the coexistence of renal and cardiometabolic disease amplifies the detrimental impact of intestinal dysbiosis.2,3

Beyond observational associations, recent evidence derived from Mendelian randomization has provided support for a potential causal contribution, suggesting that specific microbial taxa may be linked to renal function, albuminuria, and inflammatory markers, possibly mediated through immunological mechanisms. Although this approach relies on its own methodological assumptions, it reinforces the hypothesis that the gut microbiota is not merely an epiphenomenon of CRMS, but rather an active biological determinant that participates in the pathological interconnection among metabolism, the kidney, and the cardiovascular system.9

Taken together, these data position the gut microbiota as a central component in the pathophysiology of cardiorenal metabolic syndrome, integrating diet, inflammation, immunity, and organ dysfunction. Understanding this axis opens new opportunities for risk stratification, the development of translational biomarkers, and the implementation of targeted therapeutic strategies, with the potential to meaningfully impact the prevention and comprehensive management of CRMS.1,9

This study is a narrative review conducted to evaluate the relationship between the gut microbiota and cardiorenal metabolic syndrome. Given the exploratory and integrative nature of the topic, a narrative rather than a systematic approach was adopted; consequently, the review does not aim to provide a quantitative synthesis of the retrieved evidence. A structured, non-systematic literature search was performed across major databases—PubMed/MEDLINE, Embase, and Google Scholar—covering the period from January 2015 to December 2025, and was restricted to articles published in English or Spanish. The search was last executed on 31 January 2026. The search combined terms related to gut microbiota and dysbiosis with terms related to insulin resistance, type 2 diabetes mellitus, obesity, metabolic syndrome, cardiorenal metabolic syndrome, chronic kidney disease, and heart failure, using Boolean operators and, where available, the corresponding MeSH descriptors. Eligibility was assessed at title/abstract and full-text levels. Inclusion criteria were: studies conducted in humans or in relevant preclinical models; observational studies (cohort and cross-sectional), clinical trials, systematic reviews, meta-analyses, and mechanistic studies addressing the relationship between the gut microbiota and the cardiorenal-metabolic axis. Exclusion criteria were: conference abstracts, letters without primary data, articles without full-text availability, and studies not focused on the gut–heart–kidney axis. Reference lists of key articles were additionally screened to identify further relevant sources. The number of records retrieved and excluded at each stage is reported below and summarized in Supplementary Fig. S1, adapted from the PRISMA 2020 framework. The main domains of evidence retrieved, together with their predominant study designs and an overall appraisal of the level of evidence, are summarized in Table 1.

Heart failure (HF), whether with reduced or preserved ejection fraction, represents a central clinical manifestation of CRMS and is closely associated with metabolic and renal disturbances. In this context, the gut microbiota emerges as a relevant modulator of HF progression through inflammatory, metabolic, and hemodynamic mechanisms. The splanchnic hypoperfusion and venous congestion inherent to HF promote intestinal barrier dysfunction, increased permeability, and bacterial translocation, thereby amplifying the low-grade systemic inflammation characteristic of CRMS.10–15

It is worth highlighting that the intestinal dysbiosis associated with cardiorenal metabolic syndrome and heart failure is characterized by specific alterations in the taxonomic composition of the microbiota. Consistently, a reduction in beneficial short-chain fatty acid-producing bacteria has been described—particularly within the genera Faecalibacterium, Roseburia, and Eubacterium (phylum Firmicutes)—along with a decrease in Akkermansia muciniphila (phylum Verrucomicrobia), a key microorganism for maintaining intestinal barrier integrity. In contrast, a relative increase in potentially pathogenic bacteria has been observed, especially within the phylum Proteobacteria (including Escherichia, Klebsiella, and Enterobacter), associated with greater lipopolysaccharide production, metabolic endotoxemia, and systemic inflammation. Furthermore, alterations in the Firmicutes/Bacteroidetes ratio, as well as an increase in proteolytic bacteria producing uremic metabolites and nitrogenous compounds, have been linked to endothelial dysfunction, neurohormonal activation, and poorer cardiovascular outcomes. These taxonomic patterns reinforce the notion that the dysbiosis observed in CRMS is not nonspecific, but rather reflects reproducible microbial signatures with pathophysiological relevance and potential value as clinical biomarkers.13–18

Additionally, microbiota-derived metabolites—including SCFAs, trimethylamine N-oxide (TMAO), and other products of protein metabolism—directly influence endothelial function, neurohormonal activation, and myocardial remodeling, acting as key mediators of cardiovascular damage. As illustrated in Fig. 1, intestinal dysbiosis associated with heart failure is linked to heightened systemic inflammation, vascular dysfunction, and activation of neurohormonal pathways. Observational studies and systematic reviews have demonstrated that unfavorable microbial profiles are associated with greater inflammatory burden, vascular dysfunction, and worse prognosis in patients with heart failure.13,15–18 Likewise, unhealthy dietary patterns—common among patients with heart failure and metabolic comorbidity—are associated with intestinal dysbiosis and increased production of pro-inflammatory metabolites, contributing to the progression of cardiovascular disease.1,19 Taken together, these mechanisms position the gut microbiota as a central pathophysiological link between diet, inflammation, and cardiac dysfunction within CRMS (Fig. 1).

Fig. 1.

Schematic representation of the bidirectional interaction between the gut microbiota and heart failure within cardiorenal metabolic syndrome (CRMS). The venous congestion and splanchnic hypoperfusion inherent to heart failure promote intestinal barrier dysfunction, increased permeability, and bacterial translocation, thereby amplifying the low-grade systemic inflammation characteristic of CRMS. The resulting dysbiosis disrupts the production of microbial metabolites including short-chain fatty acids (SCFAs) and trimethylamine N-oxide (TMAO) which in turn influence endothelial function, neurohormonal activation, and myocardial remodeling. These mechanisms integrate diet, inflammation, and cardiac dysfunction, positioning the gut microbiota as a central pathophysiological modulator of CRMS.

Chronic kidney disease (CKD) is a structural component of CRMS and a potent amplifier of cardiovascular risk. CKD is associated with a characteristic intestinal dysbiosis—termed uremic dysbiosis—marked by a reduction in SCFA-producing bacteria and an expansion of microorganisms that generate uremic toxins such as indoxyl sulfate and p-cresyl sulfate. These alterations promote systemic inflammation, oxidative stress, endothelial dysfunction, and immune activation, all of which are central mechanisms in cardiorenal progression.2,10,11,20,21

Clinical evidence demonstrates that dietary composition is associated with changes in the gut microbiota in patients with CKD, influencing relevant inflammatory, metabolic, and cardiovascular biomarkers.2,19 Furthermore, Mendelian randomization studies have suggested a possible causal link between specific microbial taxa and renal function, albuminuria, and immune activation, supporting the concept of the gut microbiota as a potentially active determinant—rather than a mere epiphenomenon of renal and cardiovascular damage.9 From this perspective, the gut–kidney axis constitutes a critical node within CRMS, with both pathophysiological and therapeutic implications.11,20,21

CRMS is characterized by a complex network of endocrine–metabolic interactions in which insulin resistance, chronic low-grade inflammation, and hormonal dysfunction play a central role. The gut microbiota may influence these pathways through SCFA production, modulation of the innate and adaptive immune system, and interaction with hormonal axes such as glucagon-like peptide-1 (GLP-1), peptide YY (PYY), and other incretins.11,16,24,25

SCFAs particularly butyrate and propionate exert anti-inflammatory, immunomodulatory, and metabolic effects, with potential impact on insulin sensitivity, lipid metabolism, and energy homeostasis. However, in dysbiotic states associated with CKD, obesity, and CRMS, the reduction of SCFA-producing bacteria contributes to a pro-inflammatory environment that perpetuates endocrine–metabolic dysfunction and accelerates cardiovascular damage.3,16,24,25 This phenomenon pathophysiologically integrates the gut microbiota with the metabolic and hormonal components of CRMS.

Obesity represents the metabolic core of cardiorenal metabolic syndrome (CRMS) and one of the primary drivers of intestinal dysbiosis. Recent evidence has demonstrated that gut microbiota composition is not only associated with obesity, but actively participates in the regulation of energy balance, lipid metabolism, systemic inflammation, and insulin resistance.15,25,26 Mechanistically, a central pathway linking diet–microbiota–obesity involves signaling mediated by G protein-coupled receptors (GPCRs) expressed on enteroendocrine cells, adipocytes, and immune cells. SCFAs—acetate, propionate, and butyrate—derived from commensal bacterial fermentation of dietary fiber, act as ligands for GPCRs such as GPR41/FFAR3 and GPR43/FFAR2 (free fatty acid receptors 3 and 2), promoting the release of satiety hormones from intestinal L-cells, particularly GLP-1 and PYY, with effects on appetite reduction, delayed gastric emptying, and improved insulin sensitivity. In obesity and low-fiber diets, the decline in SCFA-producing bacteria is associated with reduced incretin signaling, increased energy intake, and progression of the metabolic phenotype of CRMS.14,21–23

Complementarily, the gut microbiota modulates energy homeostasis through the biotransformation of bile acids, generating metabolites that interact with receptors such as Takeda G protein-coupled receptor 5 (TGR5) and the farnesoid X receptor (FXR), which are relevant to enteroendocrine signaling, lipid metabolism, and insulin sensitivity. These functional axes explain why microbiota-modulating strategies—including dietary modifications, prebiotics, probiotics, synbiotics, and bioactive compounds such as polyphenols—have shown potential to modify adverse metabolic profiles, improve inflammatory biomarkers, and modulate cardiorenal risk in models of obesity and chronic kidney disease.3,11,26,27

Dietary indices designed to reflect microbiota health thus reinforce the role of diet as an upstream intervention capable of simultaneously impacting multiple components of CRMS.1,2,19 These mechanisms are summarized schematically in Fig. 2, which illustrates the interaction between visceral obesity, diet, intestinal dysbiosis, and therapeutic microbiota modulation as an integrating axis of CRMS.

Fig. 2.

Obesity, diet, and microbiota: the metabolic core of cardiorenal metabolic syndrome (CRMS). The figure illustrates how obesity—particularly visceral adiposity—acts as the metabolic core of CRMS by promoting intestinal dysbiosis, low-grade metabolic inflammation, and insulin resistance. Unhealthy dietary patterns alter the composition and function of the gut microbiota, while modulation strategies—including dietary modifications, prebiotics, probiotics, synbiotics, and polyphenols—can partially restore microbial homeostasis and modulate cardiometabolic and cardiorenal risk.

Gut microbiota modulation is increasingly explored as a potential therapeutic component in the management of cardiorenal metabolic syndrome (CRMS) and chronic kidney disease (CKD), transcending the traditional organ-centered approach. In this context, dietary patterns rich in fiber, polyphenols, and minimally processed foods are emerging as the first-line dietary approach for cardiorenal-metabolic risk, with the potential to favorably modify the intestinal microbial profile, promoting short-chain fatty acid (SCFA) production, and improving host metabolic and immunological signaling.3,19,24,26 Population-based and mechanistic studies have demonstrated that dietary indices designed to reflect microbiota health are associated with lower systemic inflammation, improved insulin sensitivity, and reduced cardiometabolic and cardiorenal risk, reinforcing the role of diet as an upstream intervention capable of simultaneously impacting multiple components of CRMS.1,2,19

The evidence integrated in this review is consistent with a relevant pathophysiological role for the gut microbiota as a component of cardiorenal metabolic syndrome (CRMS), functioning as a transversal axis connecting obesity, endocrine–metabolic dysfunction, chronic kidney disease (CKD), and cardiovascular disease—particularly heart failure. This framework allows us to move beyond the traditional organ-centered paradigm and advance toward a systemic understanding of risk, disease progression, and therapeutic opportunities.1,9–12,15–17,19–21,24,26

From an epidemiological perspective, CRMS emerges as a direct consequence of the global nutritional transition, characterized by hypercaloric diets, low fiber intake, and high content of animal protein and ultra-processed foods. These dietary patterns are consistently associated with intestinal dysbiosis, reduced microbial diversity, and functional alterations of the gut ecosystem. Population studies and cohort analyses have demonstrated that dietary indices designed to reflect microbiota health correlate with constipation, systemic inflammation, cardiometabolic syndrome, and adverse cardiovascular outcomes, positioning diet as an upstream determinant of the gut–heart–kidney axis.1,2,19 In this context, the microbiota not only reflects lifestyle but may translate environmental exposures into biological signals with measurable clinical impact.

In CKD, the evidence is particularly robust. Uremic dysbiosis—characterized by a reduction in SCFA-producing bacteria and expansion of proteolytic microorganisms—promotes uremic toxin production, intestinal barrier deterioration, metabolic endotoxemia, and activation of systemic inflammatory pathways. This environment amplifies both renal progression and cardiovascular risk, reinforcing the concept of CKD as a key negative modulator within CRMS.2,10,11,20,21 The interaction between diet, microbiota, and inflammatory biomarkers in CKD underscores that exclusively nephroprotective therapeutic strategies may be insufficient if they do not comprehensively address the intestinal axis.

A conceptually significant advance derives from Mendelian randomization studies, which suggest a possible causal contribution, reporting associations between specific microbial taxa and renal function, albuminuria, and immune activation.9 This approach may reduce confounding and reverse causality bias, although its validity depends on assumptions that are not always fully verifiable; with this caveat, it supports the hypothesis that the gut microbiota is not an epiphenomenon of CRMS but rather an active biological determinant participating in the pathological interconnection among metabolism, the kidney, and the cardiovascular system. From an epidemiological standpoint, these findings support the microbiota as a potentially modifiable risk factor.9,17,19

In the cardiovascular domain, the gut microbiota acquires particular relevance in heart failure, where venous congestion and splanchnic hypoperfusion promote intestinal barrier dysfunction, bacterial translocation, and metabolic endotoxemia. This phenomenon perpetuates chronic low-grade inflammation, endothelial dysfunction, neurohormonal activation, and adverse myocardial remodeling, thereby contributing to the progression of heart failure.10–16 Although specific clinical studies remain heterogeneous, systematic reviews and population-based cohorts consistently identify intestinal dysbiosis and microbial metabolites as relevant modulators of the cardiorenal metabolic phenotype, particularly in patients with multimorbidity.

From an endocrine–metabolic standpoint, the gut microbiota regulates energy homeostasis, insulin sensitivity, and inflammation through SCFA production, immune system modulation, and interaction with hormonal axes such as GLP-1, PYY, and other incretins.3,15,16,24–26 The reduction in SCFA-producing bacteria observed in obesity and CKD contributes to a pro-inflammatory and proatherogenic environment that perpetuates metabolic dysfunction. In this sense, obesity should be understood not only as a risk factor but as a biological amplifier of the microbiota–inflammation–organ damage axis within CRMS.15,25,26

The therapeutic implications of these findings are promising but still incomplete. Microbiota-targeted interventions using probiotics, prebiotics, synbiotics, and nutritional strategies have demonstrated favorable effects on uremic toxins, systemic inflammation, and metabolic profiles, although no effect on hard clinical outcomes has been demonstrated.11,15,27,30 This heterogeneity likely reflects differences in strains, intervention duration, population characteristics, and the biological complexity of CRMS, suggesting that microbiota modulation should be integrated within evidence-based multifactorial cardiorenal strategies.

Specifically, a randomized clinical trial demonstrated that in dialysis patients, while probiotics did not reduce systemic inflammation (as determined by changes in the C-reactive protein (CRP)/albumin ratio at 24 weeks), they did reduce phosphorus concentrations at 16 and 24 weeks—particularly in patients using laxatives—by regulating gut microbiota balance.30 Relatedly, rodent models have demonstrated a similar phosphorus-lowering effect with synbiotic use at twelve weeks of treatment, along with reductions in serum parathyroid hormone, phosphocalcic products, and indoxyl sulfate levels compared to control animals, demonstrating promising effects in the management of hyperphosphatemia and secondary hyperparathyroidism.27

Furthermore, an umbrella review of five meta-analyses identified that microbial therapy as gut microbiota modulation has shown promise in reducing body mass index (BMI) (with the use of probiotics, prebiotics, and synbiotics) and waist circumference (with the use of prebiotics and synbiotics) in patients with metabolic syndrome; however, no statistically significant effects were identified for other anthropometric measures such as body fat percentage, waist-to-hip ratio, or body weight.15

Several limitations should be acknowledged. Most available data derive from observational or preclinical studies, which limits causal inference, while the field shows substantial methodological heterogeneity and marked interindividual variability of the microbiota, restricting the generalizability of specific microbial signatures. As a narrative review, this work did not follow a registered protocol and did not include a formal quantitative risk-of-bias assessment, although the methodological quality of the included studies was appraised with design-specific instruments in order to weight the evidence. The search was restricted to the databases available to the authors; Scopus could not be interrogated, and although the overlap between PubMed/MEDLINE and Embase makes it unlikely that relevant work was missed, the possibility cannot be excluded. Most importantly, the evidence base is built almost entirely on intermediate endpoints: reductions in uremic toxins, inflammatory cytokines and mineral metabolism parameters have been reported repeatedly, whereas no study has demonstrated a reduction in mortality, in cardiovascular events, or an improvement in kidney survival attributable to microbiota modulation. Finally, the proposed microbiota-based classification of CRMS should be regarded as conceptual and hypothesis-generating rather than a validated clinical tool, and prospective studies with hard cardiovascular and renal endpoints will be needed to confirm both the phenotypes and their derived therapeutic strategies.

Based on the available evidence, we propose a conceptual classification of microbiota-mediated cardiorenal metabolic syndrome, aimed at organizing the current evidence and guiding hypothesis generation and future research: It should be emphasized that this classification is exploratory and hypothesis-generating: it has not been prospectively validated, and its clinical applicability will need to be confirmed in future studies.

• •

  Associated with obesity, insulin resistance, and low-fiber diets.

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  Dysbiosis characterized by a reduction in SCFA-producing bacteria.

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  Predominance of low-grade metabolic inflammation.

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  Potentially reversible with dietary interventions.1,26

• •

  Associated with moderate-to-advanced CKD.

• •

  Uremic dysbiosis with increased uremic toxins and intestinal permeability.

• •

  Characterized by an expansion of proteolytic bacteria, which generate uremic toxins consistently associated with adverse outcomes, mainly indoxyl sulfate and p-cresyl sulfate, and related protein-bound solutes such as indole-3-acetic acid and p-cresyl glucuronide, together with a reduction in saccharolytic, short-chain fatty acid-producing bacteria. These solutes are poorly cleared by dialysis and have been associated with vascular disease, cardiovascular events and mortality across CKD stages.22,23 Trimethylamine N-oxide (TMAO) is another microbiota-dependent metabolite linked to cardiovascular and renal risk, although it derives mainly from dietary choline and carnitine rather than from proteolytic fermentation.

• •

  Although current evidence remains limited, prebiotics, probiotics, and synbiotics represent a strategy to be considered in these patients, aiming to improve the intestinal microbial profile, reduce uremic toxin generation, and support intestinal transit, although the available evidence is insufficient to support their routine use for slowing CKD progression or reducing cardiovascular events.

• •

  High cardiovascular risk and accelerated renal progression.

• •

  Requires combined nutritional and nephroprotective strategies.2,10,11,24,27,30

• •

  Associated with heart failure with venous congestion.

• •

  Intestinal barrier dysfunction and metabolic endotoxemia.

• •

  Systemic inflammation amplified by splanchnic hypoperfusion.10,11

• •

  Fluid overload is associated with increased mortality. Intestinal wall edema has been proposed as one potential mechanism linking venous congestion with barrier dysfunction and systemic inflammation; however, its independent causal contribution to adverse outcomes remains uncertain. Accordingly, avoiding fluid overload is a reasonable strategy to consider in this phenotype.

• •

  Dysbiosis influenced by medications (phosphate binders, opioids, and others).

• •

  Drug-induced constipation as an amplifying factor.

• •

  Frequently underdiagnosed phenotype.31

• •

  This classification is not intended to be mutually exclusive, but rather to recognize overlapping phenotypes that may coexist in the same patient, reflecting the true complexity of CRMS. See Fig. 3.

  
  

  Fig. 3.

  Cardiorenal metabolic syndrome (CRMS) classification according to gut microbiota dysfunction phenotype. The figure presents a conceptual classification proposal for microbiota-mediated cardiorenal metabolic syndrome, aimed at facilitating clinical risk stratification and the design of future interventions. Four phenotypes are proposed, which may overlap and coexist in the same patient. Authors’ own elaboration.

Recognition of the gut microbiota as an integrating axis of CRMS opens opportunities for a more personalized medicine approach, oriented toward risk stratification, the development of multi-omic biomarkers, and the implementation of targeted interventions. However, well-designed clinical trials are needed to evaluate microbiota modulation strategies with cardiovascular and renal endpoints, as well as epidemiological studies to validate this classification across different populations and clinical settings.1,9–21,24,26,27,30,31

Current evidence supports a relevant pathophysiological role for the gut microbiota in cardiorenal metabolic syndrome (CRMS), integrating obesity, endocrine–metabolic dysfunction, chronic kidney disease, and cardiovascular disease—particularly heart failure. This paradigm allows us to move beyond the traditional organ-centered approach and advance toward a systemic understanding of risk, disease progression, and the clinical complexity that characterizes patients with multimorbidity.

The available epidemiological, mechanistic, and genetic data suggest that intestinal dysbiosis is not an epiphenomenon of CRMS, but rather an active and potentially modifiable biological determinant capable of translating dietary, environmental, and pharmacological exposures into metabolic, immunological, and inflammatory signals with measurable clinical impact. In this context, diet emerges as an upstream determinant of the gut–heart–kidney axis, while chronic kidney disease and heart failure act as bidirectional amplifiers of intestinal dysfunction.

Integrating the gut microbiota within the pathophysiological model of CRMS opens new opportunities for risk stratification, the development of translational biomarkers, and the design of personalized therapeutic strategies—including dietary interventions, targeted microbiota modulation, and a more gut-conscious approach to pharmacological selection. Nevertheless, it must be stated plainly that the clinical benefit of these strategies remains unproven: the available evidence is confined to intermediate biomarkers, and no intervention has yet shown a reduction in mortality, in cardiovascular events, or in progression to kidney failure. Microbiota modulation should therefore complement, and not replace, cardiorenal therapies of established prognostic benefit, and its incorporation into clinical practice should await well-designed prospective trials powered for hard cardiovascular and renal endpoints.

Finally, the microbiota dysfunction phenotype-based classification of CRMS proposed in this review offers an integrative conceptual framework that may facilitate future research and clinical decision-making. Validating this approach across different populations and care settings will be essential to advancing toward a truly systemic and precision medicine approach in the management of cardiorenal metabolic syndrome.

All authors contributed to the writing and reviewing of each draft and reviewing and approving the final draft for submission. R.D.A., J.R.F. and C.M.R.G. conceived and designed the manuscript; J.J. was responsible for the design and preparation of the figures. All authors contributed to the writing and reviewing of each draft and reviewing and approving the final version draft for submission.

This article was funded with the authors’ own resources.

R.D.A. has received honoraria as a speaker from Novo Nordisk, AstraZeneca, Bayer, and Boehringer Ingelheim, and has participated in advisory committees for AstraZeneca, Boehringer Ingelheim, Adium, Lilly, Bayer, and Novo Nordisk. J.R.F. has received honoraria as a speaker from AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Lilly, Sanofi, Eurofarma, Adium, GSK, MSD, Merck, and Bayer. G.R.G. declares current employment at AstraZeneca in the role of Clinical Lead Renal SKG. The remaining authors declare no conflicts of interest relevant to this article. These declarations are not necessarily related to the work presented herein.