Intestinal dysbiosis, characterized by reduced SCFA-producing bacteria and decreased microbial diversity, emerges as a hallmark feature of DKD pathogenesis, directly contributing to renal fibrosis through diminished SCFA production and subsequent activation of inflammatory pathways. Numerous studies consistently show that patients with DKD harbor fewer SCFA-producing bacteria and exhibit lower microbial diversity than that of healthy controls. These microbial alterations emerge early in the course of the disease—even before significant renal injury is evident—and are associated with elevated levels of systemic inflammation markers such as interleukin-6 (IL-6), as well as declining renal function. Clinical and experimental findings reveal a consistent pattern: as kidney function deteriorates, the gut microbiota shifts toward a pro-inflammatory composition characterized by reduced SCFA biosynthesis. This section highlights key evidence from both human cohorts and animal models that establish the gut–kidney axis as a critical contributor to DKD progression.

Within the context of CKD and DN, SCFAs—particularly butyrate—exert multifaceted renoprotective effects, including anti-inflammatory actions, inhibition of fibrosis, and modulation of the gut–kidney axis. As epigenetic regulators, SCFAs reduce inflammation primarily through inhibition of class I and II histone deacetylases (HDACs), enhancing histone acetylation and downregulating key pro-inflammatory mediators such as IL-1β and TNF-α (51). Additionally, SCFA-induced activation of G protein-coupled receptor 43 (GPR43) inhibits NLRP3 inflammasome assembly, thereby suppressing the production of inflammatory mediators, including IL-1β and IL-6. This mechanism, demonstrated in intestinal models, helps alleviate local inflammation and indirectly supports renal function (52, 53).

In terms of anti-fibrotic mechanisms, SCFAs—especially butyrate—interfere with TGF-β signaling cascades. Butyrate upregulates the transcription factor KLF13, which recruits a transcriptional repressor complex containing SIN3A and HDAC1, thereby blocking TGF-β target gene expression and attenuating fibrotic processes (54). Notably, while transient TGF-β activation induces a protective KLF13-mediated feedback loop, sustained activation leads to HDAC-dependent KLF13 degradation, ultimately exacerbating fibrosis (54). ECM dysregulation is a hallmark of CKD progression, and SCFA deficiency is closely associated with enhanced TGF-β signaling, which promotes epithelial–mesenchymal transition (EMT) and excessive collagen deposition (55, 56). SCFA supplementation significantly suppresses EMT and reduces ECM accumulation. Experimental studies confirm that SCFAs attenuate renal fibrosis by antagonizing TGF-β signaling pathways (52, 54, 57).

Beyond anti-fibrotic actions, the epigenetic regulatory capacity of SCFAs also contributes to oxidative stress suppression. Acting as HDAC inhibitors, SCFAs activate the nuclear factor erythroid 2–related factor 2 (Nrf2) pathway and upregulate heme oxygenase-1 (HO-1), thereby reducing reactive oxygen species (ROS) production (58). This reduction in oxidative stress further inhibits TGF-β signaling and downstream inflammatory cascades, establishing a protective feedback loop (51, 58, 59). Through the gut–kidney axis, SCFAs influence immune regulation as microbial-derived metabolites. Activation of intestinal GPR43 receptors by SCFAs inhibits NLRP3 inflammasome activation, thereby decreasing renal accumulation of pro-inflammatory mediators such as IL-1β and IL-18 (52, 60). Furthermore, SCFAs promote regulatory T (Treg) cell differentiation and modulate Th17/Treg balance, primarily through regulation of the NLRP3/IL-1β/caspase-1 pathway (49, 58). Collectively, SCFAs exhibit substantial renoprotective effects through a combination of epigenetic modulation, oxidative stress mitigation, and immune homeostasis regulation (52, 55).

Polysaccharide-rich Chinese herbal medicines modulate the gut–kidney axis primarily by promoting SCFA production through gut microbiota modulation, which reinforces intestinal barrier integrity and regulates inflammation via SCFA-mediated pathways. Astragalus polysaccharide (APS) enhances intestinal barrier function by upregulating mucin MUC2 and tight junction proteins such as occludin, thereby restoring epithelial integrity (61–63), and directly increases SCFA production by enriching beneficial genera such as Bifidobacterium and Lactobacillus, which elevate butyrate levels to prevent pathogen colonization and ameliorate gut dysbiosis (61, 63, 64). Similar effects are observed with other polysaccharides. For instance, Moringa oleifera polysaccharide (MCE) reshapes gut microbial communities by improving the Firmicutes-to-Bacteroidetes ratio, primarily by increasing Bacteroidetes while modulating Firmicutes abundance, a shift driven by SCFA-producing bacteria that enhances acetate and propionate production, thereby mediating TCM’s anti-inflammatory effects (65–67).

The SCFAs produced by microbial fermentation of polysaccharides exert anti-inflammatory effects through multiple pathways. These include HDAC inhibition, which reduces oxidative stress and epithelial injury, and the suppression of pro-inflammatory cytokines such as TNF-α and IL-6. Concurrently, SCFAs enhance anti-inflammatory IL-10, contributing to a more tolerogenic intestinal environment (67–69). Butyrate and other SCFAs activate GPR41 and GPR43 receptors, triggering downstream signaling cascades that support barrier repair. A key mechanism involves inhibition of the NF-κB pathway, thereby suppressing pro-inflammatory signaling (68, 70). Additionally, SCFA-mediated HDAC inhibition enhances histone acetylation, which promotes regulatory T cell differentiation and the expression of anti-inflammatory genes (68, 69).

Both APS and MCE modulate immune responses through the SCFA–GPCR/HDAC axis. These polysaccharides promote M2 macrophage polarization, characterized by increased IL-10 production, while concurrently suppressing Th17 activation and IL-17 production (68, 71). Additionally, SCFAs reprogram dendritic cells to favor Treg differentiation. Through HDAC inhibition, they enhance tight junction integrity, reinforcing epithelial barrier function and providing multilayered intestinal protection (63, 71). Figure 2 illustrates how herbal polysaccharides leverage SCFA production to coordinate these anti-inflammatory mechanisms. Beyond gut-mediated mechanisms, emerging evidence reveals direct effects of certain herbal components on renal cells. Both APS and resveratrol, for instance, exert antifibrotic activity through distinct signaling pathways. Resveratrol modulates the SIRT3/TGF-β1/Smad axis, effectively downregulating pro-fibrotic signaling in experimental models of renal fibrosis (72). Similarly, APS and related compounds directly target the TGF-β/Smad and NF-κB pathways, mitigating inflammation and fibrogenesis at the cellular level. APS has also been shown to regulate Wnt signaling, promoting renal cellular repair and reducing oxidative stress (73, 74). These direct effects on renal cells complement microbiota-mediated effects, providing a multifaceted antifibrotic strategy for addressing DKD.

Resveratrol protects kidney function by remodeling the gut microbiome to enhance SCFA production, especially butyrate (75). This polyphenolic compound selectively promotes the proliferation of SCFA-producing genera such as Allobaculum and Bifidobacterium, thereby reversing the dysbiosis associated with DN and increasing fecal SCFA concentrations (66, 76). Resveratrol’s mechanism specifically involves upregulation of bacterial genes encoding key enzymes in the butyrate synthesis pathway, including butyryl-CoA:acetate CoA-transferase, which directly enhances the microbiota’s capacity to produce SCFAs from dietary fiber fermentation. Among the SCFAs produced, butyrate plays a pivotal role in mediating renoprotective effects by exerting anti-inflammatory effects and reinforcing intestinal barrier integrity (77–79). Experimental studies involving FMT and antibiotic-depleted mice demonstrate that resveratrol’s protective effects on the kidney are largely microbiota-dependent, highlighting the necessity of an intact microbial community for its full therapeutic efficacy (76).

Butyrate and other SCFAs inhibit NF-κB signaling, thereby reducing the production of pro-inflammatory cytokines such as IL-1β and TNF-α (80). Resveratrol-induced SCFA elevation also activates antioxidant defense pathways, which synergize with NF-κB suppression to alleviate renal inflammation and oxidative stress (81). Additionally, SCFAs upregulate tight junction proteins, enhancing intestinal barrier function and preventing endotoxin translocation, which would otherwise provoke systemic inflammation and exacerbate kidney injury (82, 83). First, SCFAs inhibit fibrosis by antagonizing TGF-β1 signaling, thereby preventing collagen accumulation and tubulointerstitial scarring, as demonstrated in DN models (76). Second, SCFAs suppress inflammation by blocking the TLR4/MyD88/NF-κB signaling cascade, which reduces macrophage infiltration and pro-inflammatory cytokine release, ultimately preserving renal architecture (81). Third, SCFAs enhance antioxidant defenses via Nrf2 pathway activation, neutralizing ROS and reinforcing cellular protection (81). Complementing these microbiota-mediated effects, resveratrol also directly exerts antifibrotic effects on renal cells. It modulates intracellular pathways such as the SIRT3/TGF-β1/Smad axis to suppress TGF-β activation and attenuate renal fibrosis (84). Furthermore, resveratrol inhibits fibroblast activation and collagen deposition by targeting the p38 MAPK and PI3K/AKT signaling pathways (84, 85), and promoting autophagy and apoptosis in renal cells, providing a synergistic, microbiota-independent antifibrotic activity (86).

Resveratrol induces a coordinated protective cascade by remodeling the gut microbiota to enhance SCFA production, which in turn inhibits NF-κB-mediated inflammation and TGF-β1-driven fibrosis (76, 78, 87). This integrative mechanism—reliant on both beneficial gut bacteria and their SCFA metabolites—yields anti-inflammatory, antioxidant, and antifibrotic effects (76, 87). These findings underscore the therapeutic potential of microbiota-targeted strategies for CKD management (52).

SCFAs combat inflammation through distinct yet complementary molecular pathways that converge to suppress renal damage. First, SCFAs directly target inflammatory signaling by binding to GPR43, which triggers a cascade that dismantles the TLR4/MyD88 complex and stabilizes IκBα. This dual action blocks NF-κB from entering the nucleus and halts the production of pro-inflammatory cytokines including TNF-α, IL-6, and IL-1β (98, 99). Simultaneously, SCFAs function as potent HDAC inhibitors, promoting histone acetylation that drives IL-10 expression—a key anti-inflammatory mediator. This epigenetic reprogramming further dampens inflammation by preventing IKK phosphorylation, creating a reinforcing anti-inflammatory loop that protects renal tissue (106, 107).

Suppression of NLRP3 inflammasome activation represents a key mechanism by which the TCM–SCFA axis mitigates renal inflammation and fibrosis in DKD. SCFAs limit NLRP3 inflammasome assembly by reducing mitochondrial reactive oxygen species (mtROS) production and oxidative stress signaling, thereby preventing NLRP3 oligomerization and activation (107, 108). Additionally, SCFAs inhibit caspase-1 auto-activation and the cleavage of pro-IL-1β, which collectively lowers mature IL-1β secretion and dampens downstream inflammatory amplification (109, 110). These anti-inflammatory actions are further potentiated by TCM-derived phytochemicals, which synergistically suppress NLRP3/ASC/caspase-1 complex formation, reduce IL-1β maturation, and modulate TGF-β/Smad pathway phosphorylation, ultimately attenuating renal fibrotic responses (111, 112).

TCM potentiates the effects of SCFA regulation by promoting the proliferation of butyrate-producing bacteria via the microbiota–metabolite axis, thereby increasing SCFA concentrations (113, 114). These elevated SCFAs activate GPR43 receptors, which in turn suppress NLRP3 inflammasome activation and downregulate TGF-β-mediated Smad2/3 phosphorylation, leading to reduced collagen deposition (111, 112). In parallel, SCFA-dependent pathways modulate NF-κB signaling, thereby suppressing TGF-β-induced EMT and delaying tissue fibrosis progression (107, 112).

Evidence from DKD-specific models underscores the protective role of SCFAs and their associated pathways in mitigating core renal damage. In vitro, treating human kidney 2 (HK-2) cells with butyrate under high glucose conditions—mimicking the diabetic renal environment—significantly suppresses NLRP3 inflammasome activation and IL-1β release, thereby reducing tubular inflammation (51). Complementary in vivo findings in non-obese diabetic Akita mice reveal that acetate supplementation mitigates glomerular injury, evidenced by preservation of WT1-positive podocytes and reduced glomerular collagen IV deposition, indicating direct renoprotection at the structural level (51).

Preventing kidney fibrosis requires disrupting the TGF-β/Smad pathway through two converging mechanisms: epigenetic regulation and metabolic reprogramming (113, 114).

Butyrate, a key SCFA, acts as an HDAC inhibitor, increasing acetylation at histone residues H3K9 and H3K27 to open chromatin structure and suppress TGF-β1 transcription (115). This epigenetic remodeling reduces Smad2/3 phosphorylation and downstream deposition of collagen I/III and fibronectin. Additionally, butyrate inhibits EZH2-mediated H3K27 trimethylation, upregulating Smad7—a natural antagonist of TGF-β/Smad3 signaling that provides negative feedback inhibition (116, 117). TCM-derived phytochemicals amplify these effects. Curcumin prevents Smad7 degradation, maintaining its inhibitory action on TGF-β receptors and thus slowing glomerulosclerosis (118, 119). Beyond this, curcumin alleviates fibrosis by downregulating inflammatory cytokines and modulating key profibrotic signaling pathways in renal cells (120, 121). Puerarin operates via a different mechanism by upregulating miR-342-3p, which inhibits the TGF-β/Smad axis (122), and simultaneously attenuates fibrosis by suppressing oxidative stress and ferroptosis (123). Another compound, altenusin, blocks EMT in tubular epithelial cells, thereby reducing abnormal ECM accumulation and contributing to fibrosis prevention (124, 125). This direct antifibrotic effect involves antagonism of the TGF-β/Smad signaling pathway in renal proximal tubular cells (126). Mechanistic studies isolating the impact of hyperglycemia confirm the direct action of TCM-derived compounds on core DKD pathology, independent of obesity-related confounders. For example, investigations in experiments in streptozotocin (STZ)-induced diabetic rats demonstrate that curcumin directly inhibits TGF-β1–induced Smad2/3 phosphorylation within renal cortical tissues, thereby reducing ECM accumulation in both glomeruli and the tubulointerstitium (127). In vitro experiments using high glucose-stimulated mouse podocytes further reveal that berberine—a major active component of Huanglian Jiedu Decoction—ameliorates podocyte injury and cytoskeletal disruption by enhancing autophagy via activation of the AMPK/ULK1 pathway (128). These findings collectively highlight the ability of TCM compounds to directly target fundamental fibrotic processes within the kidney parenchyma, independent of systemic metabolic factors such as obesity​.

In addition to epigenetic regulation, metabolic reprogramming targets lipotoxicity in DKD. TCM-derived gypenosides activate the AMPK/PGC-1α signaling pathway, promoting a metabolic shift in renal tubular epithelial cells from fatty acid synthesis toward fatty acid oxidation (129–131). This reprogramming alleviates intracellular lipid accumulation and reduces the expression of fibrotic markers, including α-smooth muscle actin (α-SMA) and plasminogen activator inhibitor-1 (PAI-1). Glycolysis exerts dual effects: while excessive glycolytic flux can induce histone lactylation, particularly H4K12la, thereby driving proinflammatory gene expression, inhibition of the glycolytic enzyme PFKFB3 has been shown to prevent this modification and attenuate oxidative injury (132, 133). Butyrate coordinates these metabolic pathways by upregulating miR-29b, which simultaneously suppresses collagen I and III gene expression and enhances glycolysis to sustain energy production under cellular stress (134). Additionally, miR-29b downregulates SETD2, thereby modulating H3K36me3 levels and further inhibiting TGF-β signaling (117, 134).

Synergistic mechanisms amplify protection against renal fibrosis through coordinated epigenetic and metabolic regulation. Epigenetic enzymes such as HDACs and EZH2 regulate both fibrotic gene expression and metabolic enzyme activity, forming reinforcing feedback loops that sustain pathological signaling (51, 115, 117, 135). TCM formulations strategically exploit these interactions. For instance, Huanglian Jiedu Decoction promotes miR-663a expression to inhibit the lncRNA C18orf26-1/TGF-β/Smad axis, effectively blocking EMT and ECM deposition (118, 119, 136, 137). Liposomal gypenosides activate AMPK and suppress Smad2/3 phosphorylation, targeting fibrosis through both metabolic and epigenetic pathways (129–131). A comprehensive overview of the molecular mechanisms by which the TCM–gut microbiota–SCFAs axis attenuates renal fibrosis is illustrated in Figure 4 . This conceptual model delineates a stepwise sequence: (I) TCM-derived phytochemicals selectively enrich butyrate-producing gut bacteria; (II) Elevated SCFA levels act as signaling molecules and potent epigenetic modifiers—functioning as HDACi and EZH2i inhibitors—to suppress profibrotic gene expression and stabilize inhibitory regulators such as Smad7; (III) SCFAs directly inhibit renal fibrotic signaling, particularly the TGF-β/Smad3 pathway, by activating GPR that engage AMPK and NF-κB signaling, increasing Smad7 expression, inhibiting Smad2/3 phosphorylation, and preventing EMT blockade; (IV) Synergistic effects are further reinforced through gut–brain axis crosstalk, glucagon-like peptide-1 (GLP-1)-mediated metabolic improvements, and enhanced antioxidant defenses within renal tissue. The convergence of these direct and indirect mechanisms results in the attenuation of ECM accumulation and preservation of renal structure, offering a multi-layered strategy for delaying the progression of DKD.

Although growing evidence supports the potential of TCM to modulate the gut microbiota–SCFA axis in DKD, several critical limitations hinder clinical translation. First, the underlying molecular mechanisms remain incompletely understood. While TCM-derived polysaccharides and polyphenols have been shown to elevate SCFA levels—particularly butyrate and propionate—through gut microbiota modulation and ameliorate renal fibrosis (47), the specific microbial enzymatic pathways responsible for SCFA biosynthesis remain undefined, despite evidence that TCM polysaccharides such as APS promote probiotic growth (162, 164). Moreover, the interactions between SCFAs and host receptors, especially GPR41 and GPR43, lack comprehensive validation in the context of DKD (5). Downstream mechanisms, such as NF-κB signaling inhibition, remain speculative without direct molecular evidence (15). Mechanistic studies are also often limited by their reliance on comorbidity models involving diabetes and obesity (165), rather than isolating core DKD pathologies such as glomerular and tubular injury. Furthermore, high-quality human data are scarce; most findings are derived from preclinical animal models or in vitro models (88), with a notable absence of large-scale RCTs evaluating the efficacy of TCM in modulation of the microbiota–SCFA axis in patients with DKD (52, 166). Finally, current studies lack a dynamic, longitudinal monitoring of SCFA levels in fecal or blood samples, making it difficult to establish clear associations between SCFA fluctuations and renal outcomes (26).

In the clinical management of DKD, future research should prioritize the elucidation of underlying mechanisms, with multi-omics technologies serving as pivotal tools. Metagenomic analyses, such as 16S rDNA sequencing, can characterize gut microbiota dysbiosis in DKD, particularly identifying reductions in SCFA-producing taxa like Clostridium butyricum (161, 169). Complementary metabolomic approaches, including gas chromatography-mass spectrometry, allow for precise quantification of key SCFAs such as butyrate and propionate, thereby advancing our understanding of metabolite fluctuations in relation to disease progression (161). Preclinical evidence demonstrates that SCFAs, particularly butyrate, exert renoprotective effects by suppressing pro-inflammatory cytokines like IL-6 and TNF-α, underscoring their immunomodulatory potential in DKD (169, 170). However, these findings are largely based on murine models, necessitating validation in human populations with larger, more diverse sample sizes (171).

Gut dysbiosis has been strongly linked to DKD pathogenesis, characterized by reduced microbial diversity and decreased abundance of SCFA-producing bacteria. These microbial alterations correlate significantly with markers of renal dysfunction, including eGFR decline and elevated urine albumin-to-creatinine ratio (UACR) (39, 172), supporting the rationale for stratified patient management (163). Based on this foundation, future phase III RCTs could adopt microbiota-guided stratification strategies. For instance, individuals with specific dysbiotic microbiota profiles could be preferentially assigned to receive Huangkui capsule, a TCM shown to modulate microbial composition and mitigate renal pathological injury in DKD (173). This design aims to validate the differential therapeutic efficacy of targeted interventions in patients with specific microbial phenotypes. By screening microbiota-responsive populations and leveraging Huangkui capsule’s regulatory effects on pathogenic microbiota (173), this approach facilitates the development of precision treatment models linking DKD-associated microbiota subtypes with TCM therapeutic responses (173, 174). Such methodology holds promise for advancing clinical translation and optimizing individualized therapeutic strategies.

Regarding clinical research optimization, robust associations between gut microbiota characteristics and DKD progression have been established. Specifically, microbiota compositional changes, such as reduced diversity and lower abundance of SCFA-producing bacteria, are significantly correlated with renal function indicators—notably declining eGFR and elevated UACR—providing a rationale for individualized patient stratification (172, 175). Moreover, findings from animal models demonstrate that fluctuations in SCFA levels often parallel renal function impairment, supporting the feasibility of using SCFAs—particularly butyrate—as biomarkers in blood or feces (161, 176). However, SCFA detection methodologies require standardization to ensure reproducibility and clinical reliability (167, 171).

For microbiota-targeted therapy, microbial intervention strategies include the use of specific probiotic strains that enhance SCFA production, as well as prebiotics such as dietary fiber, which increase SCFA production and mitigate renal injury (9, 43, 58). Additionally, natural compounds like resveratrol modulate gut microbiota composition, resulting in elevated SCFA levels and subsequent attenuation of renal fibrosis (39). In support of causal mechanisms, Mendelian randomization analyses have provided genetic evidence for associations between the gut microbiota and DKD. Specifically, changes in the abundance of SCFA-producing bacterial genera have demonstrated causal relationships with renal injury risk, where reductions in key microbial populations are associated with negative renal outcomes (158, 177). To strengthen causal inference, future studies should integrate clinical datasets, combining metagenomic profiles with renal function markers such as eGFR, while carefully controlling for confounding factors (158, 176). Overall, future research should prioritize mechanistic elucidation, clinical translation, and optimization of therapeutic strategies to facilitate the development of precision medicine approaches in DKD. Figure 5 outlines a proposed roadmap for this clinical translation.