DKD is associated with a distinct gut microbial profile, notably a decreased abundance of butyrate-producing bacteria, which leads to reduced synthesis of beneficial SCFAs (4–6). Simultaneously, the accumulation of uremic toxins, such as indoxyl sulfate, exacerbates renal injury (2, 7, 8). These changes drive systemic activation of the renin–angiotensin system (RAS) and foster renal fibrosis (2, 7, 9).

SCFA deficiency impairs their anti-inflammatory effects and the inhibition of histone deacetylases (HDACs) (4, 6, 10). Meanwhile, accumulation of microbial toxins acts synergistically with hyperactivation of the TLR4/NF-κB pathway (9, 11), leading to chronic systemic inflammation and oxidative stress that accelerate renal damage.

Dysbiosis impairs the integrity of intestinal epithelial tight junctions—such as zonula occludens-1 (ZO-1)—facilitating translocation of endotoxins into the bloodstream (8, 12). This establishes a deleterious “leaky gut–renal injury” cycle, which is further aggravated in DKD by hyperglycemia-induced depletion of the intestinal mucous layer, setting DKD apart from non-diabetic kidney diseases (NDKD) (5, 12, 13).

Compared with NDKD, the gut–kidney axis in DKD exhibits unique metabolic features: chronic hyperglycemia selectively suppresses butyrate metabolic pathways (6, 14), and the synergy between advanced glycation end products (AGEs)-RAGE signaling and gut-derived toxins accelerates the development of renal fibrosis (2, 7). In this review, we systematically explore the mechanisms whereby the interplay of metabolism, immunity, and barrier dysfunction propels DKD progression to ESRD. Additionally, we critically appraise the translational potential of microbiota-targeted interventions, such as dietary fiber supplementation to enhance SCFAs–GPR43 signaling, and probiotic modulation of Akkermansia to promote barrier restoration.

MR has become a crucial approach for establishing causality in the relationship between GM and DN. While accumulating evidence from MR analyses suggests the existence of causal links at the genetic level, several key areas remain contentious, particularly concerning the directionality of effects and the clarification of underlying molecular mechanisms.

Comparative analysis between DN and NDKD reveals disease-specific patterns of GM dysbiosis, which are critical for understanding pathogenesis and guiding personalized treatment strategies. Current evidence indicates that DN and NDKD display distinct alterations in both metabolic and pathogenic microbial taxa, resulting in different responses to microbial interventions.

Despite significant advances in understanding the gut microbiota - diabetic nephropathy relationship, several critical controversies and knowledge gaps persist. First, while MR studies provide genetic evidence of causality, experimental validation using animal models remains essential. Integrated studies have demonstrated associations between clinical GM profiles and DN, yet in vivo models are necessary to elucidate causal mechanisms (33). Although FMT represents a promising therapeutic approach, standardized protocols for DN are lacking, necessitating additional animal studies to validate causal relationships through approaches such as transplanting DN-associated microbiota into healthy recipients (17, 35).

The translation of microbiota-targeted therapies to clinical practice faces significant challenges. Clinical trials of probiotics and prebiotics have yielded inconsistent results, likely reflecting inter-individual microbiota variability and disease heterogeneity. While short-chain fatty acid (SCFA) supplementation demonstrates benefits in DN animal models (34), FMT outcomes in human studies remain variable due to substantial individual microbiome diversity (35). Recent investigations have proposed personalized probiotic formulations based on microbiome profiling; however, population variability and the need for standardized interventions continue to impede clinical translation (35, 36).

Furthermore, emerging evidence suggests that DN and NDKD involve distinct dysbiosis-driven immunological mechanisms. DN-associated gut dysbiosis appears to influence host immunity through metabolic-immune crosstalk, whereas NDKD may be more directly linked to immune dysregulation, particularly Th17/Treg cell axis imbalances (1). Although experimental studies demonstrate that microbiota modulation can restore Treg/Th17 balance in inflammatory conditions, these models lack kidney disease specificity. Consequently, comparative mechanistic studies examining these immunological pathways and their roles in renal fibrosis across DN and NDKD represent critical research priorities requiring further investigation.

Gut-derived microbial metabolites, particularly the reduction of SCFAs and the accumulation of uremic toxins, play critical roles in the development and progression of DN. Their pathogenic mechanisms involve oxidative stress, inflammatory responses, and fibrosis, in part through modulation of key renal signaling pathways (44, 51).

GM dysbiosis triggers a cascade of immune-inflammatory responses through both innate and adaptive mechanisms, with the NLRP3–IL-1β axis serving as a central regulatory hub. Dysbiosis increases host exposure to endotoxins such as LPS and uremic toxins, which enter systemic circulation and function as pathogen-associated or damage-associated molecular patterns (42, 67–69). These molecules initiate innate immune activation through a two-signal process: LPS activates the TLR4/NF-κB pathway (Signal 1), inducing transcription of NLRP3 and pro-IL-1β, while uremic toxins trigger potassium efflux and mitochondrial ROS production (Signal 2), promoting NLRP3 oligomerization and caspase-1 activation (69–71).

This activation specifically promotes assembly of the NLRP3–ASC–pro-caspase-1 complex via the P2X7 receptor, leading to caspase-1-dependent maturation of IL-1β and IL-18 (68, 69). Activated caspase-1 cleaves gasdermin D, forming membrane pores that induce pyroptosis in glomerular endothelial cells—a form of inflammatory cell death characterized by cellular swelling, lysis, and massive cytokine release, resulting in direct renal tissue injury (42, 72, 73). The ensuing inflammatory milieu recruits neutrophils into the renal parenchyma, amplifying oxidative stress and contributing to podocyte injury (42, 67, 74).

Concurrently, altered GM disrupts adaptive immune homeostasis. Reduced beneficial metabolites, particularly SCFAs, skews T cell differentiation toward excessive Th17 activation while impairing regulatory T cell (Treg) function (74, 75). Hyperactivated Th17 cells release elevated IL-17A, which acts on kidney-resident cells to induce neutrophil chemoattractants (CXCL1, CXCL2) (73, 74). Infiltrating neutrophils release proteases and ROS that degrade podocyte cytoskeleton proteins and disrupt the slit diaphragm, culminating in proteinuria (73, 74). Critically, IL-17A upregulates NLRP3 expression in glomerular cells, establishing an IL-17A–NLRP3–IL-1β positive feedback loop that perpetuates renal inflammation (73–75).

The NLRP3–IL-1β axis thus bridges innate and adaptive immunity in DN pathogenesis. Therapeutically, targeting the NLRP3/caspase-1 pathway significantly reduces cytokine release and ameliorates glomerulosclerosis and proteinuria, emerging as a core target for mitigating GM-driven inflammation in DN (67, 76). The “gut–kidney axis”—encompassing primary microbiota alterations, secondary metabolite regulation, and tertiary pathological effects—is illustrated in Figure 2 .

GM dysbiosis drives DN progression through interconnected metabolic pathways involving insulin resistance and lipid dysregulation. The disruption of gut microbiota significantly reduces SCFA synthesis, particularly acetate and butyrate (35, 51). SCFAs normally engage G protein-coupled receptors (GPR41/43) on intestinal L cells to promote glucagon-like peptide-1 (GLP-1) secretion, which is crucial for glycemic control (34). GLP-1 deficiency diminishes its inhibitory effect on hepatic gluconeogenesis, increasing activity of rate-limiting enzymes like phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase), thereby exacerbating hyperglycemia (34, 77). Notably, when serum butyrate levels fall below 10 μM, renal IL-6 expression significantly increases (34).

Concurrently, gut dysbiosis facilitates LPS translocation into systemic circulation, activating TLR4 signaling pathways (78). This triggers the JNK signaling cascade in macrophages, leading to increased tumor necrosis factor-alpha (TNF-α) release. TNF-α promotes serine phosphorylation of insulin receptor substrate-1 (IRS-1), disrupting the downstream PI3K-AKT pathway and impairing glucose uptake in peripheral tissues (7, 44, 78). The resulting chronic insulin resistance induces sustained hyperinsulinemia, which causes afferent arteriolar dilation and efferent arteriolar constriction, increasing glomerular capillary pressure. These hemodynamic alterations promote proteinuria and glomerulosclerosis, accelerating renal injury progression (11).

Parallel to glucose metabolism disruption, gut dysbiosis profoundly alters lipid homeostasis through impaired bile acid metabolism. The reduced formation of secondary bile acids, particularly deoxycholic acid, impairs farnesoid X receptor (FXR) activation in the intestine (77, 79, 80). Inadequate FXR signaling upregulates hepatic sterol regulatory element-binding protein 1c (SREBP-1c), driving transcription of lipogenic enzymes including fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC). This promotes triglyceride synthesis and hepatic lipid accumulation (77, 79, 81). Under physiological conditions, intestinal FXR activation stimulates fibroblast growth factor 19 (FGF19) secretion, which inhibits hepatic CYP7A1-mediated bile acid synthesis and preserves lipid homeostasis (35, 77). In DN, suppressed FXR signaling decreases FGF19 levels, leading to insufficient SREBP-1c inhibition and systemic lipid overload (77, 79, 81).The elevated circulating free fatty acids (FFA) resulting from this metabolic disruption enhance renal lipid deposition, triggering mesangial cell lipotoxicity and mitochondrial oxidative stress. This stimulates release of inflammatory mediators including IL-6 and monocyte chemoattractant protein-1 (MCP-1), culminating in mesangial matrix expansion (19, 81). The synergistic effects of insulin resistance and lipid dysregulation accelerate renal deterioration through multiple mechanisms: insulin resistance-induced intraglomerular hypertension combines with lipotoxicity-mediated mesangial cell injury to promote glomerular basement membrane thickening and excessive extracellular matrix accumulation (11, 19). Furthermore, concomitant activation of the JNK pathway (linked to insulin resistance) and FFA-driven NLRP3 inflammasome assembly (associated with lipid dysregulation) synergistically promotes macrophage infiltration in renal tissue, hastening tubulointerstitial fibrosis (78). This integrated metabolic dysfunction underscores the critical role of the gut-kidney axis in DN pathogenesis.

Probiotics, prebiotics, and synbiotics have gained increasing attention as microbiota-targeted interventions for the management of DN. An accumulating body of clinical evidence suggests that these approaches, through modulation of the gut–kidney axis, can reshape intestinal microbial composition, reduce oxidative stress, and ultimately improve renal function parameters such as serum creatinine and blood urea nitrogen (47, 82). Probiotics, by restoring the balance of the GM, have been shown to lower the risk of renal injury. Synbiotics, which combine the complementary actions of probiotics and prebiotics, produce synergistic effects by regulating the production of key microbial metabolites, such as SCFAs and secondary bile acids, thereby mitigating systemic inflammatory responses (35, 83, 84).

Several randomized controlled trials have demonstrated that these interventions may also promote glycemic control (evidenced by reduced HbA1c levels) and improve lipid metabolism (e.g., lowering low-density lipoprotein cholesterol), underscoring the close interplay between the GM and host metabolic pathways (84, 85). Nevertheless, substantial heterogeneity and limitations persist across studies. The therapeutic efficacy of specific bacterial strains varies, potentially due to inter-individual differences in baseline gut microbial communities (47, 82). Furthermore, clinical protocols regarding optimal dosing, strain selection, and duration of interventions are not yet standardized, thereby affecting the reproducibility and robustness of clinical outcomes.

Given these challenges, future research should prioritize large-scale, multicenter randomized controlled trials to comprehensively assess the impact of targeted microbiome interventions on hard endpoints in DN and to facilitate the development of next-generation precision microbiome therapeutics (86). In summary, while microbiota-targeted interventions represent a promising avenue for DN management, further rigorous clinical validation is warranted to substantiate their efficacy.

Emerging evidence highlights the therapeutic role of high-fiber diets in delaying the progression of DN, primarily through modulation of GM-derived metabolites such as SCFAs and restoration of intestinal barrier integrity. The underlying mechanisms are summarized as follows:

Butyrate, a key short-chain fatty acid derived from gut microbial fermentation, has shown notable renoprotective effects in multiple animal models of DKD and related renal injuries (34, 99). Studies have demonstrated that butyrate supplementation can markedly alleviate glomerular hypertrophy, podocyte injury, and interstitial fibrosis, as well as improve mitochondrial function and reduce serum creatinine levels in both diabetic and acute kidney injury models (100, 101). These results suggest that targeting microbial metabolites like butyrate may offer novel strategies for preserving kidney function.

Mechanistic investigations indicate that butyrate exerts its renoprotective roles via several pathways. It effectively suppresses renal inflammation and oxidative stress by downregulating pro-inflammatory mediators, such as TNF-α, and inhibits fibrosis by modulating TGF-β signaling in renal tubular cells and podocytes through GPR43 and GPR109A receptors (34, 102). In addition, butyrate acts as a histone deacetylase inhibitor, promoting beneficial epigenetic modifications and upregulating protective genes including Klotho and PGC-1α (100, 103), thereby restoring mitochondrial homeostasis primarily via the AMPK/PGC-1α pathway (80, 104).

Furthermore, butyrate reinforces the gut–kidney axis by enhancing intestinal barrier integrity and attenuating systemic inflammation, with evidence pointing to a receptor-dependent mechanism and the need for sustained supplementation to maintain its benefits (105, 106). In an adenine-induced model of CKD, butyrate has been shown to attenuate renal fibrosis by suppressing activation of the NLRP3/STING/NF-κB signaling pathway (107, 108). Collectively, these findings highlight the therapeutic potential of butyrate in DKD, supporting further clinical studies to optimize its application in patient care.

In recent years, increasing attention has been paid to the interaction between DKD and the GM, leading to the exploration of novel targeted therapeutic strategies. These strategies, primarily based on natural compounds and traditional Chinese medicine interventions, aim to regulate gut microbial homeostasis through multi-target mechanisms. Such interventions not only help restore microbial balance but also alleviate systemic inflammation and metabolic disturbances, ultimately contributing to the delay of DKD progression (109, 110).

FMT has demonstrated significant therapeutic potential in the management of DN by facilitating the reconstruction of a healthy gut microbial ecosystem and modulating relevant metabolic and immune pathways (36, 127). The current evidence is summarized below from aspects of efficacy in animal models and the progress and challenges of clinical translation.

The ambiguity of causal relationships stands as a central bottleneck in current research on DN and GM, significantly impeding clinical translation. This ambiguity arises from several layers of complexity.

Firstly, most available evidence is derived from observational studies, which inherently lack the ability to establish definitive causal links. For example, cross-sectional designs have reported alterations in GM abundance among DN patients (such as fluctuations in specific microbial taxa) (26, 28). However, such methodologies are inherently limited in clarifying the directionality of causation or adequately accounting for confounding factors such as dietary patterns or pharmacotherapy (18). As highlighted in the literature, “despite emerging evidence supporting an association, the causal relationship between them hasn’t been clarified yet”, underscoring that correlational findings alone are insufficient to define the underlying mechanism of causality (18).

Secondly, the confounding effect of extraneous variables and the possibility of reverse causality further exacerbate this uncertainty. Factors such as metabolic status may generate spurious associations (137), while reverse causality—whereby DN may induce gut microbial dysbiosis—complicates the interpretation of the microbiota as either a pathogenic driver or a biomarker (18, 137). This is exemplified by reverse MR analyses: as reported in the literature (18), such analyses assessing the impact of DN on GM “did not identify any significant associations”, suggesting that observed correlations could be driven by reverse causality rather than direct causative effects.

Finally, while MR represents a promising tool for disentangling causality, practical limitations persist. MR leverages genetic variants (e.g., GM-related SNPs) to minimize confounding (18, 138); however, its utility is constrained by the strength and heterogeneity of the instrumental variables. For instance, forward MR analyses have identified putative causal effects of certain gut microbes (18, 124), yet reverse MR analyses often yield null results, highlighting ongoing difficulties in resolving the precise directionality of the relationship. In summary, such causal ambiguity remains a major limitation hindering the development of microbiota-targeted therapies in DN, emphasizing the need to integrate more robust MR approaches for advanced causal inference.

Despite considerable advances in DN research, the mechanistic understanding remains fragmented, particularly regarding the integration of metabolic, immune, and barrier pathways. Current studies predominantly address these axes independently, resulting in a lack of comprehensive and unified framework for DN pathogenesis.

Research on metabolic pathways exemplifies this segregation. While GM-derived metabolites such as pyrroline and glycine-conjugated bile acids have been causally linked to DN progression (139), these investigations focus primarily on the microbiota–metabolite axis without addressing interactions with immune responses or barrier integrity. Potential synergistic mechanisms remain largely unexplored (51, 139). Similarly, immunoinflammatory activation, including NLRP3 inflammasome activation and macrophage infiltration, represents a well-established driver of DN (140, 141). However, most studies assess immune factors in isolation, seldom considering how immune cell dynamics interact with intestinal or renal barrier disturbances or fluctuations in microbial metabolites (139, 142). Although gut-kidney axis activation has been shown to modulate immunity (143), comprehensive elucidation of how metabolites modulate immune signaling through TLR pathways leading to barrier dysfunction remains lacking (139, 141). The investigation of barrier integrity follows a similarly narrow approach. Impairment of tight junction proteins and resulting dysfunctions of intestinal and glomerular barriers are hallmarks of DN (144, 145). Yet current research often fails to dissect how barrier injury is co-regulated by both microbial metabolites (such as acylcarnitines) and immune-inflammatory signals (such as NF-κB activation) (146, 147). For instance, while glomerular barrier damage is associated with dysregulated endothelial S1pR1 signaling (145) and certain gut-derived metabolites can restore intestinal barrier function via the AHR receptor (148), integrated models addressing cross-talk between barriers in DN are still missing.

This fragmented approach generates significant limitations in both mechanistic understanding and therapeutic development. Single-pathway analyses, while facilitating understanding of specific molecular events—such as brown adipose tissue-derived NRG4 suppressing podocyte apoptosis through the Akt-GSK3β pathway (149) —overlook the broader impact of cross-talk among metabolic, immune, and barrier pathways (150, 151). Consequently, therapies targeting isolated pathways, such as PI3K-Akt or HIF-1 signaling, often fail to achieve optimal efficacy due to neglect of feedback and interaction between pathways (152, 153). For example, while PFKFB3 contributes to glomerular barrier protection (145), its interactions with microbial metabolic profiles, including circulating acylcarnitine levels (139), remain absent from therapeutic considerations.

In summary, the current fragmented approach constrains both mechanistic insights and identification of effective therapeutic targets. Comprehensive, multi-dimensional studies integrating metabolism, immunity, and barrier biology are urgently needed to clarify DN pathogenesis and guide the development of more effective interventions.

The clinical translation of GM-based interventions for DN faces significant hurdles, primarily arising from the disconnect between findings in animal models and human clinical realities, as well as the lack of longitudinal, stage-specific data in disease progression. These barriers substantially impede the transition from bench to bedside.

One core challenge lies in the differences between animal and human GM, which restrict the reproducibility and translatability of preclinical findings. The GM composition in common animal models—such as rodents—differs markedly from that of humans, resulting in inconsistencies in intervention efficacy. Mechanisms such as short-chain fatty acid metabolism or intestinal barrier repair, which often demonstrate efficacy in animal studies, may not be directly reproduced in clinical studies due to these interspecies differences (154, 155). This limitation raises concerns regarding the extrapolation of preclinical results to human disease contexts.

Additionally, there is a conspicuous lack of systematic, longitudinal data capturing the dynamic shifts of GM throughout the various stages of DN. Most current studies are cross-sectional in design, typically comparing diabetic patients to healthy controls, and fail to longitudinally track changes in GM across clinical stages—from microalbuminuria to established renal failure (156, 157). This gap obscures the understanding of how microbial communities evolve with disease progression and limits the identification of stage-specific therapeutic targets.

The absence of robust, disease stage-oriented microbial evolution data hinders the development of tailored intervention strategies—for example, metabolic modulation in early-stage DN versus barrier restoration in advanced stages. Consequently, the true potential of personalized, microbiota-based therapies remains largely unrealized. The clinical translation workflow is summarized in Figure 3 .

At the mechanistic level, recent studies have, for the first time, systematically linked gut dysbiosis in DN with targeted intervention strategies. Specifically, current literature has demonstrated that gut microbial imbalance exacerbates glomerulosclerosis and tubular injury through both metabolic products (e.g., uremic toxins) and immune-inflammatory pathways (e.g., activation of Toll-like receptors) (17, 44). On this basis, targeted interventions aimed at restoring the gut–kidney axis—such as probiotics and prebiotics—may modulate microbial metabolism (e.g., enhancing short-chain fatty acid synthesis) and improve renal injury biomarkers, thereby attenuating kidney damage (158, 159).

Multi-omics approaches have ushered in a new framework for dissecting the mechanisms of GM in DN. Metagenomics can reveal shifts in microbial community structure among DN patients, such as alterations in the abundance of specific genera (23, 51). However, coupling with metabolomics is required to delineate the specific nephrotoxic effects of microbial metabolites like indoxyl sulfate (79). Moreover, metatranscriptomics allows for the identification of key microbe–host interaction pathways, including the regulation of inflammatory responses via the AhR pathway (18, 160), while single-cell techniques enable detailed analysis of intestinal immune cells (e.g., Th17/Treg) and their association with renal immune infiltration (160, 161). Collectively, integrated multi-omics approaches hold promise for elucidating cross-scale regulatory networks linking microbial structure, function, and host physiology (79, 162).

Strategic interventions must be tailored to distinct DN stages. In early DN, supplementation with short-chain fatty acid-producing bacteria (such as Butyricicoccus) or their metabolic products (such as butyrate) has the potential to improve insulin resistance and alleviate glomerular hyperfiltration (158, 159). In contrast, late-stage interventions require the elimination of toxin-producing bacteria (such as Escherichia species) and blockade of toxin absorption (44). Nonetheless, major obstacles remain, including inter-individual variability in response to microbiota-based therapies due to genetic and dietary factors, as well as incomplete evidence regarding long-term safety (35, 163).

Frontier technologies offer new avenues for GM-targeted therapy. Phage therapy can specifically lyse pathogenic bacteria (such as endotoxin-producing Klebsiella), and animal models have confirmed its ability to reduce serum LPS levels and proteinuria (25). Meanwhile, engineered probiotic therapies—where symbiotic bacteria are modified to express therapeutic molecules such as antioxidant enzymes—demonstrate potential in locally mitigating renal oxidative stress (45, 159). Going forward, the development of synergistic systems (e.g., coordinated phage–engineered bacteria interventions) may enable dynamic modulation of gut microbial ecology (25).

In terms of clinical translation, future directions include stratified and personalized probiotic regimens based on enterotype (161, 162), incorporation of microbiota-derived biomarkers (such as fecal butyrate) as efficacy indicators (164), and the application of artificial intelligence models to integrate multi-omics data for predictive risk assessment of DN progression (162).