Unveiling the gut-kidney dialogue in diabetic kidney disease

Abstract

Emerging evidence suggests that intestinal dysbiosis and chronic low-grade inflammation play a critical role in the development and progression of diabetic kidney disease (DKD), particularly in the elderly. Reduced microbial diversity, loss of beneficial genera and over-representation of pathogenic bacteria are closely associated with declining kidney function. There is a possible causal relationship between specific gut microbiota profiles and DKD. Experimental models also show that gut-derived metabolites and altered intestinal permeability can promote renal inflammation, fibrosis and metabolic dysfunction. This editorial discusses the implications of these findings for future research and clinical practice, emphasizing the growing potential of microbiota-targeted therapies. Understanding the gut–kidney axis could ultimately open up new avenues for precision nephrology and metabolic care.

Key Words: Diabetic nephropathy; Gut microbiota; Microbiome; Chronic kidney disease; Inflammation; Diabetes mellitus; Aging; Albuminuria

Core Tip: Diabetic kidney disease (DKD) is increasingly recognized as a systemic condition influenced by gut microbiota and chronic low-grade inflammation. Integrating microbiome science into nephrology offers new perspectives on disease mechanisms and therapeutic strategies. This editorial highlights recent evidence supporting the gut–kidney axis as a key player in DKD progression and calls for a multidisciplinary, patient-centered approach to treatment.

INTRODUCTION

The concept of the gut–kidney axis has emerged in recent years as a compelling framework for understanding the systemic nature of diabetic kidney disease (DKD). Traditionally, DKD has been viewed as an isolated complication of diabetes, but it is increasingly understood as a disease influenced by a complex interplay between the gut, immune system, and kidneys. The growing intersection between nephrology and microbiome science has added a new dimension to our understanding of DKD. The study entitled "Gut dysbiosis, low-grade inflammation, and renal impairment severity in elderly diabetic nephropathy" provides a timely and thoughtful contribution to this evolving discussion[1]. By examining gut microbiome composition and the inflammatory milieu in older adults with DKD, the authors have drawn much-needed attention to the systemic nature of this complex disease, which extends well beyond glycemic control and traditional renal markers.

DKD rarely occurs in isolation and is a consequence not only of hyperglycemia and hemodynamic stress, but also of chronic low-grade inflammation, immune system dysregulation, and, more recently recognized, an imbalanced gut microbiome.

What makes this study particularly interesting is its integrative approach: It links microbial diversity measurements (Chao, Ace, Shannon, and Simpson indices) with kidney function parameters and inflammatory markers and tracks their development over time. Its most prominent strength lies in its longitudinal design, which allows for the observation of dynamic changes in gut microbiota and their relationship with disease progression. While the work does not introduce a fundamentally new theoretical framework, as many of the implicated microbial taxa and inflammatory mechanisms have been reported, its originality resides in applying these concepts to a well-characterized cohort of older individuals in China, a population for whom evidence was previously limited.

By translating the abstract notion of the “gut-kidney axis” into specific measurable microbial and inflammatory indicators, the authors provide robust clinically relevant data that strengthen the translational bridge between microbiome science and nephrology. Their findings demonstrate that a marked decrease in microbial diversity and in beneficial genera such as Bacteroides, Bifidobacterium and Akkermansia, together with the simultaneous overrepresentation of potential pathobionts, including Klebsiella, Enterococcus and Veillonella, representing a distressed microbial ecosystem significantly associated with advanced kidney damage. Importantly, these microbial shifts were cross-sectionally correlated with renal dysfunction, but were tracked with disease progression during follow-up, suggesting both prognostic and mechanistic relevance[1].

The study also reinforces the concept of “inflammaging”, the chronic low-grade inflammation that accompanies aging and contributes to degenerative diseases, including DKD. The authors rightly emphasize that gut dysbiosis may be a driving force for inflammaging through increased gut permeability, endotoxemia, and immune activation. In this way, the study adds dynamic clinical evidence to the evolving theory of the gut-kidney axis, offering a clearer rationale for exploring microbiota-targeted interventions as a potential means of delaying DKD progression.

This work invites us to rethink the therapeutic landscape[1]. Could modulation of the gut microbiota through diet, probiotics, or even targeted microbiome therapies become a future pillar of DKD prevention? Even though such interventions are still experimental, this study lends strong biological plausibility to their logic. It also emphasizes the value of early assessment of the microbiome in patients with diabetes, especially older patients, as their immune systems are particularly susceptible to chronic inflammation.

Nevertheless, as the authors themselves admit, many questions remain unanswered. Although causality cannot be definitively established from observational data, and the confounding effects of medications, dietary habits, and comorbidities must be acknowledged, the translational relevance of this work remains noteworthy. However, translating microbial signatures into actionable biomarkers or treatments requires reproducibility in different populations.

To better treat DKD, we need to bring together microbiology, immunology and nephrology in a patient-centered framework. This study joins a growing body of literature that redefines DKD as not merely a kidney disorder, but as a systemic disease with microbial fingerprints and immune-mediated echoes[1].

Looking to the future of DKD treatment, the inclusion of microbiome science may not only be innovative but essential.

CURRENT PERSPECTIVES

Several studies have identified an important role of the gut–kidney axis in the development of DKD. A meta-analysis of 16 case-control or cross-sectional studies (578 DKD patients, 444 controls) confirmed that individuals with DKD exhibit lower microbial diversity, with depletion of beneficial taxa such as the family Lachnospiraceae and genera Roseburia, Prevotella, and Bifidobacterium, and enrichment in potential pathobionts, including Enterococcus, Escherichia, Citrobacter, Klebsiella, Akkermansia, Sutterella, and Acinetobacter[2]. A second meta-analysis of 15 studies and 1640 participants further showed that compared to those with diabetes alone or non- DKD patients, DKD patients have a distinct microbial profile characterized by enrichment of proinflammatory genera (e.g. Actinobacter, Hungatella, Bilophila, and Escherichia) and depletion of short-chain fatty acid (SCFA)-producing genera (e.g. Faecalibacterium, Butyricicoccus), with some taxa, such as the Ruminococcus torques group, negatively correlating with estimated glomerular filtration rate (eGFR)[3]. More recently, a 2024 study comparing DKD patients with and without end-stage renal disease (ESRD) to healthy controls confirmed that alpha diversity is reduced in DKD, especially in the presence of ESRD. Furthermore, the authors showed a depletion of anti-inflammatory genera (e.g., Faecalibacterium, Lachnospira, Roseburia and Lachnoclostridium) and an abundance of pro-inflammatory taxa (e.g., Collinsella and Streptococcus), with consistent correlations to declining renal function[4]. Together, these findings reinforce that DKD is marked by a reproducible pattern of gut dysbiosis: Reduced microbial diversity, loss of SCFA-producing commensals, and expansion of pro-inflammatory taxa, all of which may be linked to disease severity and progression. Notably, depletion of the Lachnospiraceae family, a key group of SCFA producers, was consistently reported[2-4], underscoring its potential role as a common microbial signature of DKD severity and progression.

Among the most studied aspects of this axis are microbially produced metabolites that accumulate as kidney function declines. Compounds such as indoxyl sulfate (IS) and trimethylamine N-oxide (TMAO) have nephrotoxic effects by promoting oxidative stress, impairing endothelial function and promoting fibrotic remodeling. These uremic toxins are produced by intestinal bacteria from dietary precursors and tend to accumulate in chronic kidney disease (CKD) due to reduced renal clearance[5]. Mechanistically, IS originates from dietary tryptophan, which gut bacteria convert into indole, primarily via bacterial tryptophanase activity. Indole is then absorbed and metabolized in the liver into indoxyl and subsequently sulfated to IS by host enzymes such as cytochrome P450 and sulfotransferases. IS can activate NADPH oxidase (NOX 4) and NF-κB signaling, increase oxidative stress and stimulate fibrotic signaling pathways via TGF-β1/Smad signaling. It also downregulates the Nrf2 antioxidant response and induces apoptosis in podocytes and tubule cells, contributing to glomerulosclerosis and tubule atrophy[6].

Meanwhile, TMAO is formed through a metaorganismal pathway: Dietary precursors, such as choline, L-carnitine, and phosphatidylcholine, are transformed by gut bacteria into trimethylamine (TMA), which is then oxidized in the liver by flavin-containing monooxygenases (e.g., FMO3) into TMAO. This metabolite exacerbates renal inflammation and fibrosis in diabetic animal models. Blocking TMA production lowers TMAO concentration and improves renal damage, while observational studies in humans show a negative correlation between eGFR and TMAO concentration. Elevated TMAO concentrations predict faster renal dysfunction progression, suggesting a bidirectional relationship in which renal damage and microbial metabolite accumulation are mutually reinforced[7,8].

Beyond IS and TMAO, other gut-derived pathways have been increasingly recognized. One is bacterial endotoxin (lipopolysaccharide, LPS) translocation due to impaired intestinal barrier function in dysbiosis. Elevated circulating LPS levels can trigger low-grade inflammation through Toll-like receptor 4 activation, promoting cytokine release (IL-6, TNF-α) and accelerating renal injury. This mechanism links gut dysbiosis with inflammaging in older adults. Another key mechanism involves SCFAs produced by bacterial fermentation of dietary fiber, such as acetate, proprionate and butyrate. SCFAs exert protective effects by maintaining epithelial tight function integrity, reducing gut permeability, modulating T regulatory cell differentiation, and exerting anti-inflammatory and antifibrotic effects within the kidney. A decreased abundance of SCFA-producing genera (e.g. Faecalibacterium, Roseburia, Lachnospira) in DKD patients has been associated with inflammation and decreased renal function. Together, these mechanisms form a multifaceted framework through which gut dysbiosis may contribute to DKD progression.

The use of prebiotics, probiotics or synbiotics to restore intestinal eubiosis is becoming increasingly common. A meta-analysis of 13 randomized controlled trials in CKD patients showed that these interventions significantly lowered C-reactive protein (CRP), malondialdehyde, LDL cholesterol and urea nitrogen, while increasing antioxidant status and high-density lipoprotein levels[9]. A systematic review and meta-analysis of ten clinical trials involving 552 patients with DKD found that probiotic supplementation significantly improved renal function markers such as serum creatinine, blood urea nitrogen, cystatin C, urinary albumin to creatinine ratio and serum sodium levels compared to control groups. Glycemic control and anti-inflammatory and antioxidant effects were also improved[10]. Supplementation was primarily based on Lactobacillus and Bifidobacterium species, either alone or in multi-strain combinations, and in some cases, include Streptococcus thermophilus or Saccharomyces boulardii[10].

Dietary modulation could also help to improve the balance of the gut microbiota. A high-fiber diet rich in prebiotics promotes SCFA production, which helps maintain intestinal barrier integrity and modulates systemic immunity[11]. A systematic review of dietary interventions found that a plant-based diet positively influences gut microbiota composition and systemic metabolic profiles in different populations. However, contradictory microbial responses have been reported for specific taxa[12]. For instance, while several studies showed that plant-based diets decrease the abundance of Enterobacteriaceae, a family often linked to inflammation, other studies observed an increase, possibly to differences in fiber type, protein content, or baseline microbial ecology. Similarly, Faecalibacterium, a key SCFA producer with anti-inflammatory properties, was enriched in some plant-based interventions but depleted in others, indicating that host factors and dietary context may modulate its response. Despite these inconsistencies, the overall trend suggests that plant-based dietary strategies may modulate inflammation and microbiome structure in ways that may be relevant to kidney disease pathophysiology. However, specific studies in kidney disease populations are still needed to clarify their therapeutic potential[12].

In a meta-analysis, Wathanavasin et al[13] analyzed 21 studies with 700 participants with CKD at different stages. They showed that dietary fiber supplementation (6-50 g/day for 4 weeks) significantly reduced circulating levels of uremic toxins such as p-cresyl sulphate, IS and blood urea nitrogen, as well as inflammatory markers such as interleukin-6 and TNF-α. These improvements were observed regardless of fiber type or CKD stage, even in patients on dialysis. However, there were no significant changes in serum TMAO, uric acid or CRP. The results suggest a shift in dietary strategies towards increased fiber intake that goes beyond traditional nutrient restriction, even in patients with kidney disease.

Finally, fecal microbiota transplantation (FMT) has proven to be a novel approach to restore microbial balance and mitigate systemic inflammation in chronic diseases. By directly restoring the gut microbial ecosystem, FMT offers a potential means of interrupting the deleterious cycles of dysbiosis, toxin production and immune activation that drive DKD progression[14]. In rodent models of diabetic nephropathy, FMT has been shown to increase the diversity of the gut microbiome, as demonstrated by a ~40 point increase in the Shannon index, and to promote the growth of SCFA-producing genera such as Bifidobacterium and Faecalibacterium. These microbial changes correspond with improved kidney function, including an approximately 25% reduction in serum creatinine and an 18% reduction in blood urea nitrogen levels[14,15].

A recent randomized, double-blind, placebo-controlled clinical trial investigated the effects of FMT on CKD progression in patients with diabetes and/or hypertension. After 6 months of follow-up, the 28 patients who received FMT experienced significantly less disease progression (13.3%) compared to the placebo group (53.8%). In addition, analysis of the gut microbiota showed a reduction in Firmicutes and Actinobacteria and an increase in Bacteroidetes, Proteobacteria and Roseburia species in FMT patients. These results suggest that FMT may be an important resource in DKD. Reported adverse effects were limited to mild or moderate gastrointestinal symptoms[16].

GUT MICROBIOTA MODULATION BY ANTIDIABETIC AGENTS

Antidiabetic pharmacotherapy has not only become a cornerstone in the treatment of type 2 diabetes mellitus (T2DM), but also a modulator of gut microbial ecology. There is increasing evidence that several classes of antidiabetic drugs have significant and potentially clinically relevant effects on gut microbiota composition and function. These drug-microbiome interactions may play an important role in both therapeutic efficacy and the occurrence of adverse events in people with T2DM.

Metformin, the most prescribed first-line oral hypoglycemic agent, has been extensively studied in this context. Numerous clinical and preclinical studies have shown that metformin administration enriches the number of beneficial microbial taxa, particularly Akkermansia muciniphila, a mucus-degrading bacterium associated with improved metabolic health. In addition, metformin promotes the proliferation of SCFA-producing bacterial groups, including the Butyrivibrio, Blautia and Faecalibacterium genera. These microbial shifts are often accompanied by increased microbial alpha diversity and improved gut barrier integrity. Through enhanced SCFA production, metformin may contribute to the reduction of systemic inflammation and renal fibrosis, providing an additional mechanistic link between microbiome modulation and improved renal outcomes. Such changes in the gut microbiota are associated with increased SCFA production, which are known to modulate host energy metabolism, improve insulin sensitivity, regulate appetite, and enhance gut barrier integrity, as well as altered bile acid profiles[17]. Taken together, these results support the hypothesis that part of the glucose-lowering effect of metformin is indirect, through its effects on the gut microbiome[18,19].

Other oral antidiabetic agents appear to affect the gut microbiota, although the evidence is less consistent and more limited in scope. For example, α-glucosidase inhibitors such as acarbose can increase the abundance of Bifidobacterium and Lactobacillus, genera commonly associated with metabolic health and gut homeostasis. Dipeptidyl peptidase-4 inhibitors and sodium-glucose co-transporter-2 (SGLT2) inhibitors have also been reported to induce changes in microbial composition, although the results of different studies vary widely and are often based on small samples or animal models. Glucagon-like peptide-1 (GLP-1) receptor agonists may also modulate gut microbial communities, but the direction and magnitude of these effects and their clinical relevance remain to be fully elucidated[20,21]. Preliminary studies indicate that GLP-1 agonists can modulate gut microbiota by promoting diversity and increasing Bacteroidetes levels, potentially contributing to their anti-inflammatory effects[22].

These results emphasize the possibility of a bidirectional relationship between antidiabetic agents and the gut microbiome. That is, while pharmacological agents modulate the composition and function of the microbiota, inter-individual variations in baseline microbiota profiles may in turn influence pharmacodynamics, therapeutic outcomes and drug tolerability. These findings pave the way for a more personalized approach to diabetes treatment, in which microbiome characteristics can serve as predictive biomarkers for drug response.

These interactions not only improve our mechanistic understanding of drug action, but also raise important considerations for optimizing therapeutic strategies. Nevertheless, further well-designed human studies are needed to clarify the clinical impact of microbiota modulation by antidiabetic drugs and to investigate the feasibility of microbiome-based personalized therapy in T2DM[23,24].

Glycemic control is particularly important in DKD, where strict management of blood glucose may delay renal damage onset and progression. Large trials such as UKDPS and ADVANCE have demonstrated that improved glucose control reduces the risk of microvascular complications, including DKD. Thus, although most mechanistic studies of drug-microbiota interactions are derived from populations of patients with T2DM, these findings are directly relevant to DKD, given that the same hypoglycemic agents form the backbone of therapy in both conditions.

FUTURE DIRECTIONS

To advance therapeutic strategies in DKD, a deeper integration of microbiome research into clinical practice is essential. Well-designed, placebo-controlled studies are needed to validate the efficacy of microbiota-targeted therapies, including FMT, engineered probiotics and individualized nutritional interventions. Emerging evidence suggests that beneficial strains such as Akkermansia muciniphila and Faecalibacterium prausnitzii may play a protective role by attenuating renal inflammation and fibrosis[25,26]. Notably, ongoing studies are investigating the potential of encapsulated FMT to reduce albuminuria in diabetic patients with early-stage kidney disease.

At the same time, the identification of predictive microbial biomarkers could improve early diagnosis and risk stratification. Altered microbial signatures in the gut, such as decreased abundance of Bacteroides and increased abundance of Enterococcus, are associated with DKD progression and inflammation. Circulating levels of gut-derived metabolites such as IS and TMAO are also under investigation as non-invasive biomarkers to monitor disease progression and therapeutic response[27].

However, several limitations and challenges still hinder translation. Variability in microbiome profiling methods, sequencing pipelines, and analytical strategies makes it difficult to compare results across studies and populations. Most existing work remains observational, limiting causal inference, while interventional trials are few and often underpowered. Diet, medications, and comorbidities can confound interpretation. Furthermore, microbial signatures remain population-dependent: Taxa associated with DKD in Asian cohorts are not always reproduced in European or American populations, limiting generalizability.

Controversies in current practice also deserve attention. Probiotics and synbiotics have shown promising results in meta-analyses, but trial heterogeneity, small sample sizes and variable formulations prevent consensus on their clinical utility. Similarly, dietary strategies with plant-based or high-fiber diets are widely recommended, but contradictory microbial responses (e.g., Faecalibacterium, Enterobacteriaceae) raise questions about which approach are most beneficial in DKD patients. Another open question is whether microbial biomarkers such as IS or TMAO should be incorporated into risk stratification models; while they correlate with renal outcomes, their added predictive value over standard markers remains debated.

Looking forward, several strategies may help overcome these barriers. First, harmonization of microbiome methodologies and standardization of sequencing and analysis pipelines are critical to reduce heterogeneity and improve reproducibility. Second, longitudinal and interventional studies with hard renal endpoints, such as sustained eGFR decline, dialysis initiation, or mortality, are necessary to establish clinical relevance. Third, integration of multiomics (including metagenomic, metabolomic, proteomics, host genetics, immune profiling) and clinical datasets could disentangle causality from correlation and enable microbiota-informed therapies tailored to individual host–microbe interactions[28].

Therapeutic prospects are equally promising. Beyond traditional probiotics and prebiotics, next-generation microbiota-targeted therapies are emerging. Engineered probiotics and prebiotics or synbiotics designed to restore SCFA production, postbiotics that deliver microbial metabolites with anti-inflammatory effects, and dietary precision strategies tailored to individual microbiota profiles could all play a role in DKD management. Encapsulated FMT and microbiome-derived small molecules are under early investigation as scalable, patient-friendly approaches. Importantly, interactions between the microbiota and antidiabetic pharmacotherapy (e.g. metformin, GLP-1 receptor agonists, SGLT2 inhibitors) suggest that microbiota-informed drug selection or combination therapy may enhance treatment efficacy.

Artificial intelligence and machine learning are already being used to cluster microbiome profiles and predict therapeutic responses in DKD patients[29]. In the future, these tools may support the development of personalized, microbiota informed-care strategies that integrate host-microbe interactions into clinical decision-making. Finally, many questions remain about how gut-derived metabolites interact with renal immunity and fibrosis pathways. Further mechanistic studies are needed to better understand these pathophysiological mechanisms and implement targeted therapies to achieve better outcomes. Understanding the molecular mediators of this interplay may reveal new targets for intervention and ultimately shift the treatment of DKD towards a systemic, precision-guided model[30].

CONCLUSION

To advance the treatment of DKD, microbiology, immunology and nephrology must be integrated into a truly patient-centered framework. This view is consistent with a growing body of research that urges us to consider DKD not just as a kidney disease, but as a systemic disease characterized by microbial signatures and immune-mediated processes. Nevertheless, the translation of microbiome science into routine clinical practice remains a challenge. Variability in microbiota profiles, together with differences in diet, medication and comorbidities, contribute to inconsistent responses in different populations. Moreover, robust, large-scale studies with hard renal endpoints, such as sustained eGFR decline or dialysis initiation, are still lacking. In addition, the complex feedback loop between renal dysfunction and microbial metabolite accumulation complicates causality assessment. Looking to the future, interdisciplinary collaboration will be essential to translate these findings into meaningful clinical benefit.