Vascular crosstalk between the gut, liver and kidney establishes a complex circulatory network that is integral for interorgan crosstalk. This network relies on portal circulation to send ~75% of the hepatic blood flow from the capillaries in the intestine into the liver to allow for the first-pass metabolism of absorbed nutrients and toxins before they are delivered throughout the body by systemic circulation (23,24). Hepatic venous outflow, which constitutes ~25% of the cardiac output, influences renal flow through changes in central venous pressure (25). This linear arrangement is key for handling and eliminating xenobiotics.

The lymphatic system is a key communication system in the gut-liver-kidney axis as it absorbs most dietary long-chain fatty acids (FAs) in the intestine, especially via lacteals in the villi, thus avoiding first-pass hepatic metabolism (26-28). Moreover, intestinal lymphatics carry immune cells and cytokines of gut origin, reinforcing an alternative route for communication besides the portal circulation (29,30). The liver is the largest lymph-producing organ, contributing 25-50% of the lymph flow in the thoracic duct, and is affected by hemodynamic variation in intrahepatic microcirculation (31,32). Thus, hepatic lymphatics serve a role in fluid homeostasis and contribute to the immune system and lipid metabolism by transferring immune cells, antigens and lipids to the surrounding lymph nodes (31,33). The lymphatic vessels in the kidneys are primarily distributed in the renal cortex. Mapping techniques have indicated that bidirectional crosstalk occurs between the renal, hepatic and lymph nodes (34,35).

Neural regulation of the gut-liver-kidney axis is coordinated by the central nervous system (CNS) through autonomic pathways. The autonomic NS (ANS), comprising the parasympathetic (vagal) and sympathetic branches, mediates bidirectional communication between the brain and peripheral organs (36). Vagal stimulation in the gut influences motility, secretion and stimulation of blood flow, which contribute to the digestion and absorption of nutrients (37). Additionally, intestinal motility and gut-organ communication are regulated by the enteric nervous system and sympathetic innervation, which provide local and systemic neural control, independent of direct vagal input (38). The ANS, particularly its sympathetic portion, controls the renal blood flow, glomerular filtration rate (GFR) and renin secretion (39,40). Sensory feedback loops are key as enteric sensory neurons sense luminal perturbations, such as nutrient content and mechanical stretch, and transmit these signals to the CNS or afferent systems, resulting in CNS-mediated adaptations in gut, liver and kidney function (41-43). In conclusion, the balance between autonomic regulation and sensory feedback within this neural network maintains organ health and its disruption can lead to disease.

The gut-liver-kidney axis maintains homeostasis through complex molecular signaling networks (Fig. 2), including endocrine orchestrators, metabolic intermediaries and beneficial microbial metabolites that coordinate bidirectional interorgan communication.

Gut hormones serve as key mediators in the gut-liver-kidney axis, serving as notable endocrine signals that coordinate metabolic, immune and homeostatic balance. Glucagon-like peptide-1 (GLP-1), predominantly synthesized in enteroendocrine L cells of the distal small intestine and colon, stimulates insulin release, improves glucose tolerance and exerts hepatoprotective and nephroprotective properties (44). In the liver, GLP-1 receptor stimulation may minimize decreased hepatic gluconeogenesis and lipid deposition as well as inhibit MASLD development (45). Additionally, GLP-1 attenuates renal inflammation and fibrosis by suppressing inflammatory signaling and antioxidant activity in the kidney (46). Another gut hormone secreted by intestinal L cells, peptide YY (PYY), affects liver metabolism by controlling lipid and glucose homeostasis (47,48). PYY may exert renoprotective effects, possibly through the amelioration of renal hemodynamics and oxidative stress (49). In CKD, and particularly in DKD, progressive enteroendocrine L cell dysfunction and GLP-1 resistance diminish this sustained renoprotective signaling, preventing inhibition of tubulointerstitial inflammation and contributing to the accelerated estimated GFR (eGFR) decline that GLP-1 receptor agonists partially attenuate in clinical trials (50,51).

Hepatokines serve as key mediators of regulation and communication between organs in the gut-liver-kidney axis. Fibroblast growth factor 21 (FGF21), an endocrine factor primarily produced in the liver, serves a crucial role in regulating global energy metabolism by increasing the hepatic and adipose FA oxidative capacity and modulating glucose homeostasis through activation of FGFR1-βKlotho (52-54). FGF21 plays a key role in systemic metabolic control. Additionally, FGF21, a key index of metabolic adaptation, serves a role in nephroprotection by enhancing renal function, relieving inflammatory response and inhibiting fibrosis progression (55). Similarly, glycoprotein fetuin-A, which paradoxically causes insulin resistance, also controls calcium metabolism (56). Under physiological conditions, fetuin-A is maintained at a level that balances metabolic functions across the hepatorenal compartment (57,58). Furthermore, adropin is a novel hepatokine that maintains cell health by promoting mitochondrial activity and insulin sensitivity (59). In the gut-liver-kidney axis, adropin prevents metabolic crosstalk, enhancing intestinal barrier function and promoting hepatorenal cell protection in an AMPK-dependent manner (60,61). Together, these hepatokines represent diverse interorgan networks that promote systemic metabolic homeostasis and are implicated in orchestrating disease pathogenesis along the gut-liver-kidney axis. Although other liver-derived factors (angiopoietin-like protein family members, leukocyte cell-derived chemotaxin 2) have been implicated in systemic metabolic regulation, FGF21, fetuin-A and adropin have the strongest mechanistic and clinical evidence within the gut-liver-kidney axis (62,63). When these hepatokine networks are disrupted in CKD, as occurs with the FGF21 resistance and elevated fetuin-A characteristic of MASLD-associated DKD, their renoprotective and anti-fibrotic actions are lost, directly favoring renal lipid accumulation, oxidative injury and fibrosis progression (63,64).

Renal-derived factors are essential for the orchestration of metabolic homeostasis and organ crosstalk that occurs within the gut-liver-kidney axis. Erythropoietin (EPO), a hormone secreted by the peritubular interstitial fibroblasts, exhibits anti-inflammatory and anti-fibrotic properties in addition to its classical function in erythropoiesis (65). EPO contributes to hepatic tissue regeneration and regulates gut immune responses associated with the preservation of intestinal barrier function (66,67). Klotho, a transmembrane protein predominantly found in the kidney, is a key antiaging factor that ameliorates insulin resistance and inhibits oxidative stress in kidney, liver and intestine (68). In the context of the gut-liver-kidney axis, klotho inhibits organ fibrosis and modulates gut microbiota composition, contributing to coordinated metabolic and inflammatory regulation across organs (69,70). Vitamin D is converted to its biologically active form 1,25-dihydroxyvitamin D via renal hydroxylation, which confers pleiotropic protective effects (71). Active vitamin D promotes intestinal barrier function to improve hepatic lipid metabolism and inhibits the progression of renal injury (72,73). Consistent with these protective roles, deficiency or impaired metabolism of active vitamin D is associated with an increased risk of CKD, MASLD and intestinal disease (74-76). Taken together, these renal factors demonstrate complexity that characterizes the endocrine role of the kidney in regulating systemic physiology. Table I summarizes the key signaling molecules mediating the gut-liver-kidney axis communication, including their primary sources, receptor targets, biological function, axis-specific mechanisms and pathological alterations in CKD.

Bile acids, which are important in lipid digestion (77), are signaling molecules that play a key role in the gut-liver-kidney axis. These lipophilic molecules are produced from cholesterol in the liver and undergo enterohepatic circulation, shuttling between the liver, intestine and enterohepatic organs (78,79). Bile acids are also recognized by nuclear receptors, such as farnesoid X receptor (FXR), and membrane-bound receptors, including Takeda G protein-coupled receptor 5 (TGR5) (80). FXR activation in the liver and intestine affects bile acid synthesis, transport and metabolism (81), whereas TGR5 activation in enteroendocrine and immune cells decrease inflammation and regulates energy metabolism (82,83). Under physiological conditions, bile acid signaling functions in metabolic homeostasis and protects organs in the gut-liver-kidney axis. In CKD, impaired renal clearance and altered bile acid composition convert this homeostatic signaling into a driver of injury: Excess and structurally altered bile acids activate pro-inflammatory and pro-fibrotic programs in renal tubular cells, directly linking bile acid dysregulation with interstitial fibrosis and functional decline.

Microbial metabolites are key mediators of the crosstalk between organs in the gut-liver-kidney axis. Short-chain FAs (SCFAs), such as acetate, propionate and butyrate, are products of gut microbiota fermentation of dietary fiber. SCFAs serve multiple roles in the human body, including acting as an energy source for colonic epithelial cells and modulating gut barrier formation and immune responses (84). SCFAs affect the lipid and glucose metabolism in the liver, thereby decreasing hepatic steatosis and improving insulin sensitivity (85). Additionally, SCFAs exert anti-inflammatory and anti-fibrotic effects that decrease renal injury (86,87). Mechanistically, these SCFAs have distinct receptor-binding profiles and physiological roles. Acetate (2C SCFA), which accounts for ~60% of total SCFAs, mainly stimulates free FA receptor 2 (FFAR2) and FFAR3 and serves a role in metabolism in hepatocytes and renal tubular cells (88,89). Propionate (3C SCFA), which accounts for 20% of the total SCFAs, inhibits histone deacetylases (HDACs), preferentially activates of G protein-coupled receptor 41 (GPR41) and enhances anti-inflammatory and metabolic functions (90,91). However, butyrate (4C SCFA and the most biologically active SCFA), exerts an anti-HDAC effect via GPR109A activation and direct metabolic effects on colonocytes in addition to stellate cells in the human liver, despite accounting for 20% of SCFAs (92,93). The receptor selectivity and metabolic differences of these SCFAs allow coordinated signals throughout the gut-liver-kidney network. These protective metabolites are the health-promoting part of microbe-host crosstalk, which ensures systemic health and balance along the gut-liver-kidney axis. For example, supplementation with SCFAs, particularly butyrate, initiates coordinated anti-inflammatory effects across the gut-liver-kidney axis. At the intestinal level, butyrate enhances epithelial barrier integrity and suppresses pro-inflammatory signaling by inhibiting HDAC (94,95). These effects decrease microbial translocation and the systemic inflammatory burden. In the liver, SCFA-mediated modulation of bile acid signaling and FXR activity contributes to improved metabolic homeostasis and the attenuation of hepatic inflammation (95). Downstream, decreased systemic inflammatory signaling and improved metabolic profiles are associated with decreased renal inflammatory activation and fibrosis, demonstrating a coordinated anti-inflammatory cascade spanning the gut, liver, and kidneys. Conversely, the SCFA depletion characteristic of CKD-associated dysbiosis (most pronounced in DKD, where butyrate-producing taxa are markedly depleted) removes this protective cascade simultaneously at all three organs, thereby accelerating endotoxemia, hepatic inflammation and renal fibrosis (96). Branched-chain amino acids are microbiota-influenced metabolites whose altered profiles are linked to insulin resistance and hepatic steatosis, though their role in CKD is indirect and less well-defined than that of SCFAs (97,98).

At the organ and systemic levels, dysbiosis-mediated signaling alterations emerge in CKD, characterized by notable changes in the gut microbiota composition that reshape molecular signaling at the gut-liver-kidney interface. For example, accumulation of uremic toxins creates a toxic intestinal milieu that selectively favors the expansion of unfavorable microbial species at the expense of beneficial commensals (115,116). Key mechanisms of dysbiosis include a shift in microbial composition toward proteolytic bacteria, resulting in decreased SCFA production and increased generation of indoles, phenols and amines (117-119) and activation of toll-like receptor (TLR) signaling, particularly TLR4 stimulation by lipopolysaccharide (LPS) derived from Gram-negative bacteria, which initiates and propagates inflammatory responses along the gut-liver-kidney axis (120).

Impairment of the intestinal barrier is a key molecular signaling failure that plays a notable role in CKD. Uremic toxins and pro-inflammatory cytokines directly impair tight junction proteins, such as claudin-1, occludin and zonula occludens-1 via several signaling pathways (121,122). At the molecular and cell levels, uremic toxins and pro-inflammatory cytokines activate NF-κB signaling and increase myosin light-chain kinase activity, leading to reduced expression of tight junction proteins and cytoskeletal reorganization, compromising intestinal barrier integrity (123-125). Disruption of the barrier permits the transit of bacteria and endotoxins, which leads to systemic inflammation via activation of the complement system and the release of cytokines. This forms a feed-forward loop in which the inflammatory signals exacerbate barrier function, which is defective.

In KD, disordered bile acid metabolism disrupts gut microflora homeostasis and promotes intestinal barrier dysfunction, thereby facilitating kidney inflammation (126-128). High concentrations of bile acids induce proinflammatory pathways in the renal tubules, leading to fibrosis-based CKD (129). Additionally, impaired renal function affects bile acid elimination by decreasing GFR and altering tubular transport systems, with accumulation of bile acids in the systemic circulation and modification of their composition (130). The decreased renal elimination establishes a cycle, wherein accumulated bile acids harm renal tubular cells, resulting in a decrease in kidney function and maintenance of the cycle.

Notably, high bile acid levels lead to paradoxical FXR desensitization and downregulation, interfering with normal metabolic control through receptor systems (80). This results in a state of bile acid resistance similar to that observed in insulin resistance with high levels of circulating bile acids, while the protective signaling effects are attenuated due to receptor dysfunction and loss of downstream effectors. Disruption of TGR5 signaling in immune cells leads to a decreased anti-inflammatory response and results in chronic inflammation in the gut, liver and kidney (131,132). Altered signaling through FXR in hepatocytes results in the disturbance of bile acid synthesis enzymes, transporters and metabolic genes. Diminished TGR5-mediated signaling in enteroendocrine cells decreases incretin hormone production and metabolic synchronization between the gut and liver across the axis (133,134).

Protein-bound uremic toxins, such as indoxyl sulfate and p-cresyl sulfate accumulate during CKD and exert toxic effects via receptor-mediated signaling pathways (135,136). Uremic toxins, the end products of gut microbiota metabolism, accumulate in the blood owing to renal malfunction. Toxins, such as indoxyl sulfate and p-cresyl sulfate, are inflammatory and oxidative stress triggers that damage various organs, including the liver and kidney (137). For example, indoxyl sulfate induces aryl hydrocarbon receptor (AhR) activation resulting in the upregulation of pro-inflammatory genes and pro-fibrotic factors (138). Activation of AhR leads to endothelial cell infiltration, oxidative stress and degeneration in various organs. The p-Cresyl sulfate impairs cell signaling by suppressing endothelial nitric oxide synthase and stimulating NADPH oxidase, resulting in vascular dysfunction and inflammation (139,140).

TMAO, a gut microbiota-derived metabolite generated by hepatic flavin monooxygenase 3-mediated oxidation of TMA, is a key pathogenic factor in the gut-liver-kidney axis (141-143). Choline, carnitine and betaine are dietary precursors that are metabolized by the gut microbiota to form TMA, which is converted to TMAO in the liver. TMAO accumulates at high levels in CKD because of the combined effects of production from aberrant gut microbiome and decreased elimination by the kidney, forming a pathological store that promotes cardiovascular-renal disease (144). TMAO directly affects the renal tubules via NLRP3 inflammasome activation in renal tubular cells, resulting in increased production of IL-1β and IL-18 as well as an acceleration of tubulointerstitial fibrosis (145,146). Moreover, TMAO induces endothelial dysfunction via oxidative stress and decreases nitric oxide bioavailability, which lead to premature atherosclerotic changes and cardiovascular events in patients with CKD (147). Notably, TMAO disrupts hepatic lipid homeostasis by blocking ATP-binding cassette transporter A1-dependent reverse cholesterol transport while suppressing cholesterol 7α-hydroxylase (CYP7A1) expression, which encodes the rate-limiting enzyme for bile acid synthesis (148,149). This disruption of hepatic cholesterol handling leads to a feed-forward pathological loop in which impaired liver lipid metabolism amplifies systemic inflammation and worsens hepatic steatosis and renal lipotoxicity. Together, these effects position TMAO as a key link connecting gut dysbiosis with coordinated liver-kidney dysfunction during the progression of cardiovascular disease. Collectively, accumulating evidence from experimental models and clinical cohorts indicates that elevated circulating TMAO is associated with CKD progression and cardiovascular risk, reinforcing its role as a key molecular nexus within the gut-liver-kidney axis (150,151).

Uremic toxins and their transduction pathways induce oxidative stress, trigger mitochondrial breakdown, block respiratory chain complexes, activate NADPH oxidase via protein kinase C pathways and disrupt intracellular antioxidant mechanisms, such as depleting glutathione and decreasing antioxidant enzyme activity (137). Concurrently, uremic toxins disrupt Nrf2 signaling, thereby promoting cytoplasmic entrapment and inhibiting nuclear Nrf2 translocation, decreasing cellular antioxidant reserves and impairing the counter-regulative response to oxidative stress (137,152). Consequently, oxidative stress extends across the gut-liver-kidney axis, leading to cell damage and pro-inflammatory signaling which promotes disease progression (153).

CKD has effects on PPAR signaling, especially for PPARα and PPARγ pathways in the gut-liver-kidney axis. In DKD, PPARα expression and activity decreases in the liver and kidney, resulting in FA oxidation impairment and lipid accumulation (154,155). This dysfunction promotes hepatic steatosis and renal lipotoxicity thus creating pro-inflammatory microenvironments that potentiate organ damage. Concurrently, PPARγ expression becomes dysfunctional in adipose tissue and immune cells and results in insulin resistance and inflammation activation (156,157). Thus, the combined alteration of PPAR signaling leads to a systemic metabolic disarray that fuels CKD progression.

Fat oxidation machinery at the molecular level is repeatedly disrupted over time in patients with CKD. Long-term inflammation and oxidative stress disrupt AMPK signaling, a central regulator of cellular energy metabolism (158,159). This impairment depresses acetyl-CoA carboxylase phosphorylation and enhances malonyl-CoA content to prevent carnitine palmitoyltransferase 1 (CPT1)-mediated inhibition of FA transfer into the mitochondria (160). Simultaneously, the expression of PPARγ coactivator-1α decreases, thereby leading to decreased mitochondrial biogenesis and oxidative capacity (161,162).

Excessive lipid storage in the liver and kidney leads to complex lipotoxicity signaling pathways that result in systematic multi-organ dysfunctions through the gut-liver-kidney axis. Saturated fat increases ceramide formation via de novo biosynthesis and/or the salvage routes, leading to ceramide accumulation. These elevated ceramides directly activate the protein kinase C (PKC) and JNK signaling cascades, which modulate hepatocyte and tubular cell apoptosis (163,164), amplify inflammatory cytokines and alter fibroblasts so they are activated by collagen deposition (165,166). Concurrently, accumulation of diacylglycerol selectively activates novel PKC isoforms (PKCδ, PKCε, PKCθ), thereby causing phosphorylation of insulin receptor substrate/activation of transcription factors such as NF-κB, resulting in hepatic and renal insulin resistance/inflammation (167). This lipotoxic microenvironment creates a self-perpetuating cycle, wherein lipid-induced inflammation may disrupt cell lipid metabolism and mitochondrial function (168,169), leading to progressive organ dysfunction combined with worsening metabolic disarray through the gut-liver-kidney network.

CKD engenders a sustained immune hyperactivation reflected by abnormal TLR signaling escalation along the gut-liver-kidney axis. The leakage of bacterial components, particularly from LPS from Gram-negative bacteria, across the partially damaged intestinal barrier activates a series of TLR4 signaling cascades in hepatic Kupffer cells, renal resident macrophages and recruitment immune cell (170,171). This translocation of bacteria at TLR4 exacerbates NF-κB nuclear translocation and transcription, resulting in continuous release of pro-inflammatory cytokines and progressive organ damage (172,173). Concomitantly, TLR2 and TLR9 are overactivated by an increasingly large pool of damage-associated molecular patterns, such as high mobility group box 1 and heat shock proteins, which are lost mainly from necrotic hepatocytes and renal proximal tubular cells (174-176). Chronic TLR activation induces the reprogramming of innate immune cells into a trained state via epigenetic changes and metabolic rewiring (176). This leads to pathological immune memory, biased inflammatory responses and tissue damage in the absence of continuous pathogen exposure. Consequently, a self-perpetuating cycle of sterile inflammation is induced by the gut-liver-kidney loop.

The complement cascade in CKD is dysregulated and induces an inflammatory pattern that amplifies organ destruction and malfunction in the gut-liver-kidney axis. Hyperactivation of the alternative complement pathway is the primary mechanism, with multiple pathways contributing to the downregulation of key complement regulatory proteins (factor H, CD55, CD46) and increased stability of the C3 convertase due to decreased decay accelerating factor activity (177-179). Aberrant activation of this downstream cascade results in the overproduction of C5a anaphylatoxin, which is a chemotaxin and neutrophil priming factor that activates tissue-resident macrophages and induces degranulation-mediated tissue damage along the hepatic sinusoids and renal interstitium (180,181). In the intestine, the complement system is activated by bacterial translocation-induced classical pathway activation and regional C3 deposition in gut epithelial cells. The classical complement pathway is compromised via autoactivation by deposited circulating immune complexes and binding of acute-phase proteins (C-reactive protein and serum amyloid P), resulting in further amplification loops of inflammation (182). Notably, unregulated systemic activation of complement has several pathological implications. These include complement-mediated glycocalyx degradation, increased platelet activation, phospholipid surface stimulation of the coagulation cascade and the ulceration of atherosclerotic plaques (183,184). Together, these effects may contribute to the increased cardiovascular morbidity observed in patients with CKD.

CKD leads to a striking dysregulation in the cytokine signaling network, characterized by sustained elevation of pro-inflammatory mediators along with impaired anti-inflammatory regulatory mechanisms at the gut-liver-kidney axis level (185). IL-6 signaling is constitutively active because of sustained phosphorylation and nuclear translocation of STAT3, which promotes hepatic acute-phase protein synthesis (C-reactive protein, fibrinogen and serum amyloid A), while simultaneously coordinating systemic inflammatory responses that disseminate along the entire axis (186,187). Simultaneously, chronic elevation of TNF-α activates sustained canonical NF-κB (p65/p50) and stress signal MAPK pathways (JNK, p38, ERK1/2), all of which result in hepatocyte apoptosis, injury to renal tubular cells, gut barrier failure and step-wise fibroblast activation for multi-organ fibrosis (188,189). Notably a paradoxical dysregulation of the anti-inflammatory cytokine network is observed, wherein IL-10 production declines following suppression of T regulatory cell activity and M2 macrophage polarization deficiency (190,191). TGF-β signaling undergoes pathological reprogramming from its protective tissue-healing role toward profibrotic action with increased Smad2/3 phosphorylation and diminished Smad7 inhibitory capacity (192,193). Dysregulation of this cytokine network contributes to a vicious cycle of chronic inflammation, which leads to progressive organ damage. Furthermore, it generates cytokine resistance signatures that compromise the ability of the host to resolve inflammation and repair tissue. This, in turn, maintains the spread of the disease within the gut-liver-kidney network.

The strategy behind probiotic supplementation is based on the re-establishment of a balanced ecosystem of beneficial microorganisms, necessary to balance gut-liver-kidney cross-talk. Microorganisms such as Bifidobacterium longum and B. bifidum are cornerstone treatment modalities owing to their ability to produce SCFAs, particularly butyrate, which has an anti-inflammatory effect on the renal tubular cells and hepatocytes and improves intestinal barrier integrity through the induction of tight junction proteins (195,196). Other studies in CKD cohorts have also demonstrated that Bifidobacterium supplementation leads to a decrease in serum inflammatory markers (IL-6, TNF-α) and suggests a trend toward improved eGFR (197,198). Akkermansia muciniphila is another target, especially in view of its role as a barrier to metabolic function. This mucin-digesting gut bacterium serves a direct role in the mucin layer thickness and intestinal permeability, modulates the production of beneficial metabolites and reverses hepatic insulin resistance with nephroprotective effects (199). In overweight and obese patients, Muciniphila markedly decreases markers of liver dysfunction and systemic inflammation, with its effects associated with gut microbiota metabolic pathways involved in FA production, branched-chain amino acid metabolism and bile acid signaling (200). Lactobacillus spp., especially L. casei and L. rhamnosus, provide benefits through immune modulation and competitive exclusion of pathogenic bacteria. Such strains stimulate the development of regulatory T cells, decrease pro-inflammatory cytokine secretion and maintain enteric pH at levels that are conducive to the growth of healthy microbiota while suppressing urease-producing bacteria required for ammonia production, leading to systemic toxicity (201-203).

Prebiotic interventions modulate discrete health-associated bacterial populations using deliberately chosen fiber substrates and resistant starches (RSs). Inulin-type fructans are selective factors for Bifidobacterium growth and SCFA production and clinical trials have shown decreased levels of uremic toxins and ameliorated renal function following supplementation in patients with CKD (204-206). RS type 2 and RS type 4 formulations selectively stimulate butyrate-producing bacteria (Faecalibacterium prausnitzii, Roseburia spp.), while lowering colonic pH and decreasing protein fermentation, resulting in a decrease in the generation of nephrotoxic metabolites (207). Additionally, novel galacto- and fructo-oligosaccharide combinations exert a combined effect in terms of stimulatory bacteria favoring multiple beneficial viable counts and deteriorating pathogenic species levels (208). Superior multimodular synbiotic formulations with designed probiotics and substrates exert a better therapeutic effect than monotherapy by significantly increasing SCFA production, decreasing uremic toxins and displaying enhanced multi-organ protection over 12 weeks (209).

FMT has been proposed as an advanced formulation for the overall restoration of the gut microbiome in patients with CKD with extreme dysbiosis. Selective donors, who have been screened amongst metabolically healthy individuals with strong SCFA-producing microbiota, provide the opportunity for rapid ecosystem recovery and access to therapeutic benefits. Studies using frozen encapsulated FMT products have demonstrated efficacy in lowering uremic toxin levels, improving kidney function and preserving the intestinal barrier (210). In FMT, donors are screened for beneficial bacteria (including Akkermansia, Faecalibacterium and Bifidobacterium) and the absence of pathogens prior to treatment, which is necessary to optimize the therapeutic effect (211). Studies on FMT have suggested improvements in microbial diversity, SCFA production and inflammatory markers along the gut-liver-kidney axis over follow-up periods of 6-12 weeks (211-213). However, the durability and long-term stability of microbiome remodeling remain incompletely defined and require confirmation in larger studies with extended follow-up periods (214).

Emerging therapeutic modalities use genetically manipulated bacterial strains targeting specific disease pathways in the gut-liver-kidney axis. For example, Lactobacillus strains have been designed to express urease inhibitors aiming to decrease intestinal ammonia production, and engineered Bifidobacterium species containing indole-metabolizing enzymes have been proposed to target uremic toxin precursors (215,216), however, these remain proof-of-concept designs at the preclinical stage. Synthetic biology enables the design of chassis organisms (engineered host microbes serving as programmable platforms) programmed to deliver therapies to the gut. These designer therapeutic microbes produce protective metabolites, neutralize harmful bacterial products and sustain drug release at the site of interest within the gut. For example, preclinical studies using modified E. coli Nissle 1917 strains engineered to metabolize excess ammonia have shown promising results in mouse models of hyperammonemia and associated neurological disorder (217-219); to the best of our knowledge, these constructs have not yet been evaluated in patients with CKD. The precision microbiome transfer approach is based on the administration of characterized bacterial communities that are selected because of their therapeutic potential in KD, thus circumventing the limitations of whole-microbiome transplantation without compromising its therapeutic efficacy. Microbiome-targeted therapeutic strategies for nephroprotection are summarized in Fig. 5.

SCFA restoration may be a personalized treatment strategy for selective compensation of disordered microbial metabolite production in CKD dysbiosis. Sodium butyrate, the most commonly studied therapeutic SCFA, exerts combined beneficial effects on the gut-liver-kidney axis by inhibiting HDACs and activating GPR43 (86,243). SCFA butyrate administration suppresses the expression of an inflammatory gene program in renal tissue that is associated with NF-κB suppression and increased regulatory T cell numbers (86). Additionally, preclinical studies have shown that sodium butyrate exerts renal protective effects through multiple mechanisms, including decreasing the levels of oxidative stress and inflammation markers, improvement of mitochondrial function and regulating cell metabolic pathways in several experimental models of kidney disease, with increasing interest in DKD research (244,245). Supplementation with propionate yields metabolic benefits through independent signaling pathways associated with GPR41 activation and regulation of hepatic gluconeogenesis. Propionate promotes hepatic gluconeogenesis and enhances insulin sensitivity through olfactory receptor 78 in renal juxtaglomerular cells (246,247). This dual action is beneficial not only for the optimization of glucose homeostasis but also offers direct nephroprotection by improving renal perfusion and lowering oxidative stress. Acetate administration supports systemic energy metabolism and promotes the growth of beneficial bacteria through cross-feeding mechanisms that enhance endogenous SCFA production (248-250).

RS supplementation is an upstream therapeutic strategy that stimulates endogenous SCFA production by selectively stimulating the beneficial bacteria. With the ability to specifically promote the growth of Bifidobacterium and Faecalibacterium prausnitzii, high-amylose maize starch may be a human non-digestible carbohydrate source from RS2 that causes sustained butyrate production and improves the intestinal health (251). RS type 4 resistant starch compositions exhibit improved stability and selective colonic delivery, allowing maximal availability of the substrate for the fermentation of beneficial bacteria (252). Trials in CKD populations have shown that RS supplementation notably lowers inflammation and oxidative stress, attenuates symptoms caused by the retention of uremic toxins and improves renal function in patients with CKD (253,254). Arabinoxylan oligosaccharides (AXOS) and β-glucan supplementation demonstrate specific prebiotic responses that selectively enrich SCFA-producing bacteria while promoting other immunomodulatory effects (255). AXOS stimulates the proliferation of Roseburia and Eubacterium rectale, leading to increased butyrate production and improved intestinal barrier function by increasing the expression of tight junction proteins (256). β-glucan supplementation exerts dual actions by improving SCFA production and directly modulating the immune system through activation of dectin-1 receptor in the intestinal macrophages (257).

Complex or advanced synbiotic compositions, comprising specific probiotic strains combined with selected prebiotics that are SCFA-inducing, are more effective compared with mono-intervention (258). These pathways promote sustained SCFA levels over the duration of treatment, and demonstrate durable clinical responses beyond the period of active supplementation. Synbiotic preparations containing multiple strains, including A. muciniphila with B. longum and L. casei on a galacto-oligosaccharide substrate, exert a notable metabolic effect, increase SCFA production, strengthen barrier function and decrease inflammatory signaling along the gut-liver-kidney axis (259).

PPARα agonists, such as fibrates, are the mainstay therapies for treating severe disturbances of lipid metabolism observed with CKD development. Fenofibrate, a selective PPARα agonist exert a nephroprotective effects via induction of FA oxidation, suppression of renal lipid accumulation and inhibition of inflammatory signaling pathways (260). In renal tubular cells, PPARα activation upregulates the transcription of FA oxidation enzymes (such as CPT1 and acyl-CoA oxidase), leading to a decrease of lipid overload, which prevents lipotoxic nephrotoxicity (261). Hepatic PPARα activation decrease very low-density lipoprotein production, and improves systemic lipid profiles, thereby conferring metabolic benefits in extra-hepatic tissue, including the kidney (262). Clinical evidence has shown that fenofibrate therapy decreases cardiovascular events, increases the eGFR and decreases albuminuria in patients with CKD over 5-year period (263). Pemafibrate, a selective PPARα modulator (SPPARMα), is associated with decreased renal function decline and better safety profile than conventional fibrates (264). This next-generation PPARα agonist decreases the prevalence of MASLD with better safety in patients with CKD. The drug is metabolized in the liver and excreted via bile, resulting in minimal changes in systemic exposure, even in patients with CKD, thereby minimizing the risk of drug accumulation and supporting its safety as a therapeutic option (265).

Therapeutic benefits of PPARγ agonists are achieved by improvements in insulin sensitivity, inflammation and adipocyte function in the gut-liver-kidney axis. The thiazolidinedione PPARγ agonist pioglitazone exerts numerous pleiotropic effects on the kidney, such as improving insulin sensitivity, decreasing oxidative stress and inhibiting inflammatory cytokine production (266,267). In the kidney, PPARγ activation induces macrophage anti-inflammation and polarization, inhibits fibroblast activation and extracellular matrix deposition, and enhances podocyte survival by boosting mitochondrial function (268). Activation of hepatic PPARγ ameliorates hepatic insulin sensitivity, decreases hepatic glucose output and increases adiponectin secretion, all of which improve systemic metabolism and kidney function (269,270). SPPARMs such as telmisartan, have advantages over thiazolidinediones as they provide the beneficial effects of PPARγ activation without fluid retention and weight gain (271). These compounds exhibit a notable nephroprotective effect mediated by combined angiotensin receptor blocking and PPARγ activation, providing dual mechanisms of action.

Carnitine replacement can partially restore FA oxidation capacity in patients with CKD, in whom decreased dietary intake, impaired synthesis and increased carnitine loss are common (272). L-carnitine supplementation has been shown to improve FA oxidation and dialysis-associated symptoms (273,274). As these effects are primarily systemic rather than specific to gut-liver-kidney axis signaling, carnitine strategies are considered adjunctive within the present framework.

Emerging insights into the pathophysiology of the gut-liver-kidney axis have spurred interest in integrated multi-organ protection interventions, expanding beyond traditional organ-centric treatment modalities (17,275). Data remain scarce, but combined intervention of different organs in this axis may show better outcomes than mono-target therapy (276). The preliminary CONFIDENCE trial supported this approach, however, further confirmation of long-term kidney disease progression is required (276). This represents an initial step toward multitarget therapy in nephrology, pending confirmation from larger longer-term studies.

In addition to therapeutic interventions that target the gut-liver-kidney axis by modulation of the microbiome, restoration of metabolic pathways or axis-selective apoptosis, renal-targeted therapies act through other mechanisms. SGLT2 inhibitors and non-steroidal mineralocorticoid receptor antagonists (MRA) have shown promising nephroprotective properties against CKD with increased renal risk, especially in patients with type 2 diabetes (277). However, these agents act almost exclusively via direct hemodynamic and tubular effects on the kidney, rather than by altering the intestinal-hepatic-renal signaling pathways emphasized in the present axis. Recent clinical evidence, including that from the CONFIDENCE trial, suggests potential benefits of combination therapy with empagliflozin and finerenone in decreasing albuminuria (278). Although these effects appear promising, their mechanisms of action are primarily focused on the kidney and include glomerular hemodynamic changes, inhibition of tubular sodium-glucose transport and antagonism of mineralocorticoid receptors in renal tissue (279). The association between these therapeutic targets and gut-derived metabolites, hepatic metabolic dysfunction and microbiome-mediated signaling pathways is indirect and largely undefined. Accordingly, although SGLT2 inhibitors and MRAs are emerging as important additions for the treatment of CKD in nephrology and may be combined with gut-liver-kidney axis-targeted therapies, a detailed discussion of their mechanisms is beyond the scope of the present review. Clinicians treating individuals with DKD should consider complementary rather than mutually exclusive axis-targeted therapies and other renoprotective agents, however, the best approach to integrate these potent yet distinct therapeutic strategies awaits further evaluation. Table III provides an overview of the therapeutic approaches targeting the gut-liver-kidney axis, categorizing interventions by mechanism of action, study design, key findings and current limitations. These include microbiome-directed strategies such as prebiotic-probiotic supplementation and resistant starch (280,281), bile acid-based FXR agonists (282), PPARα modulators including fibrates and pemafibrate (283,284), direct SCFA administration with sodium butyrate and propionate (285,286), and carnitine-based interventions (287,288).

Microbiome-based therapies offer an experimental therapeutic scheme by which potential upstream contributors to gut-liver-kidney axis dysfunction can be addressed. Early interventional approaches have associated precision probiotics with tailored pre- and postbiotic supplementation to restore the entire ecosystem. Synbiotic formulations composed of multiple strains demonstrate the potential for greater therapeutic efficacy compared with single-agent probiotic strategies in cholesterol control, blood pressure regulation and anti-inflammatory activity based on small studies (289,290). In a small but well-designed SYNERGY randomized controlled clinical trial, a 6-month intervention with synbiotic therapy resulted in significantly lower levels of p-cresyl sulfate compared with placebo among patients with stage 3-4 CKD (291). However, the trial was small (37 patients) and examined biochemical markers rather than clinical measures. Serum indoxyl sulfate reduction was not the primary endpoint, however, secondary improvements were observed. The SYNERGY II feasibility trial demonstrated synbiotic supplementation may modulate the stool microbiome and is feasible in patients with CKD, achieving acceptable retention rates and potential benefits for specific secondary outcomes (280). Both of the aforementioned studies had limited sample sizes and short-to-medium-term follow-up periods, however, as proof-of-concept reports, these trials demonstrate the need for other larger-scale validation studies.

Interventions in combination that aim to positively alter the disrupted gut-liver-kidney metabolic axis seem promising based on an improved restoration of coordinated pathways. To the best of our knowledge, few clinical studies in metabolic syndrome populations have demonstrated that the combined supplementation of specific probiotic strains and (prebiotic) fibers improve insulin sensitivity and lipid profiles compared with the effects produced by compounds alone, with some effects remaining for ≥16 weeks after treatment cessation (234,292). Bile acid modulation-based combination therapies that pair FXR agonists with microbiome-targeted prebiotics may simultaneously address upstream gut dysbiosis and downstream metabolic disturbances, leading to normalization of bile acid profiles and enrichment of beneficial bacterial populations through bile acid-microbiome cross-talk (293,294). However, these methods are experimental and have limited clinical applications.

Through experimental therapeutic platforms, nanotechnology approaches are being evaluated and developed that may result in targeted multi-organ delivery with improved specificity and decreased systemic toxicity (295,296). However, these strategies remain largely in the preclinical development stage and pose translational hurdles. Emerging technologies, including drug delivery systems targeting the gut-brain-microbiome axis, suggest therapeutic potential for chronic disease intervention, however, studies in patients with CKD remain scarce and are often constrained by regulatory issues (297). Nanotechnology also aims to create lipid-based nanocarriers that may, in principle, deliver probiotics, prebiotics and bioactive compounds to target locations in the gut-liver-kidney axis; to the best of our knowledge, these remain conceptual designs without in vivo validation in CKD models, where therapeutic dose exposures can be maximized and off-target effects can be minimized (298,299). Smart polymer systems are also being developed to respond to specific tissue pH and enzymatic environments with the ability to deliver therapeutic compounds in a spatially and temporally controlled manner (300). Although conceptually attractive, such formulations have shown the early potential to deliver SCFA precursors in vitro for colon targeting, bile acid modulators to liver tissue and antioxidant compounds to renal tubular cells through selective release. Nevertheless, clinical impact, production scalability, cost-effectiveness and regulatory approval processes are impediments to clinical application.

Nanotechnology platforms are investigating advanced targeting approaches that can be applied to overcome the biological obstacles present in the gut-liver-kidney axis. Active targeting strategies include evolving surface-functionalized nanoparticles with attached organ-specific ligands such as megalin-targeting peptides for delivery to proximal tubular cells, hepatocyte-selective asialoglycoprotein receptor ligands and gut epithelial cell-binding lectins (301,302). Although these molecularly targeted platforms exhibit increased cell uptake in vitro, clinical translation faces obstacles related to their synthetic complexity, potential immunogenicity and heterogeneous pharmacokinetics in patients with CKD. Passive targeting strategies theoretically exploit the enhanced permeability and retention (EPR) effect observed in inflamed renal and hepatic tissue, wherein compromised endothelial integrity may facilitate preferential nanoparticle accumulation (303). However, the EPR effect is heterogeneous among patients and diseases and its clinical predictability remains poor. Stimuli-responsive components are added to next-generation nanocarrier constructs that may, in principle, respond to disease-specific changes in the tissue microenvironment, such as altered pH of the inflamed tissue, increased levels of reactive oxygen species or altered enzyme activity patterns characteristic of CKD progression (304). To the best of our knowledge, these measures are in the early stages of development and have not yet been clinically validated in patients with CKD.

Despite mechanistic promise, the translation of gut-liver-kidney axis-targeted therapies into clinical nephrology faces barriers in safety, tolerability, durability and regulatory pathways.

The bile acid-based FXR agonist OCA has advanced to Phase III in metabolic dysfunction-associated steatohepatitis but has not been approved, as its moderate hepatic benefit does not outweigh dose-dependent adverse effects (305). The most frequent adverse effect is pruritus, occurring in ~23% of OCA-treated patients vs. 6% of placebo-treated patients, and is typically severe at higher doses (306). OCA also induces a pro-atherogenic lipid shift, raising low-density and lowering high-density lipoprotein cholesterol, typically requiring concomitant statin therapy, alongside risks of cholelithiasis and hepatotoxicity (305,307). These liabilities are concerning in CKD, where cardiovascular risk is already markedly elevated. Non-bile acid and intestine-restricted FXR agonists (tropifexor, nidufexor, cilofexor) aim to dissociate efficacy from these effects, but dose-dependent pruritus persists and, to the best of our knowledge, no agent has yet demonstrated renal outcome benefit in CKD; CKD-specific efficacy and safety datasets do not currently exist.

FMT has shown encouraging preliminary results in CKD: In a 6-month double-blind RCT in CKD stages 2-4, fewer FMT recipients demonstrated CKD progression (13.3%) than placebo recipients (53.8%), with stable renal parameters and only mild-to-moderate gastrointestinal adverse events and an exploratory trial in IgA nephropathy reported acceptable safety (308). However, the evidence base is limited by small sample sizes, heterogeneous protocols, absence of standardization and undefined long-term durability and safety, including donor-dependent variability and theoretical infection transmission risk (213,309). To the best of our knowledge, no Phase III renal outcome trial exists, and regulatory frameworks for microbiome therapeutics in chronic, non-infectious indications remain immature.

Engineered therapeutic bacteria and nanotechnology-based delivery systems remain preclinical, facing barriers of manufacturing scalability, immunogenicity, heterogeneous pharmacokinetics in CKD and the absence of regulatory precedent for multi-organ, axis-targeted agents. Across all modalities, the key bottleneck is the absence of adequately powered, CKD-specific RCTs with hard renal endpoints and long-term safety follow-up.