Changes in Firmicutes, Proteobacteria, and Bacteroidetes are dominant in DN vs. non-DN (He et al., 2022). A prominent marker of DKD is the low ratio of Firmicutes (Gram-positive)/Bacteroidetes (Gram-negative) (Zaky et al., 2021; Grasset et al., 2017). The stool of patients with diabetic nephropathy shows a relative increase in Bacteroides stercoris, Verrucomicrobia, Proteobacteria, Fusobacteria (Lin et al., 2022), Haemophilus, Escherichia–Shigella, Megalococcus, Veillonella, and Anaerostipes (Du X. et al., 2021), and a relative decrease in butyrate-producing bacteria (Roseburia, Faecalibacterium, Clostridium, Coprococcus, and Prevotella) (Jiang et al., 2017) as well as in potential probiotic genera (Trichella spp., Enterobacteriaceae, Lactobacillus, and Bifidobacterium). Additionally, a significant association between creatinine and Clostridium was seen in the stool of patients with DN, highlighting the significance of gut microbiota for these individuals (Zhang L. et al., 2022). In addition to validating the relationship between gut microbiota and DN in biological models such as mice, Mendelian randomization analyses have revealed a significant association between Errucomicrobiae, Verrucomicrobiales, and Verrucomicrobiaceae and DN (Yan et al., 2024). Later studies showed that the genera Terrisporobacter and Lachnospiraceae UCG008 were associated with the severity of DN, whereas the phylum Proteobacteria and Dialister may protect the condition (Fang et al., 2024). These studies help to understand the relationship between DN and gut microbiota.

The intestinal epithelial cells have a crucial role in the intestinal tract. On the one hand, they have pattern recognition receptors (PRRs) on their surface that recognize the microbial cell wall and thus activate the immune response and the inflammatory response. For example, toll-like receptor (TLR) is a type of PRRs, which activates phagocytes Th17, Th1 and thus stimulates the release of pro-inflammatory cytokines by recognizing segmented filamentous bacteria and Salmonella (Seo et al., 2015). On the other hand, the intestinal epithelial cells are also a barrier. When various pathogenic factors cause damage to the intestinal epithelial cells, the intestinal barrier is damaged and the permeability of the intestinal barrier is increased, which in turn invades the circulation and exacerbates intestinal inflammation, in a process known as “gut leaky” (Paray et al., 2020). In healthy individuals, dietary proteins are metabolized to produce uremic solutes, including p-Cresyl sulfate (PCS), indoxyl sulfonate (IS), indole-3-acetic acid, trimethylamine N-oxide (TMAO), and phenylacetylglutamine (PAGIn) (Amini Khiabani et al., 2023; Chen et al., 2019). Butyrate decreases serum levels of renal inflammatory and uremic toxins, whereas end-stage renal disease (ESRD) patients with end-stage testing of flora found a reduction in butyrate-producing bacteria, Roseburia, Faecalibacterium, Clostridium, Coprococcus, and Prevotella (Jiang et al., 2017; Li et al., 2022). Meanwhile, within this disease state, uremic toxins accumulate in large quantities, with the decline of renal excretory function, and the colon becomes the main part of the elimination of urea and uric acid. This process will lead to an increase in the pH value of intestinal fluids, which disrupts the intestinal homeostasis. Consequently, the microbiota changes, further aggravating the accumulation of uremic toxins (Hatch and Vaziri, 1994; Bourke et al., 1966). It has been shown that continued exposure of colonic epithelial cells to urea disrupts their barrier protection, resulting patients in “gut leaky” with increased levels of systemic endotoxins and bacterial products leading to chronic, systemic inflammation (Vaziri et al., 2012; Vaziri et al., 2013). In conclusion, the course of kidney disease affects the damage to the intestinal barrier, which exacerbates the progression of kidney disease, creating a vicious circle (Figure 1). DN is the main cause of ESRD in most developed countries (Umanath and Lewis, 2018). Therefore, in order to slow down the process of evolving into ESRD in the DN state, intervention of the gut microbiota and its metabolites is necessary.

Dietary fiber and resistant starch are fermented by gut microbes to form metabolites known as SCFAs, which are primarily acetic, propionic, and butyric acids. SCFAs play an important role in regulating host metabolic health and immune response. SCFAs can reduce intestinal and renal inflammatory responses, which is particularly important in patients with DN. As chronic inflammation, SCFAs is a key factor in the progression of DN, with resisting oxidative stress by propionate and butyrate, and exacerbating the progression of DN by acetate (Tian et al., 2023). SCFAs can be used as an energy source for intestinal cells, aiming to improve metabolic status, and participate in the regulation of blood lipid levels and blood pressure regulation, which can help lower blood pressure and reduce the risk of cardiovascular disease. In contrast, SCFAs can improve insulin sensitivity and help lower blood sugar levels, in the interest of patients with DN. Furthermore, SCFAs with vasodilating properties can enhance renal function by increasing blood flow to the kidneys (Zaky et al., 2021; Deng et al., 2022; Li et al., 2020; Tang et al., 2022). SCFAs are also extensively involved in the immune response, such as stimulating the production of IL-18 by binding to G protein-coupled receptors, and thus promoting the repair of the intestinal epithelial barrier (Macia et al., 2015). SCFAs also enhance phagocytosis by neutrophils and inhibit the production of inflammatory mediators by macrophages (Vinolo et al., 2009; Chang et al., 2014). In conclusion, gut microbes can maintain the integrity of the intestinal barrier by modulating the immune response through the production of SCFAs, which further may slow down the progression of kidney disease. Inulin-type fructans (ITFs) can shield kidney injury in db/db mice by producing gut bacteria that control SCFAs (Luo et al., 2022). On the other hand, empagliflozin can mitigate kidney damage in DN-affected mice by elevating the SCFA-producing bacteria Odoribacter and Bateroid while lowering the LPS-producing Oscillibacter (Deng et al., 2022).

Trimethylamine (TMA) is mostly oxidized by gut microbes, and can produce TMAO. Ingested nutrients like choline and lecithin are broken down by gut microorganisms to create TMA, then TMA transported to the liver via the portal vein circulation and converted to TMAO. Patients with diabetes may produce more TMA due to an imbalance in their gut microbiota, which raises the blood level of TMAO. Furthermore, it has been discovered that TMAO increases platelet hyperresponsiveness, inhibits cholesterol reverse transport, and encourages the development of macrophage foam cells, all of which may aid in the development of endothelial dysfunction and atherosclerosis to causes diabetic microvascular damage. TMAO can accelerate the development of DN by activating inflammatory pathways, such as NLRP3 inflammasome signaling pathway and nuclear factor kappa B (NF-κB) signaling pathway, leading to the release of inflammatory factors and promoting tubulointerstitial injury and renal fibrosis. Therefore, chronic inflammation and TMAO may play a significant role in the development of DN (Tian et al., 2023; Tanase et al., 2020; Kalim and Rhee, 2017; Huo et al., 2023; Fang et al., 2021). On the whole, the gut microbial metabolites mentioned above have a significant impact on renal function and metabolism in addition to being engaged in inflammatory and immunological responses in diabetic nephropathy. Regulating the gut microbiota may help improve the condition of people with DN.

The metabolism of primary bile acids by gut microbes results in the production of secondary bile acids, which are involved in controlling the host’s immunological and metabolic reactions. In addition to inducing renal fibrosis and inflammation through the NF-κB and other inflammatory signaling pathways being activated, gut microorganisms can also create secondary bile acids that support renal integrity of the intestinal barrier, stop the growth of bacteria in the gut and their byproducts (e.g., urotoxins) from entering the bloodstream, and reduce the burden on the kidneys (Lu et al., 2018). Secondary bile acids are also good at regulating metabolism, and they may have a positive impact on metabolic control in DN patients by binding to receptors in host cells, such as farnesoid X receptor (FXR), which are involved in regulating host metabolic processes, including lipid, glucose, and energy metabolism (Yang et al., 2021). As an illustration, it raises muscle energy expenditure and, through encouraging GLP-1 (glucagon-like peptide-1) release, may enhance insulin resistance and blood glucose metabolism. Ursodeoxycholic acid (UDCA) is a secondary bile acid. And it was reported that UDCA has shown a protective effect on the kidneys of diabetic rats by decreasing SGLT2 expression and reducing oxidative stress, which provides a new potential avenue for the treatment of DN (Osorio et al., 2012).

TCM prescription is one of the important forms of TCM treatment, which is also essential in DN therapy (Table 1; Table 2). Xiancao Granule (CXCG) is a traditional Zhuang medicine prescription derived from Zhuang folk herbs in Guangxi, China. The Zhuang are an ethnic minority in China with a rich ethnic medicine culture and traditions. Mo et al. (2024) showed that CXCG could increase the relative abundance of beneficial bacteria (e.g., Alloprevotella, Oscillibacter, Anaeroplasma, and Anaerotruncus) and decrease the relative abundance of harmful bacteria (e.g., Faecalibacterium), improving the structure of intestinal microbiota in DN rats. By increasing the abundance of gut microbiota with anti-inflammatory properties, CXCG may help reduce inflammatory markers associated with DN, such as serum levels of IL-6, TNF-α, and MCP-1. In addition, it can also improve the metabolic disorders of DN rats by regulating metabolic pathways related to carbohydrate and amino acid metabolism, such as TCA cycle, vitamin C and aldehyde metabolism, and C-type lectin receptor signaling pathway. The microbiota and metabolism were regulated to improve the renal function parameters of DN rats, including decreased levels of urine microalbumin (MUA) and serum creatinine (Scr), as well as less degenerative kidney tissue damage. Qing-Re-Xiao-Zheng formula (QRXZF) is a TCM prescription (Wang et al., 2023; Gao et al., 2021) that reduced the release of inflammatory factors by inhibiting the activation of inflammatory signaling pathways such as TLR4/NF-κB/NLRP3. Meanwhile, QRXZF reduced renal inflammatory response by enhancing intestinal barrier function, reducing intestinal permeability, translocation of endotoxins (such as lipopolysaccharide LPS), and the production of inflammatory factors. Among them, polysaccharides and other ingredients not only have antioxidant effects, but also scavenge free radicals, reduce oxidative stress, and protect kidney cells. Moreover, QRXZF enhanced the balance of intestinal microecology and accomplished the goal of treating diseases by encouraging the growth of helpful bacteria and preventing the reproduction of bad bacteria through the metabolism of intestinal microorganisms. According to Hong et al. (2023) it lessened the buildup of urinary toxins such as trimethylamine-N-oxide, p-cresyl sulfate, and indoxyl sulfate. It also lessened inflammation by lowering levels of inflammatory cytokines like NLRP3, IL-6, and IL-17A. In addition, its active ingredient, calycosin-7-O-β-D-glucoside, interacted with the gut microbiota and stimulated the growth of probiotics, thus exerting its therapeutic effect. Besides, it was reported that Jingui Kidney Qi Pills, Ginseng Qi Dihuang Decoction, Shrinking Spring Yi Kidney Fang, Yuye Tang, Bekhogainsam Decoction, and Jowiseungki decoction (JSD) have similar regulatory mechanisms (Zhang et al., 2024; Meng et al., 2020a; Meng et al., 2020b; Guo et al., 2024; Du X. M. et al., 2021; Yao et al., 2020). And Yuye Tang also improved intestinal barrier function, lower intestinal permeability, and raised the expression levels of the colonic mucosal barrier proteins Occludin and ZO-1, which stopped bacteria and toxins from translocating. Reducing the risk of systemic inflammation and organ damage by regulating the levels of cAMP and cGMP, Yuye Tang affected the body’s energy balance and metabolic processes, which might help to improve energy metabolism and overall health in patients with DN. Xiaoli Wang, et al. noted that nephritis rehabilitation granules (Wang et al., 2018) concentrated more on the regulation of gut microbiota metabolites, which is manifested in reducing inflammation by enhancing the role of certain SCFAs in the intestine or increasing their production. These included propionic acid and butyric acid, which inhibited the production of inflammatory cytokines like TNF-, IL-2, and IL-6, thereby playing a role in anti-inflammatory. In the bargain, SCFAs could promote the secretion of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), hormones that helped lower blood glucose levels and improved glycolipid metabolism. Strengthening the intestinal barrier, restricting the entry of hazardous substances, controlling intestinal motility, and providing the primary energy source for colon cells are all made possible by SCFAs. At the same time, clinical trials have also achieved good results. Clinical observations indicated the anti-inflammatory and intestinal barrier-protecting properties of SCFAs, Huangkui capsule had a role in improving the gut flora’s subpopulations and dispersion by regulating the amount of gram-positive and gram-negative bacteria in the colon, Qiditang nephroid formula (QDTS) had a great effect on bile acid metabolism, and affects bile acid metabolism by changing the gut microbiota (Wei et al., 2021). Bile acids in QDTS constituted important byproduct of the metabolism of gut microbes and were essential for controlling the host’s inflammatory and metabolic reactions. Certain bile acids, such taurocholic acid (TCA), tauro-Mulisiccic acid (T-MCA), deoxycholic acid (DCA), and murichticolic acid (-MCA), was reduced in serum levels by QDTS. Bile acids were associated with the activation of FXR, which was highly expressed in the kidney. While, db/db animals treated with QDTS did not show a substantial change in FXR expression in their kidneys, QDTS may have an indirect effect on FXR activity by altering the amount of bile acids, which would protect the kidneys. San-Huang-Yi-Shen (SHYS) is a TCM formula. The study discovered that SHYS influenced the β diversity of gut microbiota in DN model rats, as well as the relative abundance and metabolite levels of particular bacterial genera. It also affected a range of metabolic pathways, including glycerophospholipid metabolic processes, tryptophan metabolic rate, alanine, aspartic acid and glutamic acid. digestion, the arginine metabolism, tricarboxylic acid (TCA) cycle, tyrosine metabolic processes, Arginine and proline metabolic rate, phenylalanine, tyrosine, and tryptophan biosynthesis, phenylalanine respiration, and D-glutamine and D-glutamate the metabolism pathways, thus ameliorate the disease. of glyconephrium (Su et al., 2021).

The active ingredients are the target site for the effectiveness of TCM. Various TCM ingredients were identified by morden technology and were used for conducting experiments on the treatment of DN (Table 3; Table 2). The composition of corn silk polysaccharides (CSPS) has the potential to enhance the gut microbiota’s structure (Dong et al., 2023). Patients suffering from DN frequently have an imbalance in their gut microbiota. CSPs can regulate the dominant strains in the gut, such as Firmicutes, Bacteroidetes, Lachnospiraceae-NK4A136 and Dubosiella. Meanwhile, CSPs can affect the metabolism of key endogenous metabolites that interact with the gut microbiota, including glycerophosphate, fatty acids, bile acids, tyrosine, tryptophan, and phenylalanine. Variations in these metabolites are directly linked to the onset of DN and are linked to changes in the gut flora. Among these, the intestinal microbiota has a major impact on bile acid metabolism. CSPs can control bile acid metabolism and minimize bile acid buildup in the body, which lowers the inflammatory response and kidney cell damage. Peony peel polysaccharide (MC-Pa) improves the pathological condition of DN by influencing the gut microbiota and its byproducts through several means. It can improve the structure of the intestinal microbiota and enhance the intestinal barrier function, among which it is worth noting that MC-Pa can promote the production of SCFAs and reduce the production of branched-chain fatty acids (BCFAs), thereby exerting a positive therapeutic effect on DN (Zhang M. et al., 2022). In addition to the regulation of the structure of the gut microbiota and its metabolites, cinnamaldehyde, rehmannia leaf glycosides, Yam polysaccharides and total phenolic acids were all effective in improving renal function and regulating the gut microbiota (Zhang et al., 2021; Xu et al., 2021; Dai et al., 2017; Wang et al., 2018). Magnesium lithospermate B (MLB), a drug used to treat angina, has been found to improve kidney damage in a mouse model of DN via alterations to the bile acid biosynthesis and gut microbiota, in addition to which MLB may indirectly improve kidney function by affecting microbiota associated with blood pressure regulation (Zhao et al., 2019). But, the results on experimental animals can not completely represent the clinical effects. Surprisingly, a clinical study shown that sodium ferulate have great potential in the management of DN patients by alterations to the gut microbiome (Zheng et al., 2011). On the basis of animal experiments, it is believed that more TCM active ingredients will also be able to be applied in clinical practice.

When treating DN, single herb Chinese medicine is also effective in controlling the gut flora and its metabolites (Table 4). For example, Danshen from the roots of Salvia miltiorrhiza plants can alleviate the glucose kidney lesions by increasing the relative microbial abundance. In addition, the stems and leaves of Salvia miltiorrhiza are usually discarded as waste, which were proved to have certain pharmacological activities to regulate gut microbiota, providing a basis for the comprehensive utilization of Salvia miltiorrhizae plants (Xu et al., 2021; Cai et al., 2021). It can be seen that Salvia miltiorrhiza has an important role in the treatment of DN, by regulating the interaction between the gut microbiota and metabolites, such as phosphatidylcholine (PC), phosphatidylethanolamine (PE), lysophosphatidylcholine (LysoPC), sphingomyelin (SM), and other metabolites. Its complex mode of action involves not just interacting with metabolites or gut microbiota individually, but also regulating the balance of the gut microbiota as a whole and the interaction with individual microorganisms (Gill et al., 2006). Dendrobium can not only improve the abundance of gut microbiota, but also increase the relative abundance of beneficial bacteria such as Prevotella/Akkermansia, and reduce the relative abundance of harmful bacteria such as S24-7/Rikenella/Escherichia coli, which may be associated with inflammation and insulin resistance. It also impacts the synthesis of fatty acids, such as SCFAs, which can modify lipid metabolism and lower dangerous levels of cholesterol and triglycerides while improving the barrier function of colonic epithelial cells and reducing inflammation (Li et al., 2018). However, there is no clinical research on a single herb Chinese medicine. These studies are still in the animal experimental stage, and clinical trials and applications are worth looking forward.