The normal gut microbiota plays a vital role in preserving the structural and functional integrity of the intestinal mucosa. AKI triggers systemic inflammatory responses and fluid overload, which alter the permeability of the mesenteric vascular bed and contribute to intestinal edema, ultimately resulting in secondary damage to the intestinal epithelial barrier (58). Histological analyses of the small intestine following AKI have revealed apoptosis of the deep villous capillary endothelial cells, increased vascular permeability, and epithelial necrosis (59). Tang et al. reported that patients with immunoglobulin A nephropathy (IgAN) exhibit significant gut microbiota dysbiosis and elevated levels of biomarkers indicative of intestinal mucosal barrier injury, including diamine oxidase, soluble intercellular adhesion molecule 1 (sICAM-1), d-lactate, and lipopolysaccharide (LPS) (60). Similarly, in CKD, the intestinal barrier is compromised due to disruption of epithelial tight junction proteins, leading to increased permeability and translocation of bacteria and endotoxins, such as LPS, into the systemic circulation (61). Tang et al. also observed elevated levels of intestinal permeability markers, such as LPS, sICAM-1, and D-lactate, in IgAN mouse models (62). Yang et al. demonstrated that in 5/6 nephrectomized mice, gut microbiota dysbiosis was positively correlated with the severity of intestinal barrier impairment and aberrant mucosal immune responses (63). These findings suggest that disruption of the intestinal barrier may play a critical role in the pathogenesis and progression of CKD (61).

A growing body of evidence has confirmed that kidney diseases are associated with distinct alterations in metabolic profiles, with numerous metabolites being significantly linked to renal function decline (64–69). Gut microbial metabolites have been described as multiple biochemical intermediates (70). Dysbiosis of the gut microbiota can lead to abnormal accumulation of gut-derived uremic toxins such as indoxyl sulfate (IS). Clinical studies have demonstrated that elevated IS levels in patients with AKI are closely associated with poor prognosis. Under pathological conditions, these toxins compromise the intestinal mucosal barrier, exacerbating endotoxemia and systemic inflammation (71).

In CKD, metabolic disturbances impair protein digestion and absorption, contributing to microbial dysbiosis and increased production of protein-derived metabolites, such as p-cresol, indole, phenol, and trimethylamine. These compounds serve as precursors for hepatic synthesis of uremic toxins, including p-cresol sulfate (PCS), IS, phenyl sulfate (PS), and TMAO, which are strongly correlated with deteriorating renal function (72–76). Although partially excreted by the kidneys and intestines, these metabolites exert nephrotoxic effects and are classic uremic toxins. They can activate signaling pathways involved in inflammation and fibrosis, promoting renal inflammation, fibrotic progression, and functional decline (77, 78). The accumulation of uremic toxins can injure renal tubular cells, accelerate glomerulosclerosis and tubulointerstitial fibrosis, and ultimately lead to end-stage renal failure (79).

In addition to protein metabolites, bile acids synthesized from cholesterol via hepatic enzymes also play a role in kidney pathology. This process is regulated by gut microbiota such as Bacteroides, Bifidobacterium, and Lactobacillus (80, 81). Elevated bile acid levels have been identified as an independent risk factor for adverse renal outcomes in diabetic nephropathy (DN) (82). TMAO, which is derived from the microbial degradation of dietary choline and carnitine, is another key metabolite implicated in renal disease. Clinical studies have shown significantly higher TMAO levels in patients with DN than in those with diabetes alone, with a positive correlation between TMAO concentration and the urine protein-to-creatinine ratio (83, 84).

Indole-3-propionic acid, a gut-derived tryptophan metabolite, is significantly reduced in both the gut and serum of patients with IgAN, likely because of the decreased abundance of Bacteroides (85). Microbial community profiles also differ across kidney diseases. For example, patients with membranous nephropathy (MN) and IgAN exhibit higher levels of Megasphaera and Bilophila and lower levels of Megamonas, Veillonella, Klebsiella, and Streptococcus than those with MN (86). In end-stage renal disease, nearly 190 operational taxonomic units (OTUs) show altered abundance relative to that in healthy controls (87). Experimental studies have demonstrated that gut microbiota depletion via antibiotic administration reduces TMAO levels and attenuates the transition from AKI to CKD (88). Moreover, supplementation with SCFAs in IgAN mouse models decreased IgA deposition, mesangial proliferation, and proteinuria levels (89). These findings highlight the critical role of gut microbiota dysbiosis and its metabolites in the pathogenesis of kidney disease, highlighting their potential as novel diagnostic biomarkers and therapeutic targets.

Probiotics are live microorganisms that, when administered in adequate amounts, confer health benefits to the host (90). These organisms exert their effects by correcting gut microbial imbalances, producing antimicrobial compounds that inhibit pathogenic bacteria, and enhancing the integrity of the intestinal barrier (90–92). Probiotics also contribute to the restoration of the normal gut pH, suppress the overgrowth of harmful bacteria, promote the production of SCFAs, and maintain gastrointestinal homeostasis.

A clinical study investigating probiotic supplementation in patients with sepsis-induced AKI reported no significant improvement in renal function recovery; however, a downward trend in mortality was observed in the intervention group (93). In a mouse model of ischemia-reperfusion injury (IRI)-induced AKI, Yang et al. demonstrated that Bifidobacterium bifidum (BGN4) enhanced microbial evenness and inhibited the proliferation of hallmark AKI-associated taxa, such as Enterobacteriaceae and Bacteroidaceae. BGN4 administration also significantly reduced neutrophil and macrophage infiltration, and lowered renal interleukin-6 mRNA expression levels. Ikeda et al. identified two novel probiotic strains isolated from fruits and vegetables and found that their supplementation alleviated oxidative stress and AKI by increasing the abundance of Akkermansia muciniphila (94). In a study by Miao et al., the taxonomic lineage Bacilli–Lactobacillales–Lactobacillaceae–Lactobacillus–Lactobacillus johnsonii were found to be strongly associated with CKD progression, with a significant reduction in L. johnsonii abundance observed in rats with adenine-induced CKD. Supplementation with L. johnsonii mitigated renal injury (95). The relative abundance of L. johnsonii was significantly decreased with progressive CKD in rats with adenine-induced CKD. L. johnsonii supplementation attenuates renal damage (95). Ranganathan et al. demonstrated that treatment with Bacillus pasteurii and Lactobacillus sporogenes effectively slowed CKD progression in a rat model (96). Similarly, Zhou et al. found decreased levels of Bacteroides fragilis in both patients with CKD and unilateral ureteral obstruction (UUO) mice. Oral administration of activated B. fragilis mitigated renal fibrosis in UUO and adenine-induced models, possibly through mechanisms involving decreased LPS levels and increased concentrations of 1,5-anhydroglucitol (97). Moreover, probiotic therapy has shown beneficial effects in patients undergoing peritoneal dialysis (PD), improving treatment outcomes and offering a potential adjunctive approach in PD management (98). These findings suggest that probiotic supplementation is a promising therapeutic option for kidney disease as it modulates the composition and function of the gut microbiota.

Prebiotics are defined as non-viable microbial components or substrates selectively utilized by host microorganisms to confer health benefits (99). Compared to live probiotics, prebiotics offer improved stability and safety profiles, making them suitable for various clinical applications (91, 100). These compounds are typically fermentable organic substances that selectively stimulate metabolism and proliferation of beneficial gut bacteria, contributing to host health. Common prebiotics include inulin, fructooligosaccharides (FOS), galactooligosaccharides (GOS), polyphenols, and lactulose (101). While most studies on prebiotics have focused on their effects on CKD, few studies have investigated their role in AKI (101). In a clinical trial by Esgalhado et al., patients with CKD undergoing dialysis were administered resistant starch and compared with a placebo group. The intervention group showed a significant reduction in circulating inflammatory markers and uremic toxins (102). Similarly, in an animal study, CKD rats receiving a diet supplemented with lactose exhibited improved blood urea nitrogen and serum creatinine levels along with reduced tubulointerstitial fibrosis (103).

Multiple studies have demonstrated that prebiotic supplementation can exert renoprotective effects by modulating the gut microbiota composition and restoring intestinal barrier function. This, in turn, helps prevent bacterial translocation and systemic dissemination of harmful microbial metabolites. However, emerging evidence also highlights the potential risks. For instance, a study reported that approximately 40% of TLR5-knockout mice fed a diet containing inulin developed hepatocellular carcinoma, which was associated with a marked increase in Proteobacteria and Clostridium in the gut microbiota. In contrast, wild-type mice with intact gut microbiota do not develop liver tumors under the same dietary conditions (104). These findings suggest that, while prebiotic intake may improve renal function and inflammation in CKD patients with pre-existing gut dysbiosis, the potential for adverse effects, particularly under conditions of impaired microbial-host immune signaling, warrants careful evaluation and further investigation.

Synbiotics are defined as combinations of probiotics and prebiotics. Several studies have shown that synbiotic supplementation can positively modulate gut microbiota composition in patients with CKD, including an increase in Bifidobacterium and a reduction in Akkermansia muciniphila abundance (105, 106). In addition, synbiotics have been reported to reduce serum levels of p-cresol sulfate in both patients with CKD and those undergoing hemodialysis, although they do not appear to significantly affect the serum levels of indoxyl sulfate in CKD patients.

In a clinical trial involving 60 hemodialysis patients, Haghighat et al. demonstrated that synbiotic supplementation significantly reduced serum LPS levels. Moreover, levels of systemic inflammatory markers, including C-reactive protein (CRP), interleukin-6 (IL-6), and anti-heat shock protein 70, were significantly lower in the synbiotic group than in the probiotic and placebo groups (107). These findings suggest that synbiotics may help restore intestinal barrier function, inhibit the overgrowth of gram-negative bacteria, reduce LPS translocation into systemic circulation, alleviate microinflammation, and potentially slow the progression of kidney disease. However, the current evidence on the efficacy of synbiotics in renal disease is limited, and the overall quality and quantity of supporting clinical studies remain relatively low. Further well-designed randomized controlled trials are needed to confirm their therapeutic potential and to establish clinical guidelines for their use in kidney disease management.

A growing body of research has demonstrated that natural products exhibit promising clinical efficacy for the treatment of various kidney diseases (108–114). The bioactive components of these natural products can modulate the composition and abundance of the gut microbiota in a holistic manner, alleviating kidney disease progression and renal fibrosis through microbiota-targeted interventions (115–120).

Recent studies have shown that resveratrol significantly reduced serum urea and 24-h urinary protein levels in db/db mice. Additionally, it increases the abundance of beneficial gut bacteria, such as Bacteroides, Lachnospiraceae, and Faecalibacterium, which are associated with anti-inflammatory effects (121). These findings suggest that resveratrol, known for its anti-inflammatory, antioxidant, and anti-glycation properties (122), has therapeutic potential in both AKI (123) and DN treatment (124).

Curcumin, a natural polyphenol and principal renoprotective constituent of turmeric, has also shown beneficial effects (125). In a study by Shi et al., treatment with a docosahexaenoic acid-conjugated curcumin diester significantly reduced the serum levels of blood urea nitrogen, creatinine, LPS, and TMAO in an AKI model. It also decreased malondialdehyde (MDA) concentrations in renal tissues, increased glutathione levels, and altered kidney fatty acid composition, indicating that curcumin effectively suppressed inflammation, oxidative stress, and apoptosis (126). Similarly, Lyu et al. found that astragaloside IV restructured the gut microbiota of DN mice by decreasing the relative abundance of Firmicutes and increasing Bacteroidetes, Akkermansia muciniphila, Lactobacillus, Ligilactobacillus, Mucispirillum, and Sphaerochaeta. Conversely, it reduced the abundance of pro-inflammatory taxa such as Lachnospiraceae_NK4A136_group, Lachnospiraceae, and Streptococcus. These microbial changes are associated with decreased LPS levels, improved intestinal mucosal barrier integrity, and reduced renal inflammation (127). In addition, other natural compounds, such as fucoidan (128), peony bark polysaccharide (129), and total alkaloids from mulberry branches (130) have been reported to modulate gut microbiota composition, regulate microbial metabolites, reduce intestinal permeability and systemic inflammation, and attenuate renal pathological damage.

Despite encouraging findings, most current studies on natural products are preclinical and rely heavily on animal models. Few studies have directly correlated microbial changes with renal outcomes in humans. Therefore, future research should emphasize well-designed clinical trials and employ metagenomic or multi-omics approaches to comprehensively elucidate the microbiota-mediated mechanisms by which natural products exert renoprotective effects.

Fecal microbiota transplantation (FMT) is a therapeutic approach that involves transferring functional gut microbiota from the feces of a healthy donor into the gastrointestinal tract of a recipient via various delivery routes. It is aimed to reconstitute the recipient’s gut microbial community and achieve therapeutic benefits. FMT is considered one of the most direct and effective strategies for restoring gut microbial balance (131, 132). Compared with targeted interventions, such as probiotics, prebiotics, and synbiotics, FMT offers a comprehensive method for eliminating uremic toxins by introducing a diverse and functional microbial ecosystem. Through the introduction of hundreds of commensal microbial species, FMT facilitates intestinal barrier repair, promotes systemic immune modulation, and reestablishes gut–kidney axis homeostasis.

While natural products can exert anti-inflammatory and microbiota-regulating effects via multi-target mechanisms, their clinical application is limited owing to the complex chemical composition and challenges in standardization. In contrast, FMT has shown promise in addressing persistent infections, a major clinical challenge in patients with advanced uremia and those undergoing dialysis. FMT can eliminate multidrug-resistant bacterial colonization through ecological competition, offering long-term control of resistant infections (133). Given its broad-spectrum regulatory capacity, FMT has recently gained attention as a potential therapeutic strategy for the treatment of various kidney diseases. This may represent a promising alternative for protecting renal function by directly modulating the gut microbiota and reducing the inflammatory and toxic burden.

Diabetic nephropathy (DN) is one of the most common microvascular complications of diabetes and is characterized by a range of pathological changes, including mesangial matrix expansion, excessive extracellular matrix deposition, podocyte effacement, glomerulosclerosis, and tubulointerstitial fibrosis, largely driven by persistent hyperglycemia (163). Accumulating evidence indicates that the gut microbiota of patients with DN is significantly altered (164).

Proteinuria is a hallmark of DN. One study demonstrated that differences in gut microbiota might influence renal function in DN mouse models depending on the sequence of FMT and streptozotocin (STZ) administration (133). In this study, severe proteinuria (SP) and mild proteinuria (MP) mouse models were established via intraperitoneal injection of STZ. Microbiota analysis revealed that the Firmicutes/Bacteroidetes ratio was higher in the MP group than that in the SP group. At the genus level, Allobaculum and Anaerosporobacter were enriched in the SP group, whereas Blautia was more abundant in the MP group.

FMT experiments have also demonstrated that inulin-type fructans (ITFs) may prevent the development of DN by modifying the gut microbial composition and enhancing SCFA production, as confirmed by FMT-based verification (165). Similarly, Lu et al. reported that FMT from healthy donors significantly improved podocyte insulin sensitivity, alleviated glomerular injury, and reduced proteinuria in DN rats (166). Shang et al. conducted in vivo experiments in which DN mice were first treated with broad-spectrum antibiotics to eliminate endogenous microbiota, followed by FMT in healthy donors. The study found significant differences in fecal microbiota composition between the FMT group and the untreated DN model group, confirming that FMT can modulate microbial communities and improve the metabolic phenotype of DN mice (167). Additionally, Cai et al. transplanted fecal microbiota from resveratrol-treated donors into db/db mice and found that FMT not only restored the gut microbial balance but also significantly reduced inflammatory responses (121). This result further supports the role of the microbiota–gut–kidney axis in the protective effects of resveratrol against DN. Similarly, a study involving astragaloside IV (AS-IV) demonstrated that FMT using microbiota from AS-IV-treated donors reshaped gut microbial composition, improved intestinal permeability, and attenuated renal dysfunction in db/db mice (127). Although numerous animal studies have confirmed the beneficial effects of FMT in DN models, clinical trials are scarce. Therefore, further research, particularly well-designed human studies, are warranted to explore the clinical applicability of FMT in DN treatment.

Although the precise etiology and pathogenesis of IgAN remain incompletely understood, accumulating evidence has revealed a strong association between gut microbiota dysbiosis and the development and progression of the disease (168). In one study, fecal, urinary, and serum samples from patients with IgAN were analyzed and compared with those of healthy controls, revealing marked differences in gut microbial composition and associated metabolites (169).

Zhao et al. reported the first case study on the use of FMT in two patients with refractory IgAN unresponsive to immunosuppressive therapy (170). The patients underwent regular FMT via an endoscopic intestinal tube over a 6–7 month period. Follow-up results showed that 24-h urinary protein excretion was reduced to less than 50% of the baseline values, achieving partial clinical remission without any adverse events. Prior to treatment, both patients exhibited reduced microbial diversity and altered gut microbiota composition, which were significantly corrected after FMT. Similarly, Zhi et al. described a case of IgAN in which oral administration of fecal microbiota capsules led to clinical symptom improvement. A six-month follow-up revealed no serious adverse events (171). To further assess the safety and efficacy of FMT in IgAN, Zhi et al. conducted a clinical observational study involving 15 patients (172). Urinary protein levels, gut microbiota profiles, and fecal metabolomic data were analyzed before and after FMT. The study found significant alterations in microbial composition and metabolites. The relative abundances of Phocaeicola_vulgatus, Bacteroides_uniformis,Prevotella_copri,Parabacteroides_distasonis, Phocaeicola_dorei,Bacteroides_sp._HF-162, Bacteroides_ovatus, Bacteroides_xylanisolvens, Bifidobacterium_pseudocatenulatum and Bifidobacterium_longum changed after FMT, indicating successful microbiota reconstruction and suggesting a link between these changes and improved renal function.

In mechanistic studies, Zhu et al. demonstrated that gut microbiota dysbiosis can stimulate the overproduction of galactose-deficient IgA1 (Gd-IgA1), a key pathogenic molecule in IgAN, via the Toll-like receptor 4 (TLR4) signaling and B-cell activation pathways (173). Lauriero et al. further observed elevated levels of Gd-IgA1 and serum B-cell-activating factor in patients with IgAN. In an IgAN mouse model, FMT from healthy human donors significantly reduced proteinuria and renal inflammation (160). These findings suggest that reshaping gut microbiota through FMT may modulate immune responses and renal injury in IgAN.

These studies highlight the therapeutic potential of FMT in IgAN by restoring the gut microbial balance, altering metabolite profiles, and modulating key pathogenic pathways. However, further clinical trials are needed to establish the efficacy, safety, and standardized treatment protocols for FMT in IgAN management.

Membranous nephropathy is the most common pathological subtype of nephrotic syndrome among adults. It is primarily characterized by the deposition of immune complexes on the outer aspect of the glomerular basement membrane, leading to diffuse thickening (174). The standard treatment strategies for MN include supportive care, corticosteroids, and immunosuppressive agents (174). In recent years, increasing attention has been given to the gut–kidney axis in MN, with studies revealing significant differences in gut microbiota composition between patients with MN and healthy individuals (175, 176). Shang et al. analyzed 825 fecal samples collected from patients with MN and healthy controls across Central, East, and South China using 16S rRNA gene sequencing. The study reported markedly reduced microbial diversity and richness in MN patients compared to healthy individuals, and subsequently developed a non-invasive diagnostic model based on these microbial differences (177). Furthermore, the role of gut microbiota in MN pathogenesis was investigated using a rat model. Elimination of the gut microbiota in MN model rats prevented disease onset, whereas FMT restored the proteinuria phenotype, suggesting a causal role of gut dysbiosis in MN development. In a related study, Shi et al. collected fecal samples from 82 individuals with idiopathic MN and healthy volunteers. They identified 20 characteristic microbial biomarkers that were significantly correlated with the clinical features of MN and constructed a predictive diagnostic model with an accuracy of 93.53%. FMT experiments in MN model mice showed that dysbiosis leads to impaired intestinal permeability and activation of renal NOD-like receptors, contributing to MN pathogenesis (175). Zhou et al. reported a clinical case of successful MN treatment using FMT (178). After stringent donor screening, fecal microbiota were obtained from a 14-year-old male donor and prepared for transplantation. The patient underwent two FMT procedures 1 month apart. Following treatment, improvements were observed in serum albumin and total protein levels, and 24-h urinary protein excretion significantly reduced. A transient low-grade fever occurred after the first FMT, but resolved spontaneously, suggesting a generally favorable safety profile.

While these findings indicate the potential of FMT as a novel biological therapy for MN, further validation is necessary. Large-scale clinical trials and mechanistic studies are needed to better establish the therapeutic efficacy, mechanisms, and safety of FMT for MN management.

Focal segmental glomerulosclerosis (FSGS) is a common and treatment-resistant form of nephrotic syndrome, characterized by effacement of podocyte foot processes and, under electron microscopy, thickening of the glomerular basement membrane and mesangial expansion in sclerotic regions. Zhi et al. reported a case in which FMT using fecal microbiota capsules led to clinical improvement in a patient with FSGS (179). The patient had previously required glucocorticoid maintenance to control serum creatinine levels. Following FMT, renal function remained stable despite glucocorticoid tapering, and reductions were observed in proteinuria and triglyceride and cholesterol levels, ultimately achieving complete clinical remission. This case suggests that FMT may serve as a potential adjuvant therapy for FSGS by reconstituting the gut microbiota to improve renal function and prevent metabolic abnormalities. However, no randomized controlled trials have defined the specific or long-term efficacy of FMT for FSGS. Therefore, further clinical research is essential to evaluate its safety, therapeutic value, and mechanisms of action in this context.

Although FMT represents an innovative therapeutic strategy for kidney disease, its application remains largely confined to preclinical research. Existing clinical trials are limited by small sample sizes and short follow-up periods, and the long-term efficacy and safety of FMT in larger patient populations have yet to be fully established.

With ongoing advances in biological research, studies investigating the role of FMT in kidney diseases, particularly through modulation of the “microbiota–gut–kidney axis,” are becoming increasingly comprehensive. Strengthening research on gut microbiota is critical for the prevention and treatment of kidney diseases. Thus, the application of FMT in this field holds considerable promise. Future research directions may include the following.