Gut microbiota dysbiosis in CKD patients intensifies in a graded manner as proteinuria worsens, characterized by declining beneficial taxa, enrichment of potentially pathogenic bacteria, and metabolic dysfunction including overactivated nitrogen metabolism and suppressed unsaturated fatty acid synthesis.
Key Findings
Results
CKD patients exhibited significantly reduced gut microbiota α-diversity compared to healthy controls, with diversity declining further as proteinuria worsened.
α-diversity was measured using Chao1 and Shannon indices via 16S rRNA gene sequencing of fecal samples.
The study enrolled 148 participants: 54 healthy controls (HC), 49 CKD patients with mild proteinuria (PROU_L), and 45 with massive proteinuria (PROU_M).
Diversity reduction was progressive across the three groups, increasing in magnitude from HC to PROU_L to PROU_M.
β-diversity also differed significantly among all three groups, indicating distinct microbiota community structures.
Results
The Faecalibacterium-dominated enterotype (considered beneficial) declined progressively with increasing proteinuria severity.
Faecalibacterium-dominated enterotype prevalence was 50.0% in healthy controls (HC).
Prevalence declined to 40.82% in mild proteinuria patients (PROU_L).
Prevalence further declined to 28.9% in massive proteinuria patients (PROU_M).
This represents a near halving of the beneficial enterotype from HC to PROU_M.
Results
The Prevotella-dominated enterotype (considered potentially pathogenic) increased progressively with worsening proteinuria.
Prevotella-dominated enterotype prevalence was 7.4% in healthy controls (HC).
Prevalence increased to 20.41% in mild proteinuria patients (PROU_L).
Prevalence further increased to 24.4% in massive proteinuria patients (PROU_M).
This represents more than a three-fold increase from HC to PROU_M.
Results
Probiotic bacterial taxa including Akkermansia and Coprococcus decreased progressively with worsening proteinuria in CKD patients.
Both Akkermansia and Coprococcus showed progressive reductions from HC to PROU_L to PROU_M.
These taxa are described as probiotics in the context of this study.
The progressive decline was identified through differential taxa analysis using 16S rRNA gene sequencing.
Loss of these beneficial taxa paralleled the enrichment of potentially pathogenic bacteria.
Results
Potentially pathogenic bacteria including Enterobacteriaceae, Haemophilus, and Ruminococcus were progressively enriched with worsening proteinuria.
These taxa are described as uremic-toxin producers in the context of the gut-kidney axis.
Enrichment was graded, increasing from HC to PROU_L to PROU_M.
Differential taxa analysis was performed using 16S rRNA gene sequencing of fecal samples.
The enrichment of these pathogenic taxa occurred concurrently with loss of beneficial taxa.
Results
KEGG-based functional analysis revealed that gut microbiota nitrogen metabolism became increasingly overactivated from healthy controls to mild and then massive proteinuria patients.
Functional potential was characterized using Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis.
Nitrogen metabolism overactivation was graded across HC, PROU_L, and PROU_M groups.
Concurrently, unsaturated fatty acid synthesis was progressively inhibited with worsening proteinuria.
Enzyme fumarate reductase activity correlated with the degree of proteinuria.
Results
Fumarate reductase enzyme levels correlated with the degree of proteinuria in CKD patients.
Fumarate reductase was identified through KEGG-based functional pathway analysis.
Correlation was observed across the three participant groups (HC, PROU_L, PROU_M).
This finding links a specific microbial enzyme to clinical severity of kidney disease as measured by proteinuria.
Fumarate reductase is implicated in nitrogen metabolism pathways.
Discussion
The study identified stage-specific microbial biomarkers that could potentially serve for precision risk stratification in CKD.
Biomarkers were identified across three disease stages: healthy controls, mild proteinuria, and massive proteinuria.
The graded dysbiosis pattern provides a framework for staging CKD by microbiota composition.
Specific taxa and metabolic pathways showed stage-specific patterns of enrichment or depletion.
Authors describe these as 'tractable microecological targets for early intervention.'
What This Means
This research suggests that the community of microorganisms living in the gut becomes increasingly imbalanced as kidney disease worsens in patients with chronic kidney disease (CKD). The study compared gut bacteria from 54 healthy people, 49 CKD patients with mild protein loss in their urine, and 45 CKD patients with heavy protein loss. Using genetic sequencing of stool samples, researchers found that the diversity and composition of gut bacteria changed in a stepwise pattern that tracked with how much protein was being lost in patients' urine — a key marker of kidney disease severity.
Specifically, beneficial bacteria like Akkermansia and Coprococcus progressively disappeared as kidney disease worsened, while potentially harmful bacteria including Enterobacteriaceae and Haemophilus became more abundant. The community shifted away from a type dominated by the beneficial bacterium Faecalibacterium (present in half of healthy people but only about a quarter of the sickest patients) toward a type dominated by Prevotella, which was three times more common in the sickest patients than in healthy controls. The gut bacteria in sicker patients also showed altered metabolic activity, with overactive nitrogen processing and reduced production of beneficial unsaturated fatty acids.
This research suggests that the gut-kidney axis — the biological communication between gut microbes and kidney function — may play a meaningful role in how kidney disease progresses. The graded nature of these microbiota changes with disease severity raises the possibility that gut bacteria composition could one day serve as a biomarker for risk stratification or as a target for interventions aimed at slowing kidney disease progression. The specific bacteria and metabolic pathways identified provide concrete targets for future research into microbiome-based treatments.
Wang P, Wang M, Shen Y, Yao Y, Yan K, Wang S, et al.. (2026). Linkage of gut microbiota dysbiosis to chronic kidney disease in patients with graded proteinuria levels.. Microbiology spectrum. https://doi.org/10.1128/spectrum.03294-25