The principal limitation of kidney disease (KD)
research is the organ-centric view that renal pathology can be
separated from the contributions of other organs. Early description
of the renin-angiotensin-aldosterone system in
hypertension-mediated nephropathy transformed understanding of
intrarenal hemodynamics (1,2).
By the late 1990s, the 'hyperfiltration theory' and its systematic
account of diabetic glomerulosclerosis through renal hemodynamic
alterations offered key insights into the pathophysiological
mechanisms and therapeutic targets for KD (3,4).
More recently, the development of sodium-glucose cotransporter-2
(SGLT2) inhibitors and other renal-directed therapies has continued
to augment the therapeutic spectrum (5,6).
Nevertheless, clinical problems, particularly in individuals with
diabetic KD (DKD), which commonly occurs concomitantly with other
complications, remain unresolved. This suggests the intricate organ
crosstalk between the liver and intestine, as an important
metabolic and inflammatory driver in renal dysfunction, requires
further investigation to understand multi-organ involvement in
disease progression (7,8). This organ-centered approach
prevents proper understanding of the multi-organ injury axis of
visceral dysbiosis, gut barrier failure, hepatic insulin resistance
and lipotoxicity in tubulocentric injury (9-11). However, this knowledge gap
persists despite advancements in clinical practice as the current
guidelines dedicate minimal attention to gut-liver-kidney crosstalk
in the 2024 Kidney Disease: Improving Global Outcomes (KDIGO)
recommendations (12).
Against this historical basis and in the context of
comorbidities now recognized as a key challenge in global health,
multi-organ communication networks are essential for systemic
homeostasis (8). Notably, a
complex interplay exists between intestinal dysbiosis, metabolic
dysfunction-associated steatotic liver disease (MASLD) and chronic
KD (CKD), all episodic or concurrent, owing to common risk factors
(such as insulin resistance, obesity, type 2 diabetes and systemic
inflammation) and pathophysiological mechanisms (including gut
dysbiosis, chronic low-grade inflammation, oxidative stress and
metabolic dysregulation). The gut microbiome serves as an initiator
and mediator of this axis, generating metabolites and inflammatory
cues that have effects on hepatic and renal function. In addition
to their classic roles, recent research indicates that kidneys
impact on pulmonary, intestinal, hepatic and muscular functions, as
well as on neurological function in altered states, with
multi-organ dysfunction responsible for increasing death and
disability (13).
Therefore, composite endpoints combining gut
permeability and microbiome testing should be integrated in
clinical trials of patients with CKD. However, classic
renal-metabolic studies incorporate gut-derived uremic toxins and
liver metabolic factors, evaluated against kidney-relevant
outcomes. Nevertheless, this nephrocentric but integrative model
would more comprehensively represent the role of intestinal
dysbiosis and hepatic damage in CKD progression, thus offering
insight into new therapeutic targets that afford renoprotection by
targeting these upstream causes of kidney injury from the gut-liver
axis. This is particularly relevant as a recent meta-analysis
reported a 38% increased CKD risk (95% CI: 1.28-1.50) in MASLD
populations (14). Additionally,
in June 2023, the global hepatology societies changed the
terminology non-alcoholic fatty liver disease to MASLD based on the
Delphi consensus of >200 experts (15). This modification was made due to
concerns about stigmatizing language and a more accurate
description of the metabolic pathogenesis involved in
gut-liver-kidney axis dysfunction (16).
The present review aimed to provide a novel
viewpoint and extend current single-organ research by examining the
gut-liver-kidney axis from microbial, metabolic, inflammatory and
hemodynamic perspectives, with DKD as an example of multimorbidity.
Thus investigating the bidirectional signaling may provide insight
into how altered gut microbiota and permeability precede and
augment liver and kidney dysfunction. In addition, the present
study aimed to suggest novel diagnostic strategies using microbiome
signatures and gut-derived metabolites as early biomarkers of
kidney injury and therapeutic strategies to manipulate the
intestinal ecosystem for renoprotection. Existing reviews have
largely treated the axis components in isolation, with gut-kidney
literature focusing on microbial dysbiosis and uremic toxins, the
gut-liver literature on hepatic metabolic dysfunction and the
MASLD-CKD literature on epidemiological association, while
typically treating the liver as a passive conduit rather than an
active regulatory hub (17-19). The present review aimed to
position the liver as a co-equal node uniting the gut-kidney and
gut-liver axes into a single tripartite framework. The present
study aimed to apply systems biology methodology that reframes
these mechanisms as an analyzable, self-perpetuating network and
describe subtype specificity (DKD vs. non-DKD CKD) and therapeutics
strategies (20,21). The literature search strategy and
selection criteria are provided in Supplementary material 1.
The gut-liver-kidney axis is a complex physiological
system that mediates systemic homeostasis through sophisticated
anatomical connections, molecular signaling pathways and integrated
physiological responses (Fig.
1). These organs have evolutionarily conserved regulators of
bidirectional communication, which are key for nutrient
assimilation, immune surveillance, detoxification and
fluid-electrolyte balance (22).
An appreciation of this three-organ association is critical to
better understand how alterations in one organ can lead to
pathogenic cascades that affect distal tissue in other organs but
share a common link in terms of etiology and may impact the
development and progression of KD.
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.
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).
The gut-liver-kidney axis is a physically and
biochemically coupled system, integrated through portal and
systemic vascular networks, enterohepatic bile acid circulation and
a shared endocrine and microbial-metabolite signaling milieu.
Translating this coupled architecture into a tractable analytical
framework capable of supporting causal inference, predictive
modeling and rational therapeutic targeting requires explicit
systems biology methodology. The molecular signaling network
underlying this axis operates across multiple biological scales
from intracellular receptor cascades to interorgan metabolite
shuttling and cannot be adequately captured by reductionist,
single-pathway analyses. A systems biology scaffold provides the
analytical apparatus required to translate this complexity into
causal, predictive and dynamic models of CKD progression. This
framework is organized as a multi-layer analytical pipeline
spanning biological data, analytical methods and the core organ
axis that converges on causal and dynamic modeling of the
gut-liver-kidney axis (Fig.
3).
Co-expression analyses identify associations but not
directionality. Bayesian network frameworks, including dynamic
Bayesian networks applied to longitudinal multi-omics microbiome
data, prioritize candidate causal drivers and have been validated
in inflammatory bowel disease and associated axis-pathology
contexts (103). Mendelian
randomization (MR), using genetic variants as instrumental
variables, has been applied to test causal links between gut
microbiota composition and renal traits in large biobank cohorts,
identifying specific taxa (such as Bacteroidia) with strong causal
associations with eGFR decline (104) and revealing gut
microbiota-immune system-kidney mediating pathways that
operationalize the axis at the genetic-causal level (105). Notably, bidirectional MR
analyses indicate that elevated circulating trimethylamine N-oxide
(TMAO) in CKD may partly reflect decreased renal clearance rather
than upstream causation, with type 2 diabetes and kidney disease
shown to causally increase TMAO levels; this has implications for
whether TMAO-targeted interventions can modify renal outcomes
(106).
Ordinary differential equation (ODE) models capture
the temporal cyclicity that defines axis pathology.
Multi-compartment ODE frameworks of bile acid enterohepatic
circulation, incorporating FXR-mediated autoregulation and
selective transport mechanisms across hepatic, intestinal and
systemic compartments, have been developed and calibrated against
human pharmacokinetic and physiological datasets (107,108). By encoding production,
degradation and interaction kinetics across organ compartments,
integrated ODE models enable in silico screening of
interventions, such as SCFA supplementation, FXR agonism and fecal
microbiota transplantation (FMT), before initiating costly clinical
trials, and can identify tipping points at which compensatory
mechanisms form a self-perpetuating pathological loop.
Together, network-based module identification,
causal inference and dynamic simulation constitute the quantitative
scaffold on which the systems biology framework rests, integrating
heterogeneous biological data into a unified network that links
molecular perturbations with the self-perpetuating organ-axis loop
and downstream CKD outcomes (Fig.
3). Their integration into routine gut-liver-kidney axis
research remains in its early stages, with most studies applying
individual tools rather than the unified pipeline (109-111). The development of standardized
multi-organ, multi-omics CKD datasets, together with computational
platforms supporting joint analysis, represents both the principal
bottleneck and the most promising direction for axis research.
In CKD, dysregulation of gut-liver-kidney
communication is an integrated, self-perpetuating loop in which
each module amplifies the others across organ boundaries (Fig. 4). Intestinal barrier failure
releases endotoxins and uremic toxin precursors into the portal
circulation; hepatic exposure to these signals exacerbates bile
acid dysregulation, lipotoxic signaling and acute-phase
inflammation; the resulting systemic milieu (elevated TMAO, indoxyl
sulfate, pro-inflammatory cytokines and dysregulated peroxisome
proliferator-activated receptor (PPAR)/FXR signaling) precipitates
renal tubular injury and fibrosis; the consequent decline in renal
clearance feeds back to alter gut microbial composition, bile acid
pool homeostasis and tight junction integrity, completing the
cycle. The intestinal barrier, microbial signaling dysregulation,
bile acid-hepatic signaling pathway disruption, uremic toxin
signaling cascades, lipid metabolism signaling network
dysregulation and immune signaling imbalance are not parallel
disease mechanisms but interlocking nodes of a positive-feedback
network whose collective dynamics, rather than any single
component, drive CKD progression across multiple biological scales,
from intracellular signaling to organ-level dysfunction and
systemic inflammation.
The gut-liver-kidney axis does not operate uniformly
across CKD etiologies; its dysfunction is most pronounced and most
therapeutically tractable in DKD, where metabolic, hepatic and
renal compartments are tightly coupled. In DKD, all three arms of
the axis are simultaneously engaged. Hyperglycemia and insulin
resistance drive hepatic steatosis, with MASLD affecting the
majority of patients with type 2 diabetes and increasing CKD risk
(14,112). The gut microbial signature of
DKD is distinctive, differing from that of diabetes without
nephropathy in both the expansion of pathobionts and the depletion
of butyrate-producing taxa (113,114). Together, these shifts amplify
SCFA depletion, endotoxemia and uremic toxin generation, situating
DKD as the prototypical setting in which gut dysbiosis, hepatic
lipotoxicity and renal injury reinforce one another. In non-DKD
CKD, including IgA nephropathy, hypertensive nephrosclerosis and
autosomal dominant polycystic KD, the axis is engaged more
selectively. Intestinal dysbiosis and uremic toxin accumulation
accompany advanced renal dysfunction regardless of etiology, but
the hepatic-metabolic arm is less prominent in the absence of
insulin resistance and MASLD (113). Consequently, the
gut-liver-kidney framework carries greatest explanatory and
therapeutic weight in metabolically driven CKD, whereas in non-DKD
subtypes, axis-directed interventions remain more speculative and
etiology-dependent. This underscores the need for
subtype-stratified evaluation of axis-targeted therapies (Table II).
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 therapeutic strategies span a spectrum of
clinical maturity, from mechanistic preclinical studies to
late-phase randomized controlled trials (RCTs). Notably, the
majority of gut-liver-kidney axis-targeted interventions remain at
the preclinical or early-phase stage, and the few therapies
supported by Phase III renal-outcome evidence (SGLT2 inhibitors,
finerenone, GLP-1 receptor agonists) act predominantly through
direct renal or systemic metabolic mechanisms rather than through
the gut-liver axis.
The gut microbiome is a key therapeutic target in
the gut-liver-kidney axis, as dysbiosis initiates pathological
cascades ranging from barrier dysfunction to multi-organ injury.
Recent microbiome-based interventions, such as prebiotics,
probiotics, synbiotics and engineered live biotherapeutics
(194), present an upstream
therapeutic window for combating the pathophysiological causes of
KD and deliver parallel hepatic and systemic benefits by restoring
commensal microbial populations and their protective metabolic
functions.
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.
FXR agonists are recognized as a complex option to
treat the disrupted bile acid signaling network through the
gut-liver-kidney axis (80).
Obeticholic acid (OCA), a semi-synthetic bile acid analog and
selective FXR agonist, exerts hepatoprotective and nephroprotective
effects through several integrated mechanisms (220,221). OCA-mediated activation of FXR
markedly suppresses CYP7A1 expression, the rate-limiting enzyme in
bile acid synthesis, thereby decreasing the total size of the bile
acid pool and protecting the liver from accumulation (222). Concomitantly, FXR activation
increases the expression of bile salt export pump and multidrug
resistance-associated protein 2, promoting the efficient efflux of
bile acids from hepatocytes and decreasing intracellular
lipotoxicity (223,224). In the renal compartment, FXR
activation confers direct protection to the kidney by inhibiting
inflammatory cytokines (TNF-α, IL-1β and IL-6) in tubular
epithelial cells, downregulating fibroblast activation and
decreasing collagen deposition (225). Novel FXR modulators, such as
tropifexor and nidufexor, have shown improved tissue selectivity
and, in early-phase clinical studies, more favorable side-effect
profiles than first-generation compounds, although dose-dependent
pruritus persists and renal outcome data in CKD are lacking
(226-228). Tropifexor, an extremely potent
full agonist of FXR, exhibits strong anti-fibrotic activity owing
to its selective activation in the liver and gut with minimal
off-target engagement in other tissue. Nidufexor, a tricyclic
dihydrochromenopyrazole structure with partial FXR agonism,
mediates specific modulation of the FXR-gene network that results
in significantly decreased steatosis, inflammation and fibrosis in
preclinical MASLD models (228-230). These two compounds have
proceeded to phase II clinical trials, where they are under
evaluation for MASLD and DKD, suggesting their potential as dual
therapeutic interventions against metabolic, hepatic and renal
complications (231,232). These second-generation FXR
agonists retain therapeutic activity at lower doses to minimize
bile acid synthesis suppression and dyslipidemia.
TGR5 agonists exert additional therapeutic effects
through unique mechanisms, promoting metabolic health and
anti-inflammation along the gut-liver-kidney axis. INT-777, a
selective TGR5 agonist, stimulates adenylyl cyclase and
intracellular cAMP generation in enteroendocrine cells to increase
GLP-1 and PYY secretion (233,234). This incretin response
contributes to glucose homeostasis, increases insulin sensitivity
and exerts nephroprotective effects through the activation of the
GLP-1 receptor in renal tubular cells (235,236). Immune cell activation of TGR5
induces anti-inflammatory signaling cascades via cAMP-dependent PKA
and phosphorylation of cAMP response element-binding protein,
resulting in decreased pro-inflammatory cytokine production and
increased synthesis of anti-inflammatory mediators (237). Derivatives of lithocholic acid,
especially lithocholic acid acetate and 3-keto lithocholic acids,
are endogenous TGR5 ligands with the potential for CKD treatment.
These compounds exert anti-inflammatory and metabolic effects via
TGR5 signaling in hepatic Kupffer cells and renal macrophages
(238,239). More recently, preclinical
studies have shown that selective TGR5 agonism attenuates renal
fibrosis and improves GFR and survival in experimental mouse)
models of CKD (240,241); to the best of our knowledge,
these findings have not yet been confirmed in clinical trials.
Combinations of the FXR and TGR5 modulators may
have synergistic effects, where the effect of using both drugs is
greater than the sum of their individual effects. BAR502, a dual
FXR/TGR5 agonist, controls metabolism by concomitantly activating
both signaling pathways (230,242). This combination strategy
achieves bile acid homeostasis and generates more effective
anti-inflammatory and metabolic benefits in the gut-liver-kidney
axis. Clinical development programs for dual modulators may be
promising strategies for the complex pathophysiology of
CKD-associated metabolic dysregulation through the restoration of
whole-body bile acid-triggered signaling (80).
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.
The evolution of nephrology toward a system-based
paradigm represents a fundamental transformation in the
conceptualization, diagnosis and treatment of CKD. Fig. 6 illustrates the integrated
framework for future gut-liver-kidney axis research and clinical
translation, encompassing systems biology approaches, personalized
medicine strategies and novel clinical trial designs that
collectively advance precision nephrology.
Nephrology may approach toward systems medicine
beyond the current multi-omics integration efforts. Such advances
could feature the availability of organ-specific biosensors that
allow real-time monitoring of gut-liver-kidney axis activity.
However, current biosensor technology has limitations in
operational accuracy, biocompatibility and long-term stability.
Additionally, new systems of disease classification, in which the
molecular associations in the network space replace organ regions
(or traditional pathology), may be developed over time, which will
require validation prior to community acceptance.
The future of precision nephrology may involve the
creation of a full individual 'axis fingerprint' that includes
genomic, epigenomic, microbiome, metabolomic and environment
exposure information, which can be used to develop personalized
treatment algorithms. In this regard, machine learning-based
clinical decision support systems have already been developed.
Continuous wearable monitoring systems may be integrated into
future clinical practice; however, currently available wearables
have low accuracy for most clinically relevant biomarkers and
potential issues with patient use and data interpretation.
The changing face of trial design may increasingly
incorporate adaptive, platform-oriented designs that may assess
several interventions over the gut-liver-kidney axis once patient
heterogeneity is considered. Table
IV compares traditional nephrology trial designs with emerging
gut-liver-kidney axis approaches, highlighting key differences in
the study focus, endpoints, temporal framework, trial design,
sample size consideration, statistical methods, inclusion criteria,
intervention strategies, biomarker strategies and regulatory
pathways. Future trials should include master protocols that allow
integration of combination therapies, however, these designs are
complex (requiring statistical and regulatory expertise). Further
development of endpoints may also be directed toward composite
endpoints incorporating patient-reported outcomes, biomarker
changes and functional testing, following an extensive research
process and validation, as well as answerability from regulators.
The continuous progress in regulatory science may permit the
acceptance of surrogate endpoints using validated molecular
signatures, however, this may require extensive evidence generation
and might take years.
The future landscapes of translation in gut-liver
kidney axis therapeutics may be influenced by the need to overcome
fundamental hurdles that include cross-species translational gaps
as well as regulatory complexity for multi-organ intervention and
growth realistic preclinical models that more closely mimic human
physiology (310,311). In this regard, the
establishment of international research consortia may facilitate
access to resources and standardized methodologies. Regulatory
guidelines need to be revised to meet and support multi-organ
therapeutics that are different from traditional approval pathways.
Value-for-money assessments in relation to comprehensive
axis-targeted strategies are key for health economics research; to
the best of our knowledge, however, evidence of the effectiveness
and economic efficiency of these interventions is lacking.
The 2024 KDIGO Clinical Practice Guideline for CKD
represents a notable advance, incorporating SGLT2 inhibitors,
finerenone and GLP-1 receptor agonists and emphasizing a
comprehensive approach to slowing progression (12). Notably, several of these endorsed
agents, particularly GLP-1 receptor agonists, whose enteroendocrine
origin places them within the axis, intersect mechanistically with
gut-liver-kidney signaling, even though the guideline does not
frame them in these terms. The axis framework suggests directions
for future guideline refinement: First, incorporation of validated
gut-derived metabolite biomarkers (TMAO, p-cresyl sulfate, indoxyl
sulfate) into CKD risk stratification, complementing eGFR and
albuminuria; second, explicit recognition of MASLD as a modifiable
comorbidity in CKD risk assessment, given the 38% increased CKD
risk in MASLD populations and the axis coupling in DKD; third,
structured dietary fiber and microbiome-directed nutritional
recommendations, building on the existing nutritional framework;
and fourth, adoption of composite endpoints integrating microbiome
signatures and metabolite panels in future axis-targeted trials, to
generate the high-level evidence that current guidelines
require.
The present review repositions CKD from an isolated
renal disorder to a manifestation of gut-liver-kidney axis
dysfunction. The present study defines the gut-liver-kidney axis in
CKD through a systems biology framework. By integrating anatomical
foundations (portal circulation, hepatic lymphatics, renal
innervation), molecular mediators (gut-derived hormones,
hepatokines, renal-derived factors) and quantitative methodologies
(WGCNA-based module identification, Bayesian causal inference and
ODE-based dynamic modeling), the axis is positioned as a tractable,
analyzable systems-level entity. This framework reconciles the
clinical comorbidity of CKD, MASLD and intestinal dysbiosis under a
unified mechanistic architecture, and is most explanatory in
metabolically driven CKD, such as DKD. Second, the present review
integrates multiple pathological pathways into a single
self-perpetuating cycle. Intestinal barrier failure, bile
acid-FXR-TGR5 receptor dysregulation, protein-bound uremic toxin
and TMAO signaling, PPAR/AMPK-mediated lipid metabolic dysfunction
and TLR-complement-cytokine immune hyperactivation are not parallel
processes but interlocking nodes of a positive-feedback network.
Each module amplifies the others across organ boundaries (gut
dysbiosis fueling hepatic lipotoxicity, hepatic lipotoxicity
precipitating renal injury and renal failure feeding back to
reshape gut microbiota and bile acid composition) creating the
pathological inertia that characterizes CKD progression. Third, the
present review summarizes precision therapy and novel trial designs
along a preclinical/Phase I/II/Phase III spectrum, explicitly
acknowledging clinical translation bottlenecks (FXR
agonist-associated pruritus and dyslipidemia, FMT donor variability
and durability and nanotechnology scalability) and propose concrete
directions for incorporating gut-derived biomarkers and composite
endpoints into future KDIGO guideline refinement and adaptive trial
designs. Translating this framework into practice requires rigorous
validation, multi-center axis-targeted trials and regulatory
pathways capable of evaluating combination interventions.
Evidence-based standard therapies remain foundational; the
gut-liver-kidney axis framework supplements rather than displaces
current practice, while offering a route to address the upstream
pathology that organ-centric strategies cannot reach.
Not applicable.
JYH, YXW, LP, ZW and YTL conceived the study. JYH,
YTL and SJL performed the literature review, constructed the
figures and wrote the manuscript. QQL, WJL and HJZ wrote the
manuscript. YXW, LP and ZW revised the manuscript critically for
important intellectual content. All authors have read and approved
the final manuscript. Data authentication is not applicable.
Not applicable.
Not applicable.
The authors declare that they have no competing
interests.
Not applicable.
The present study was supported by National Natural Science
Foundation of China (grant nos. 82574992 and 82274460), the Key
Discipline Construction Project of the National Administration of
Traditional Chinese Medicine (Nephrology of Traditional Chinese
Medicine, Beijing University of Chinese Medicine; grant no.
zyyzdxk-2023260) and the Chinese Medicine Inheritance and
Innovation Talent Project-Leading Talent Support Program of
National Traditional Chinese Medicine (grant no. 2018, No. 12).
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