Uric acid (UA) is the end product of purine metabolism, catalyzed by xanthine oxidase (XOD), which is mainly expressed in the liver. In addition to XOD, blood uric acid levels are dynamically regulated by various transporters in the kidney and gut, as well as by some oxidants or nitric oxide (Gersch et al., 2008; Imaram et al., 2010). In human beings, a physiological level of uric acid (3–5 mg/dL) exists in the bloodstream in the form of soluble urates, while high concentrations of urates that exceed its solubility in the blood (serum uric acid >6.8 mg/dL) contribute to MSU crystalline deposits. Approximately two-thirds of uric acid excretion occurs through glomerular filtration and tubular reabsorption, which relies on urate transporter proteins in the kidneys, including URAT1 (encoded by the SLC22A12 gene), glucose transporter 9 (GLUT9, encoded by the SLC2A9 gene), and organic anion transporter 4 (OAT4, encoded by the SLC22A11 gene). Generally, serum uric acid (sUA) levels are modulated dynamically by two categories of transporters: urate reabsorption-promoting transporters (URAT1, GLUT9, sodium-dependent phosphate transporter protein 1 (NPT1), and NPT4 (Maiuolo et al., 2016), OAT4, OAT10, etc.) and urate excretion-promoting transporters (ABCG2, OAT1, OAT3, etc.). Benzbromarone and probenecid achieve uric acid-lowering function by inhibiting URAT1 and GLUT9, thereby increasing UA excretion (Figure 1). However, some clinical trials reported that 10% hyperuricemic patients treated with benzbromarone could not achieve satisfactory clinical outcomes with a standard therapeutic dose and duration, which might be attributed to its inhibition of OAT1 and ATP-binding cassette subfamily G member 2 (ABCG2). URAT1 facilitates the reabsorption of uric acid from the renal tubules to the tubular epithelial cells and then to the renal interstitium, thus elevating serum uric acid. Conversely, as urate reabsorption-promoting transporters, inhibition of OAT1 and ABCG2 might partially counteract urate-lowering effect of benzbromarone. Therefore, drug discovery targeting urate transporters with high selectivity has attracted significant attention in the pharmaceutical industry, and has been extensively reviewed in elsewhere (Hou et al., 2023; Shi et al., 2022).

Uric acid possesses both antioxidant and pro-oxidant properties (So and Thorens, 2010). It exists in the body in soluble form, as well as crystalline form. An imbalance in uric acid metabolism can result in severe kidney diseases. Research has shown that uric acid metabolism is closely linked to the development of renal disease. Notably, the role of the intestinal tract in the metabolism of purines and uric acid has been confirmed, as about one-third of uric acid is discharged by gut (Eckenstaler and Benndorf, 2021). This is achieved through three main approaches: one involves a serial of urate transporters in the gut, the second one is the direct involvement of the intestinal flora in the metabolic breakdown of purines and uric acid (Table 1), and the third involves metabolites such as short-chain fatty acids (e.g., acetate, butyrate) produced by intestinal bacteria provide energy to intestinal epithelial cells, supporting the excretion of uric acid. Currently, it is well-acknowledged that the uric acid transporters in the intestine include ABCG2, MRP2, MRP4, GLUT9, MCT9, NPT4, its homologs, OAT10, and YgfU (Xu et al., 2016). As a potent anti-hyperuricemic agent, most attention has been concentrated on the development of URAT1 inhibitors, such as dotinurad, epaminurad (URC-102) and XNW3009. In addition, ABP-671 (developed by New Elemental Pharmaceuticals) has emerged as a promising therapeutic candidate due to its concurrent inhibition of URAT1 and GLUT9, demonstrating synergistic dual-target inhibition of urate reabsorption. clinical trials have demonstrated a 30% improvement in urate-lowering efficacy compared to single-target agents, particularly in treatment-refractory populations (Dong et al., 2019). Recently, Granados et al. discovered a transport route from gut microbes to the liver, and then to kidney-mediated OAT1 transport for the gut-derived metabolites (e.g., indolyl sulfate, p-cresol sulfate, deoxycholate, etc.), indicating a central role for kidney urate transporters in modulating gut flora-dependent metabolism (Granados et al., 2023). Mechanistically, OAT1 plays a role in transporting uremic solutes or uremic toxins in the circulation by directly interacting with multiple gut-derived metabolites (Granados et al., 2023). Nevertheless, the specific role of urate transporters in modulating the intestinal microbiome and its metabolites needs further investigation to discover novel therapeutic strategies for delaying the progression of HN.

Escherichia coli and Aspergillus spp., which secrete XOD have been verified to catalyze purines into uric acid in the intestinal tract, thus reducing intestinal absorption of dietary purines (Crane et al., 2013). Yamada et al. (2016) discovered that Lactobacillus spp. regulate serum uric acid levels by uptaking and utilizing purines. The PICRUST analysis indicated that hyperuricaemia was associated with prominent alterations in gut microbiota involved in nucleotide and lipid metabolism. Allopurinol and benzbromarone exhibited uric acid-lowering potency by modulating microbial genera in hyperuricaemic rats, characterized by an increase of Bifidobacterium and a decrease of Adlercreutzia Anaerostipes (Yu Y. et al., 2018). Surprisingly, these two microbial genera have been confirmed to be closely related with the reduction of UA. Moreover, Spearman analysis showed a strong correlation between the increased in the genus Adlercreutzia and the trimethylamine-N-oxide (TMAO) levels in CKD patients with low glomerular filtration rates (GFRs, GFR < 7 mL/min/1.73 m²) (Xu et al., 2017), which could further exaggerate hyperuricaemia. Therefore, it can be speculated that intestinal flora-derived metabolites with nephrotoxic properties, such as TMAO, raise blood UA by injuring renal function (Yu Y. et al., 2018). However, beneficial intestinal flora indirectly moderate serum UA levels by producing small molecule metabolites, such as short-chain fatty acids (SCFAs), including butyrate, and propionate (Chu et al., 2021), etc. SCFAs have been proved to play a direct and indirect role in regulating metabolism, inflammation, immune response, and maintenance of mucosal barrier function (Mann et al., 2024). Growing evidence has demonstrated that gut-derived SCFAs, mainly produced by anaerobic bacilli, bifidobacteria, fungi, streptococci, and Lactobacillus, regulate host health through energy regulation, intestinal mucosal barrier, and immune regulation, which are involved in water-electrolyte homeostasis, oxidative stress and immuno-inflammatory responses in the gut. Previous studies have found that SCFAs could significantly reduce the serum uric acid levels in HUA mice induced by potassium oxonate and hypoxanthine. Moreover, SCFAs supplementation has a dose-dependent inhibitory effect on renal transporters, URAT1 and GLUT9, with the inhibitory effect of SCFAs on GLUT9 being reversible. Activating G protein-coupled receptors (GPCRs, such as GPR41 and GPR43) (Li Y. et al., 2022) and inhibiting the activity of histone deacetylase (HDACs) (Thomas and Denu, 2021), intestinal SCFAs might attenuate the immuno-inflammatory response of gut and other organs induced by hyperuricemia through activating GPCRs and PI3K/AKT/mTOR signaling (Zhao et al., 2018) pathways and weakening HDACs activity. However, the specific mechanism needs further investigation.

SUA has various effects on the kidney, including pathological and physiological processes such as renal arteriopathy, glomerulosclerosis, tubular injury, interstitial fibrosis, and tubular hypertrophy (Jing et al., 2020). Studies have reported that SUA can act as an antioxidant, scavenging unpaired oxygen, oxygen radicals, and peroxynitrite, as well as chelating transition metals. Its antioxidant capacity accounts for half of the total antioxidant capacity of human plasma (Kumar et al., 2015). As demonstrated, physiological concentrations of SUA inhibit the expression of TNF-α and IL-1β-induced inflammatory factors in primary porcine chondrocytes and exert a protective effect on cartilage in collagen-induced arthritis in mice (Lai et al., 2017). Interestingly, SUA exhibits pro-oxidant and pro-inflammatory properties in several studies (So and Thorens, 2010). SUA induces vascular endothelial injury, which is closely related to micro-inflammation, oxidative stress, and lipid metabolism disorders. Notably, the modeling concentration of uric acid used in vitro experiments reached 20 mg/dL (namely, 1,200 μmol/L) (Yin et al., 2019), which is much higher than the common pathological levels in hyperuricemic individuals. Therefore, it is suggested that the modeling conditions for hyperuricemia and HN should be consistent with the actual pathological situations.

Once inside the cells, SUA acts as a pro-oxidant molecule, activating fibrotic signaling pathways, including AMPK, ERK1/2, PI3K/Akt, JAK/STAT, NF-κB, and the NLRP3 inflammasome, which trigger oxidative stress and inflammatory responses in the kidney (Li K. et al., 2023). In addition to stimulating an increase in nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and reactive oxygen species (ROS) production (Sautin et al., 2007), low concentrations of supraphysiologic SUA act as a pro-oxidant, playing a role in renal pathophysiology. Studies have demonstrated that mild hyperuricemia in mice that underwent 5/6 nephrectomy, exhibited significant renal injury and inflammatory responses (Omizo et al., 2020). In contrast, febuxostat protected the kidneys from hyperuricemia, suggesting the protective role of a uric acid-lowering strategy targeting XOD in the kidneys. Given that hyperuricemic nephropathy is a progressive condition, the pro-oxidant and pro-inflammatory roles of SUA need to be clarified more specifically at different stages of CKD progression.

In clinical observations, MSU deposits can be detected by ultrasonography and dual-energy CT examination in the renal tissues and joints that have been affected. As a damage-associated molecular pattern (DAMP), MSU deposition activates a local immuno-inflammatory response, leading to the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome, which produces and releases active IL-1β and IL-18. This alteration initiates the amplification of the inflammatory cascade and profibrotic degeneration in the kidney, ultimately causing glomerular and tubular pathology (Mei et al., 2022). Notably, it has been found that MSU affects the binding of the uric acid transporter URAT1 to Numb, a protein that controls the endocytosis process (Wu et al., 2015), as well as OAT1 membrane endocytosis (Wu et al., 2016). This leads to elevated URAT1 expression and reduced OAT1 expression, which exacerbate the imbalance in urate metabolism, thereby deteriorating renal function. In addition, MSU promotes the apoptosis of kidney cells by inducing the production of reactive oxygen species, increasing nitric oxide synthase activity and mitochondrial caspase enzymes activity, as well as the activation of apoptosis-dependent signaling pathways (Choe et al., 2015), thus exacerbating kidney injury. It cannot be ignored that MSU accumulates in the urinary system, transforming from urate crystals into urate stones, which increases the risk of obstructive nephropathy, urinary tract infections, and kidney damage (Jiang C. et al., 2023). Therefore, it is generally believed that local immuno-inflammatory responses, renal fibrosis, apoptosis, and renal obstruction are responsible for the renal injury caused by MSU crystals.

Currently, the pathophysiological role of gut microbiota has been confirmed in various chronic kidney diseases. It has been discovered that patients with gout and hyperuricemia exhibit an imbalance in intestinal ecology, along with increased levels of harmful metabolites in the serum and intestines (Guo et al., 2016). The intrinsic barrier of the intestinal mucosa consists of intestinal epithelial cells, associated connective structures, and robust immunity. Intestinal epithelial cells protect the intestinal barrier by forming physical and biochemical barriers against pathogenic microorganisms, thus participating in the regulation of the mucosal immune system (Yang et al., 2023). When the intestinal barrier function is impaired, endotoxins released by pathogenic microorganisms enter the bloodstream from the intestinal tract, which tends to trigger a series of immune-inflammatory responses (Peterson and Artis, 2014) (Figure 2). Guo et al. (2019) discovered that hyperuricemic mice, in which the uric acid oxidase gene was knock out, showed intestinal barrier dysfunction, subsequent elevated intestinal permeability, and exacerbated renal dysfunction, presumably associated with uric acid-induced inflammatory responses. This suggests a close relationship between hyperuricemic-induced kidney insult and the disruption of intestinal immune barrier. Meanwhile, SUA upregulates the expression of urate transporters PDZK1 (PDZ domain-containing protein 1) and ABCG2 in HT-29 (human colon cancer cells) and Caco-2 cells (human colorectal adenocarcinoma cells) by activating the TLR4-NLRP3 inflammasome and PI3K/Akt signaling pathways, thereby promoting the excretion of uric acid in intestinal cells (Chen et al., 2018). Conversely, previous studies have considered the protective role of SUA in NSAID-induced enteropathy due to the antioxidant effect of uric acid. Yasutake et al. (Yasutake et al., 2017) demonstrated that the oral administration of uric acid and intraperitoneal injection of inosinic acid and potassium oxonate ameliorated NSAID-induced enteropathy in mice by decreasing oxidative stress, lipid peroxidation, and cytotoxicity induced by indomethacin. This implies the potential therapeutic role of SUA in inflammatory enteritis.

In addition to maintaining urate homeostasis by modulating urate transport-related proteins in the intestine, the gut macrobiotic communities and their metabolites affect hyperuricemia and HN progression by regulating “chronic low-grade inflammation” and activating pro-fibrotic signaling. In addition to its pro-inflammatory role in the progression of renal fibrosis, serum urate, together with pro-inflammatory cytokines and mediators, aggravates renal fibrosis via multiple signaling pathways, including PI3K/AKT/mTOR, MAPK/NF-κB-NLRP3 inflammasome, IL-6/JAK2/STAT3, TGF-β/SMAD3, and Wnt/β-catenin signaling pathways. More recently, the roles of pyroptosis, neutrophil extracellular traps formation (Wu et al., 2024), and ferroptosis (Li et al., 2024) in HN have been emphasized, suggesting novel potential approaches for treating progressive HN.

Hyperuricemic animals induced by high-fat and high-fructose diets and alcohol abuse exhibit a disordered gut microbiome, which parallels that seen in hyperuricemic and gouty patients (Zhang C. et al., 2022). The concept of the “gut-kidney axis” was introduced by Meijers et al., in 2011 (Meijers and Evenepoel, 2011), highlights the bidirectional relationship between the gut microbiota and kidney function. Moreover, insoluble fiber from diets and probiotic supplements attenuate renal injury and fibrosis induced by hyperuricemia by restoring the gut microbiota and SCFAs (Li Y. et al., 2022). Furthermore, a growing body of literature has demonstrated that strategies targeting the gut microbiota and inflammation can alleviate renal fibrosis in hyperuricemia (Lv et al., 2020; Pan et al., 2020). However, well-designed experiments are needed to distinguish whether alterations in the gut microbiota are a primary cause or secondary to hyperuricemia. Notably, the role of gut therapy in HN appears to change dynamically with disease progression and the individual differences of the patients. In patients with early-stage HN or those exhibiting compensatory enhancement of intestinal uric acid excretion, therapies targeting the gut microbiota (e.g., probiotics, fecal microbiota transplants) may serve as a core therapeutic strategy. These interventions aim to restore microbial imbalance and alleviate uric acid accumulation. Conversely, in cases of advanced renal impairment, a combined approach integrating renoprotective therapies with gut-targeted interventions may be required to optimize patient management. In summary, the relationship between the gut and the kidney influences the disease process by regulating urate metabolism and transport processes. Therefore, this paper summarizes single herb and TCM formulas that have dual-regulatory effects on both the gut and the kidney. This summary aims to develop new perspectives and research ideas for the clinical treatment of hyperuricemic nephropathy and the development of TCMs drugs.

The gut (about 30%) and the kidney (about 70%) are the main pathways for uric acid excretion. When renal function is impaired, intestinal excretion may be compensatorily increased and become a key pathway for lowering serum uric acid. On the one hand, the accumulation of toxins in the circulation induced by the renal dysfunction, leads to an imbalance in the intestinal flora. On the other hand, the alteration of intestinal flora leads to the release of a large number of toxic metabolites and endotoxin, activating the immune-inflammatory response and destroying the intestinal mucosal barrier. This, in turn, aggravates to the renal dysfunction in the hyperuricemia. Therefore, the multiple modulatory effects of TCMs on intestinal excretory capacity (e.g., inhibition of the intestinal urate transporter), the abundance of specific bacteria associated with purine and uric acid metabolism, and the disturbed intestinal flora composition may become an alternative therapeutic strategy for HN.

TCMs play a key role in increasing the beneficial intestinal flora, such as E. faecalis spp. and Bifidobacterium spp. etc., which aid in digestion and absorption, and stimulate the body’s immune function to protect health. It also regulates the neutral flora, such as L. spp., E. coli, Streptococcus spp. etc., which, if imbalanced, can lead to an increase in harmful substances and toxins, promoting aging. Additionally, it helps decrease harmful flora, such as A. spp. and Bacteriodesmus spp. etc., which can reduce intestinal infections (Li X. et al., 2021). Therefore, an imbalance in the intestinal flora may lead to abnormal purine metabolism and increased uric acid production, while microbial metabolites (such as SCFAs) may affect renal inflammation and fibrosis through the “gut-kidney axis.” Intervention of intestinal flora may reduce the source of uric acid and alleviate renal injury. Notably, for patients with significant gut microbiota dysbiosis (e.g., those with chronic inflammatory bowel disease or metabolic syndrome), the gut-kidney axis could be discussed as a central mechanism. In cases of advanced renal impairment, a combined approach integrating renoprotective therapies with gut-targeted interventions may be required to optimize patient management. Growing evidence has revealed that TCMs exhibit anti-HN potential via multi-target, multi-pathway, and multi-approach. Some animal experiments have shown that TCMs (e.g., Bining Decoction, Poria, Astragalus, etc.) can both inhibit uric acid production and restore the balance of intestinal flora, suggesting the centrality of intestinal therapy. However, the causal relationship between intestinal flora and HN is still unknown. Thus, it is suggested that the causative role of gut microorganism in the development and progression of HN should be investigated through the depletion of intestinal flora. Previously, Emal et al. (2017) depleted the intestinal microflora by applying antibiotics, treated with oral administration of faecal suspensions from healthy mice for 3 days, and subsequently established a mouse model of renal ischemia-reperfusion, and found that the intestinal flora exacerbated renal ischemia-reperfusion injury by modulating macrophage maturation and chemotaxis, while faecal transplantation attenuated the renal injury, suggesting that intestinal flora plays a central role in the progression of renal diseases. This provides a basis for targeting microorganisms in the treatment of renal diseases. However, the specific mechanism requires further exploration, especially to clarify the causal effect of specific gut flora (e.g., urease-producing bacteria) on the progression of HN, and to develop precise therapeutic strategies targeting to gut flora. Indeed, medicines targeting to the uric acid transporters in intestines and kidneys, as the crucial research hotspot of urate-lowering therapy, has also been widely studied. It has been confirmed that TCMs with regulatory activity on urate transporters in the intestine and kidney, such as Dendrobium officinalis Six Nostrum, Combination of Polyonum Cuspidatum and Ramulus Cinnamomi and Tongfengting, mainly achieve this potential by inhibiting URAT1 and upregulating ABCG2.

In general, the role of intestinal therapy in HN may show dynamic changes with the disease course and the individual differences of the patients. In the early stage, or in patients with compensatory enhancement of intestinal excretion, intestinal modulation may be regarded as a core tool for HN management. However, in cases of severely impaired renal function, the combination of renal-targeted therapy and intestinal-targeted therapy is required. What cannot be ignored is that the multi-targeting properties of TCMs (especially dual gut-kidney regulation) provide a theoretical basis for treating HN as a potential alternative intervention.

In fact, the treatment of HN with TCMs faces many dilemmas in transitioning from basic research to clinical application, such as the complexity of Chinese medicines’ components, insufficient bioavailability, and challenges in quality control. In the future, the application of emerging technologies in the research of TCMs will provide a new technical direction for the treatment of HN with TCMs. Especially in the current fermentation processes, both single-strain and multi-strain collaborative fermentation are utilized. These methods can promote the release of effective components from TCMs and the decomposition and transformation of toxic substances, and are gradually being applied to TCM fermentation (Li Q. Y. et al., 2021; Qu et al., 2023). For example, Wang et al. used Bacillus subtilis to ferment Astragalus membranaceus, thereby increasing the bioavailability of Astragalus polysaccharides. Mechanically, fermented Astragalus membranaceus significantly decreases serum UA levels and increases the abundance of butyrate-producing enzymes in HUA mice (Wang R. et al., 2023). In addition to single-flavored Chinese medicine, fermentation technology can also be applied to TCM formulas (Selvaraj and Gurumurthy, 2023). Luo et al. fermented Simiao Pill with compound bacterium agent consisting of Mucor enzymes, Saccharomyces cerevisiae, and lactic acid bacteria, and selected frankincense-associated bacteria as the strain for fermenting Simiao Pill, which was then used to treat HN mice. Oral treatment with fermented Simiao Pill exhibited superior anti-hyperuricemic activity, possibly due to the release of more active substances (Luo, 2024). However, the technology of fermenting Chinese herbal medicine also has limitations, such as unclear mechanisms, a low degree of industrialization, and unstable safety, necessitating further research.

In recent years, with the development of nanotechnology, the “nanotization” of TCMs has brought new ideas for the innovative research of TCMs, improving the oral bioavailability and tissue targeting of active ingredients, thus promoting the transformation of TCMs from basic research to bedside application. For instance, exosomes or exosome-like nanovesicles derived from herbal medicines, as natural nano-preparations (Dad et al., 2021), have been confirmed to exhibit potent anti-inflammatory, antioxidant, immune-regulatory activities (Chen et al., 2021), as well as anti-inflammatory bowel disease (IBD) effects (Li D. et al., 2023). Besides, due to their small size, strong penetration and resistance to acid, alkali, and high temperature, plant-derived exosomes or exosome-like nanovesicles are ideal carriers for drug delivery (Kim et al., 2022). To address the low aqueous solubility and non-selective toxicity of Shikonin, Matias Cardoso et al. designed a self-assembled hyaluronic acid-zein nanogel loaded with Shikonin, which selectively inhibited LPS- and nigericin-induced activation of the macrophage NLPR3 inflammasome. In short, the application of nanoagents in the field of TCMs opens up new avenues for the treatment of HN. By improving the physical and chemical properties, biological activity, and targetability of TCMs, nanotechnology significantly promotes the clinical transformation of novel TCMs drugs in the future. Nevertheless, there is insufficient evidence on the safety of nanomaterials applied to humans, as well as regulatory policies, which should be given more attention.

At present, the research on the treatment of HN through the intestinal tract is still in the initial stage. Therefore, it is necessary to further strengthen the research to determine the optimal treatment strategy, including the regulation of intestinal flora, dosage, and duration of treatment, and other related issues, and to evaluate the effectiveness and safety of HN treatments through large-sample, multi-center studies, further clarifying the mechanisms by which intestinal therapy plays a role in the treatment of uric acid nephropathy. By combining genomics, metabolomics and spatial transcriptomics, we can systematically analyze the composition of intestinal flora, the targets of active ingredient, and the specific effect on multiple renal cell types modulated by TCMs. This approach helps to clarify the regulatory mechanisms of TCMs against HN. For instance, single-cell sequencing technology enables in-depth analysis of the effects of herbal medicines on specific cellular subpopulations, as well as the modulatory effect of TCMs on the multiple signaling pathways in the HN kidney. Particular attention is given to the origin of myofibroblasts and fibroblasts, such as EMT, macrophage-to-myofibroblast transition (MMT), etc. In the future, artificial intelligence will be applied to clinical data analysis to integrate multi-omics data (genomics, metabolomics, and microbiomics) with electronic health records. This integration aims to develop personalized TCMs treatment plans that optimize therapeutic efficacy and minimize adverse effects (Medicine, 2024).

Overall, TCM formulas and single herb that have a dual-regulatory effect on the intestine and kidneys in HN treatment, as a novel therapeutic approach, hold good prospects for preventing or alleviating the progression of kidney disease secondary to hyperuricemia. With the integration of multiple disciplines and the application of emerging technologies, further advancements will be achieved in the research of anti-HN TCMs in the future.