The Role of the Intestinal Microbiome in the Pathogenesis and Treatment of Hyperuricemia: A Review

ABSTRACT

Hyperuricemia (HUA), characterized by elevated blood uric acid (UA) levels, is a major risk factor for gout, UA nephropathy, metabolic syndrome, and other related disorders. Traditional drug therapy for HUA includes medications (e.g., allopurinol and febuxostat) and dietary changes; however, it is limited and may be accompanied by adverse side effects such as allergies, prompting the investigation of alternative therapeutic approaches. Although the newly researched “in‐situ graft polymerization” protein drug modification technology and the emerging gut microbiota transplantation technology have demonstrated innovation in regulating blood UA, they still need to overcome bottlenecks in immunogenicity, individual variability, and formulation technology. Recent research has highlighted the potential of modulating the intestinal microbiome as a promising strategy for managing HUA. Nevertheless, the mechanism by which different intestinal microbiomes affect HUA pathogenesis remains unclear. To bridge this gap, this review firstly outlines the characteristics and prevailing conditions of HUA, followed by the current status of treatment. Besides, this review integrates the findings from clinical trials and animal studies to explore in depth the pathogenic mechanisms of HUA and the potential roles and regulatory pathways of the gut microbiota in mitigating HUA. The gut microbiota act as multi‐functional factors that affect HUA by reducing UA production, enhancing purine metabolism, influencing amino acid transport, and increasing UA excretion. This review addresses critical gaps in the extant literature regarding microbiota‐mediated UA homeostasis and provides new perspectives for the future treatment of HUA.

This review summarizes the characteristics, prevalence, and treatment strategies of hyperuricemia, and subsequently examines its pathogenic mechanisms together with the potential roles and regulatory pathways of the gut microbiota in its alleviation. It seeks to address gaps in current knowledge of microbiota‐mediated uric acid homeostasis and to provide new perspectives for future therapeutic approaches to hyperuricemia.

1. Introduction

Hyperuricemia (HUA) is a common metabolic disorder characterized by abnormally high concentrations of uric acid (UA) in the blood (Galozzi et al. 2021). The prevalence of HUA has shown an increasing trend worldwide over the past decades (Dong et al. 2025). According to WHO data, 20%–30% of adults worldwide suffer from HUA to varying degrees, which poses a significant public health burden. This condition often arises from an imbalance in UA metabolism, leading to excessive production and impaired excretion. HUA can result in immediate symptoms, such as gouty arthritis, and increase the risk of kidney stones, chronic kidney disease, and cardiovascular disease. Effective management of HUA is crucial to prevent complications such as gout attacks, nephrolithiasis, and chronic kidney disease, and maintain overall health (Dong et al. 2025; Du, Zong, et al. ²⁰²⁴). Currently, the primary treatments for HUA involve drug therapy and dietary changes; however, some medications used in treatment have been associated with risks such as liver and kidney toxicity, as well as other adverse events (Bardin and Richette 2017; Nielsen et al. ²⁰¹⁸). Representative drugs such as allopurinol and febuxostat may cause serious adverse skin reactions, including diseases such as Stevens‐Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Therefore, further investigation into the underlying mechanisms of HUA and the search for more natural, effective, and safer therapeutic options has become an urgent priority.

The gut microbiota is now recognized as a functional “vital organ” owing to its multidimensional connectivity with other body systems. This interconnectedness, referred to as the gut microbiota axis, underlies critical interactions between the host and its microbes via neural, endocrine, humoral, immune, and metabolic signaling pathways (Afzaal et al. 2022). Most human gut microorganisms are harmless and maintain mutually beneficial relationships with the host, contributing significantly to immune defense against pathogens (Bai et al. 2024; Li et al. ²⁰²²). The gut microbiota has been linked to numerous health conditions, including modulating immunity, mental disorders (like anxiety and depression), cardiovascular and metabolic diseases (such as hypertension, obesity, diabetes, and phlegm‐dampness constitution), as well as inflammatory bowel diseases and cancer (Chen, Wang, et al. ²⁰²³; Li et al. ²⁰²⁵; Yan et al. ²⁰²⁵; Zeng et al. ²⁰²⁴; Zhu et al. ²⁰²²). In metabolic diseases such as type 2 diabetes, obesity, and non‐alcoholic fatty liver disease, natural compounds and microbiota‐targeted therapies have demonstrated unique value (Li et al. 2021). Probiotics, prebiotics, and dietary interventions optimize the composition of gut microbiota, promote the production of short‐chain fatty acids (SCFAs), enhance intestinal barrier function, and reduce endotoxin release (Li et al. 2021). These mechanisms collectively regulate metabolic processes and alleviate inflammation, thus offering novel pathways for the prevention and treatment of metabolic diseases.

In recent years, research has indicated that patients with HUA often exhibit gut microbiome dysbiosis, which is commonly defined as a decrease in microbial diversity, an absence of beneficial microbes, or the presence of potentially harmful microorganisms, and that intestinal microorganisms play a significant role in the pathogenesis of HUA (Cao et al. 2023; Kasahara et al. ²⁰²³; Winter and Baumler ²⁰²³; Xie et al. ²⁰²²). The limitations of traditional therapeutic approaches have prompted researchers to turn their attention to emerging areas, among which the interaction between the gut microbiota and host metabolism has become a focus of research in recent years. Increasing evidence suggests that the gut microbiota plays a key role in the development of various metabolic diseases, providing a new perspective for exploring the pathogenesis and developing therapeutic strategies for HUA. Approximately 25% of UA is excreted into the intestine, where it is metabolized by the gut microbiome (e.g., Lactobacillus, Bifidobacterium) (Chu et al. 2021; Yin et al. ²⁰²²). These intestinal microorganisms can indirectly influence UA solubility and excretion efficiency by regulating the intestinal environment (e.g., pH and redox potential) or by acting synergistically with other flora. As a result, many studies are now focusing on the intestinal tract as a critical target for reducing UA levels by regulating the metabolism of the gut microbiome (Meng et al. 2023; Yamada et al. ²⁰¹⁷).

In this paper, we describe the pathogenesis of HUA and the mechanisms through which the gut microbiome plays a therapeutic role, on the basis of an extensive review of the related literature. It provides a theoretical foundation for further research in this area and offers a new perspective on the future treatment of HUA.

2. Characteristics and Prevailing Conditions of HUA

HUA is a common chronic metabolic disorder that is associated with increased production and/or decreased excretion of UA. UA is a metabolic byproduct in the human body. Under normal conditions, the body effectively excretes UA through the kidneys and intestinal pathways. The latter accounts for around a third of total UA excretion, and maintaining UA concentrations within a reasonable range (Crawley et al. 2022; Jin et al. ²⁰¹²) (Male: 208–428 μmol/L, Female: 149–357 μmol/L). In recent years, the incidence of HUA has increased rapidly because of changes in people's dietary habits and a reduction in physical labor. However, factors such as dietary imbalances, reduced kidney function, and genetic influences can lead to an imbalance in UA production or elimination. This imbalance can result in abnormally high levels of UA in the blood, known as HUA (Fasting serum UA levels > 420 μmol/L (7.0 mg/dL) on two different days). The complex interplay between UA production and excretion is a crucial factor in the pathogenesis of HUA. The development of HUA is frequently accompanied by the presence of concomitant pathological conditions (Yang et al. 2022, 2017). Prolonged elevated blood UA levels have been demonstrated to result in the deposition of urate in joints, ankles, and other distal joints of the limbs (Wrigley et al. 2020; Yang et al. ²⁰¹⁷; Zhen and Gui ²⁰¹⁷). The global emergence of HUA as a significant health concern has been well documented.

2.1. Characteristics of HUA

HUA is a metabolic disorder characterized by abnormally high blood UA levels. The WHO defines HUA as having fasting serum UA levels exceeding 420 μmol/L (7.0 mg/dL) twice on different days (Wang et al. 2020). The deposition of sodium urate crystals caused by excess UA is the main pathomechanism of gout disease, potentially leading to joint deformity, stiffness, and even kidney damage or uremia (Shan et al. 2021). Over 80% of the UA in the body is produced from endogenous purine metabolism, primarily from nucleic acids such as adenine and guanine released by damaged or dead cells. The remaining 20% comes from exogenous purines synthesized in the liver and intestine (Jung et al. 2020).

Most mammals (such as dogs, cats, and pigs) possess uricase, which helps maintain their low baseline UA levels. Evolutionarily, humans lack uricase, the enzyme responsible for breaking down UA; this evolutionary loss exacerbates UA accumulation. As a result, UA cannot be metabolized into soluble and easily cleared allantoins. The kidney serves as the primary route for UA excretion, with two‐thirds being excreted via the renal pathway and one‐third through the intestine (Esche et al. 2020). Impaired glomerular filtration, enhanced tubular reabsorption, suppressed tubular secretion, and increased urate crystal deposition can all lead to reduced UA excretion, contributing to HUA. The related pathogenesis is summarized in Figure 1 (Esche et al. 2020; Jung et al. ²⁰²⁰; Lu et al. ²⁰¹⁹). Furthermore, when UA crystals are recognized by the immune system as a foreign body, they activate neutrophils, macrophages, and other immune cells, prompting them to release pro‐inflammatory cytokines, such as interleukin‐1 beta (IL‐1β) and tumor necrosis factor‐alpha (TNF‐alpha), which triggers a strong inflammatory response, resulting in local redness, swelling, and pain; symptoms, and persistent inflammation and abnormal immune response may further aggravate tissue damage and promote disease progression (Li, Yuan, et al. ²⁰²³; Wilson and Saseen ²⁰¹⁶). The persistent inflammation and abnormal immune response may further aggravate tissue damage and promote disease progression (Li, Yuan, et al. ²⁰²³).

FIGURE 1.

Pathogenesis mechanism of hyperuricemia.

2.2. The Current Status of Treatment of HUA

HUA is a potential predisposing factor for a wide range of severe health conditions, including cardiovascular disease, metabolic syndrome, hypertension, diabetes mellitus, and chronic kidney disease (Vareldzis et al. 2024; Yanai et al. ²⁰²¹). In addition to these cardiometabolic disorders, HUA is considered a definite predisposing factor for the development of gout and urolithiasis (kidney stones) (Ichida et al. 2012). Emerging evidence also suggests that HUA may be potentially associated with osteoarthritis, contributing to joint inflammation and cartilage damage (Hisatome et al. 2018; Zhu et al. ²⁰²⁰). Furthermore, HUA has been linked to the impairment of vascular endothelial cell function, which can lead to compromised blood flow and cardiovascular complications (Zhen and Gui 2017). The far‐reaching negative health impacts of HUA highlight the importance of careful management and monitoring of UA levels. Elevated UA levels associated with HUA can have systemic effects, predisposing individuals to various severe cardiometabolic, musculoskeletal, and vascular disorders. Proactive interventions to address HUA are crucial to mitigate these substantial health risks.

The causes of HUA can be categorized into three main types: excessive UA production, inadequate UA excretion, and a combination of both (Lima et al. 2015). The concentration of UA in the blood is determined by the balance between the purine content of the diet and the body's synthesis and excretion of UA. However, an excessive increase in UA synthesis or insufficient UA excretion can lead to elevated serum UA levels, resulting in HUA (Giordano et al. 2015). Factors contributing to increased UA production or decreased UA excretion include obesity, genetic factors, deficiencies in key enzymes involved in purine metabolism, such as phosphoribosyl pyrophosphate (PRPP) synthetase and adenosine deaminase (ADA), enhanced purine oxidase activity, and abnormal expression of urate transporter proteins such as URAT1, GLUT9, and ABCG2 (Hamada et al. 2008; Han et al. ²⁰¹⁸; Kolz et al. ²⁰⁰⁹; Li et al. ²⁰²⁰; Maiuolo et al. ²⁰²³; Yano et al. ²⁰¹⁴).

Current therapeutic approaches for lowering UA levels can be broadly categorized into two strategies: reducing UA production and promoting UA excretion. Reduced UA production can be achieved with xanthine oxidase (XOD) inhibitors such as allopurinol or febuxostat, which block the conversion of purine precursors to UA. Dietary modifications, such as limiting the intake of purine‐rich foods (animal livers, some seafood, and so on), can also help lower UA levels. Methods to enhance UA excretion include supplementation with UA oxidase to convert UA into more soluble allantoin and the use of drugs such as probenecid, benzbromarone, and sulfinpyrazone to stimulate renal UA transporters and promote urinary UA excretion (Martens et al. 2020; Matsuo et al. ²⁰²⁰).

However, these therapeutic approaches have limitations and potential adverse effects. A randomized, double‐blind, non‐inferiority trial enrolled 940 patients with gout, who received either allopurinol or febuxostat in combination with anti‐inflammatory prophylaxis. The results showed that both medications demonstrated similar efficacy in controlling gout flares, lowering serum UA levels, and ensuring overall safety (O'Dell et al. ²⁰²²). Singh et al. conducted a propensity‐matched analysis using U.S. Medicare data involving over 23,000 elderly gout patients and found that febuxostat was associated with a significantly higher risk of atrial fibrillation (HR = 1.25), especially at the 80 mg dose during the first 6 months of treatment (Singh and Cleveland 2019). Kang et al. (2021) performed a propensity score–matched cohort study including 124,434 newly diagnosed gout patients and reported a higher incidence of cardiovascular events and all‐cause mortality with allopurinol compared to benzbromarone (HR = 1.22 and 1.66, respectively) (Kang et al. 2021). Moreover, benzbromarone may pose hepatotoxicity risks (Dalbeth et al. 2019). Although these pharmacological strategies are effective in reducing UA, their long‐term safety and consistency across populations remain uncertain, often constrained by limited mechanistic understanding and a lack of standardized treatment protocols. Therefore, there is a need to explore novel, non‐toxic, and efficient approaches for managing HUA.

Recent research has highlighted the gut microbiome as a potential target for managing HUA. Alterations in the composition and function of gut microbiota have been shown to influence serum UA levels and metabolic pathways relevant to HUA. Recent advances suggest that modulation of the gut microbiome could represent a promising new therapeutic strategy, warranting further investigation into the underlying mechanisms and clinical applications.

3. Mechanism of UA Action In Vivo

UA is the terminal metabolite of purine degradation in humans. Approximately 80% of UA is produced through the metabolism of purines within the body, whereas the remaining 20% comes from the consumption of purine‐rich foods (Pan et al. 2020). Additionally, some studies have indicated that hepatic amino acids can also contribute to purine production via the de novo synthesis pathway, thereby promoting UA generation. UA is primarily produced in the liver, intestines, muscles, endothelium, and kidneys, and is excreted through the kidneys and intestines (Jalal et al. 2013). Figure 2 illustrates the mechanism of UA production in the human body. The process starts with ribose 5‐phosphate and ATP combining via PRPP synthetase to form PRPP. PRPP undergoes reactions to generate inosine monophosphate (IMP), which interconverts with adenosine monophosphate (AMP) and guanosine monophosphate (GMP) (Ames et al. 1981; Stewart et al. ²⁰¹⁹; Waring ²⁰⁰²). AMP is converted to IMP and adenosine by 5′‐nucleotidase (5′NT); adenosine becomes inosine via ADA (Waring et al. 2001). GMP is converted to guanosine by nucleotidase and purine nucleotide phosphorylase (Frei et al. 1989; Simic and Jovanovic ¹⁹⁸⁹).

FIGURE 2.

Production pathways of UA in the body.

Conversely, it has been demonstrated that UA is an antioxidant only in hydrophilic environments and may function as a pro‐inflammatory factor involved in the generation of intracellular oxidants through nicotinamide adenine dinucleotide oxidase‐dependent pathways. This process potentially leads to oxidative stress and induces dysfunction in mitochondria, the endothelium, proximal renal tubules, and other tissues (Choi et al. 2014; Sautin and Johnson ²⁰⁰⁸; Xiao et al. ²⁰¹⁵). Furthermore, UA may be linked to altered nitric oxide release in the endothelium and changes in acetylcholine‐induced vasodilation (Waring et al. 2000). When UA levels exceed the physiological range, as seen in HUA, the body's antioxidant capacity becomes overwhelmed. A recent high‐impact review points out that high UA can mediate the innate immune response. It activates the NLRP3 inflammasome, leading to the maturation and release of interleukin‐1β (IL‐1β), which in turn triggers a robust inflammatory reaction. Moreover, in the process of XOR‐mediated UA production, a large amount of reactive oxygen species (ROS) is generated. Excessive ROS can react with UA, further promoting oxidative stress and inflammation (Du, Zong, et al. ²⁰²⁴).

The roles of UA as both an oxidant and an antioxidant are not fully understood and remain under investigation. However, it is well documented that persistently elevated UA levels above the physiological range are associated with the development of several conditions, such as gout, urinary calculi, and kidney stones (Frei et al. 1989; Yamanaka ²⁰¹¹). Overall, UA exhibits a dual nature, exerting both protective and harmful effects within the body. Further studies are needed to clarify the mechanisms underlying these effects, including studies on microbiome‐mediated modulation of UA's redox activity and to determine the physiological balance between its oxidative and antioxidant activities.

There are close interactions between the UA metabolic pathway and the enzymes and metabolites of intestinal microorganisms (Wang et al. 2022). Enzymes produced by intestinal microorganisms (e.g., enzymes involved in purine metabolism) can directly affect the catabolism of UA precursor substances, whereas their metabolites, SCFAs, indirectly contribute to the metabolism of UA by modulating the function of the intestinal barrier and the state of systemic inflammation (Wang and Ye 2024). In addition, xanthine oxidase inhibitors of microbial origin can inhibit the activity of key enzymes of UA production and thus regulate the metabolic homeostasis of the UA pathway (Rao et al. 2024), and these interactions provide new perspectives for understanding the mechanism of UA metabolic disorder.

4. Pathogenic Mechanisms of HUA

Genetic and dietary factors significantly influence HUA. Genetic factors play an important role in the development of HUA, and if there is a family history of the condition, the risk of developing it increases. Dietary habits are also an important cause of HUA. Excessive intake of purine‐rich foods (e.g., visceral foods, seafood, and red meat), sugary drinks, and alcohol promotes UA production and interferes with UA excretion, resulting in elevated blood UA levels.

Genetic factors lay the foundational framework of gut microbiota composition through gene polymorphisms (such as ABCG2 gene variants), whereas dietary components like high‐purine and high‐fat diets dynamically reshape microbial structure (e.g., increasing the abundance of urate‐producing bacteria). These two factors collectively influence UA metabolism by regulating microbial metabolic activity, impacting UA production and excretion. Meanwhile, genetically determined activities of UA‐metabolizing enzymes (e.g., xanthine oxidase) synergize with diet‐induced microbial metabolites (e.g., SCFAs and phenols) to alter key enzymatic activities in UA metabolic pathways and amplify disease risks via the inflammation–oxidative stress network, making genetically susceptible individuals more prone to gout, metabolic syndrome, and other diseases under specific dietary exposure.

4.1. Genetic Factors

Genetic predispositions play a key role in the development of HUA and gout. Early studies identified several rare single‐gene disorders, such as deficiencies in enzymes involved in purine metabolism and abnormalities in the renal transport of UA, which can lead to severe HUA and gout. Although these single‐gene disorders are uncommon, they provide important insights into the molecular mechanisms regulating UA metabolism. In recent years, large‐scale genome‐wide association studies (GWAS) have identified several common gene loci associated with serum UA levels and gout susceptibility. The most important of these include SLC2A9, ABCG2, and SLC22A12, which encode renal and intestinal UA transport proteins (Merriman and Dalbeth 2011). Variations in these genes regulate the uptake and secretion of UA in the kidneys, thereby affecting serum UA concentrations and consequently altering the risk of gout development in individuals. It has been found that variants in these UA‐related genes account for approximately 3%–5% of the variation in serum UA levels.

In addition to genes directly related to UA metabolism, a GWAS identified a few loci related to energy metabolism, inflammation, and other processes, which may also affect UA metabolism and gout development through indirect mechanisms. This suggests that UA metabolism is a complex process involving the coordinated regulation of multiple physiological systems (Tin et al. 2019). However, the variation in serum UA levels explained by these genetic factors is too small to be used alone for gout risk prediction. Furthermore, UA‐related genetic variants were not significantly associated with cardiovascular outcomes, suggesting that serum UA levels may not be an independent risk factor for cardiovascular disease (Martinez‐Quintana et al. ²⁰¹⁶). In addition, specific HLA genes are associated with severe hydroxypurine reactivity, which can be used to screen for and prevent adverse drug reactions. This provides new ideas for the individualization of UA‐lowering therapies.

Overall, the findings from GWAS studies have improved our understanding of the genetic basis of UA metabolism and gout. However, further research is required to fully elucidate the complex mechanisms involved and to develop more effective and personalized treatment approaches. Kolz et al. (2009) conducted a meta‐analysis of 14 GWAS involving 28,141 individuals of European descent. The study identified 954 significantly associated SNPs across nine genetic loci, including five novel loci: SLC22A11, SLC16A9, GCKR, LRRC16A, and the region near PDZK1. Previously known UA–associated genes such as SLC2A9, ABCG2, SLC17A1, and SLC22A12 were also validated. These newly identified loci reveal novel biological pathways related to UA metabolism. Notably, the minor allele of SLC2A9 rs734553 was more strongly associated with UA reduction in females, whereas ABCG2 rs2231142 significantly increased serum UA levels in males. Additionally, the SLC16A9 rs12356193 variant was strongly correlated with the levels of DL‐carnitine and propionylcarnitine—two metabolites closely associated with serum UA—suggesting a complex role in urate regulation. Overall, this study not only expands our understanding of the genetic regulation of UA metabolism but also highlights solute transporters as promising therapeutic targets for HUA and gout, providing new directions for future mechanistic studies and drug development. Using a GWAS, Tin et al. (Köttgen et al. 2013) identified 18 new genetic loci associated with serum UA concentrations in European and Asian populations. These loci are involved in various biological processes, such as UA transport, renal function, and inflammation regulation, providing important insights into the genetic basis of UA metabolism regulation. Vitart et al. (Li et al. 2007) found that the UA transporter protein encoded by SLC2A9 plays a key role in UA metabolism and that polymorphisms in SLC2A9 can significantly affect serum UA levels, thereby increasing the risk of developing HUA and gout. Köttgen et al. (Major et al. 2018) identified 18 new loci associated with serum UA levels through a large‐scale genomic association analysis, providing important clues for exploring the role of genetic factors in the pathogenesis of HUA. Yerlikaya et al. (2017) demonstrated that GLUT9 is an important genetic factor in the regulation of serum UA levels and that polymorphisms in GLUT9 are significantly associated with the development of HUA.

Genetic factors play an important role in the pathogenesis of HUA and gout, and GWAS have revealed several key genes that regulate UA metabolism, providing new insights into the pathogenesis of this disease. However, the clinical application of GWAS must be further explored because of large individual differences. The future of precision medicine requires a comprehensive assessment and intervention that takes both genetic and environmental factors into account. Building on this foundation, future efforts may explore personalized risk assessment on the basis of genetic susceptibility to optimize the management of HUA. In addition, targeted interventions aimed at regulating specific functional gene variants could offer more precise and sustained therapeutic options for high‐risk individuals. The advancement of these strategies is expected to facilitate a shift in HUA treatment from traditional symptom‐based approaches to mechanism‐driven, personalized precision interventions.

4.2. Dietary Factors

In recent years, driven by changes in dietary habits and lifestyle, the incidence of HUA has been steadily increasing (Cao et al. 2017). Studies have shown that diets high in fructose, purines (such as those found in animal offal, red meat, and seafood), and fats can directly cause a marked increase in the levels of UA, urea nitrogen, and creatinine, as well as the production of inflammation in the body. These dietary factors can also directly alter the composition of intestinal microorganisms, such as decreasing the proportion of probiotic bacteria like Lactobacillus and Bifidobacterium, whereas significantly increasing the proportion of pathogenic bacteria. This shift leads to the accumulation of UA, reduced excretion, and increased XOD activity, thereby exacerbating HUA symptoms, thus exacerbating the symptoms of HUA. Fructose intake elevates xanthine oxidase (XOD) activity through hepatic fructokinase‐mediated ATP depletion, which accelerates purine degradation and converts xanthine dehydrogenase to XOD, thereby enhancing UA production and reactive oxygen species (ROS) generation. Concomitantly, fructose‐induced ROS and UA trigger inflammasome activation (e.g., NLRP3) and NF‐κB signaling, promoting the release of pro‐inflammatory cytokines (TNF‐α, IL‐6) and exacerbating systemic low‐grade inflammation via gut‐liver axis disruption or direct hepatic stress responses. Additionally, HUA can worsen gut microbiome disorders and UA levels, creating a vicious cycle (Massy and Drueke 2021; Zmora et al. ²⁰¹⁹). UA accumulation exacerbates intestinal dysbiosis by inducing gut inflammation, disrupting intestinal barrier integrity, or altering gut pH, thereby promoting the overgrowth of pro‐inflammatory microbiota and inhibiting the metabolic activity of beneficial bacteria. This imbalanced state further drives the progression of metabolic disorders like insulin resistance, lipid metabolism dysfunction, and obesity by reducing the production of protective metabolites (e.g., SCFAs), triggering endotoxemia, or activating systemic oxidative stress pathways (Massy and Drueke 2021; Zmora et al. ²⁰¹⁹).

Diet is a key factor influencing the structure and function of gastrointestinal microorganisms, which can alter their diversity and result in changes to microbial metabolites (Nakagawa et al. 2019; Vedder et al. ²⁰¹⁹). This effect worsens over time. Therefore, avoiding long‐term intake of HUA‐inducing foods, such as sweets, seafood, and fried foods (Figure 3), represents a feasible strategy to prevent elevated UA levels and intestinal dysfunction. Specific foods, such as dairy products, cherries, and celery, can help relieve HUA symptoms (Chen, Luo, et al. ²⁰²³; Luyun et al. ²⁰¹⁸). Furthermore, dietary recommendations for managing HUA should be developed within a broader public health framework, especially in the context of the rising global burden of metabolic disorders. Policy guidance, nutrition education, and environmental interventions should be employed to promote healthy eating patterns across the population, thereby reducing the incidence of HUA and related metabolic disturbances.

FIGURE 3.

Mechanism of action of probiotics in reducing UA through the liver and intestine.

4.2.1. High‐Sugar Diet

Fructose, the sweetest natural sugar, is widely used in foods such as soft drinks, fruit juices, and baked goods. When fructose is absorbed by the small intestine and metabolized in the liver, a large amount of ATP is consumed during catabolism. This process depletes ATP and produces excess AMP, which then degrades into hypoxanthine (Yamada and Sherman 1981). Hypoxanthine is further broken down into metabolic intermediates such as UA and lactic acid, leading to abnormally high blood UA levels (Figure 2) (Park et al. 2017; Zhang, Li, et al. ²⁰²⁰). The catabolism of fructose also induces metabolic stress, inflammatory responses, and endothelial dysfunction, which can contribute to the development of metabolic diseases, including HUA, diabetes mellitus, obesity, and atherosclerosis (Ebrahimpour‐Koujan et al. ²⁰²⁰).

In recent years, fructose intake has increased annually, and there is a positive correlation between fructose consumption and the incidence of HUA in the population (Do et al. 2018; Silva et al. ²⁰¹⁸; Zhang, Bian, et al. ²⁰²⁰). Massy and Drueke (2021) found that a high‐fructose diet can significantly reduce intestinal microbial diversity in a short time, increasing the abundance of Firmicutes and decreasing the abundance of Mycobacterium avium , which further decreases the content of SCFAs in the gut. Additionally, a high‐fructose diet induces an “endotoxemic state” in the host, leading to chronic inflammation. Similarly, Do et al. (Sun et al. 2010) found that in mice fed a high‐fructose diet, gut microbial diversity was reduced, with a lower proportion of Mycobacterium species and a significantly higher proportion of Aspergillus species. Silva et al. (Yu et al. 2013) showed that fructose‐fed groups had increased production of bile acids and taurine compared to normal mice, which induced metabolic disturbances in the host and further compromised the integrity of the intestinal barrier. In conclusion, managing fructose intake may help restore gut microbiome balance and reduce HUA incidence. However, some studies have found no significant relationship between a high‐fructose diet and the incidence of HUA. Global consumption of high‐fructose diets exhibits significant regional variations: North America is dominated by high‐fructose corn syrup with large consumption volumes; Europe, constrained by policies, favors sucrose; Asia sees rapid growth with distinct local characteristics; and the Middle East features a coexistence of traditional high‐fructose foods and industrial beverages. These differences are closely linked to economic development, food industries, policies, and cultural practices. For example, Sun et al. (2020) analyzed data from the American Health and Nutrition Examination Survey (AHANES) database from 1999 to 2004 and found no correlation between a high‐fructose diet and the prevalence of HUA in healthy populations. Yu et al. (2018) also found that the metabolic characteristics of high‐fructose corn syrup and sucrose intake were similar, with a lower urinary tract temperature than that of high‐fructose corn syrup. Furthermore, the metabolic characteristics of high‐fructose corn syrup and sucrose intake in healthy humans were similar, and UA levels did not significantly differ. An acute fructose challenge study found that individuals carrying specific SNPs experienced a more significant increase in serum uric acid levels after consuming a high‐fructose beverage, indicating that genetic polymorphisms play a role in short‐term urate metabolism (Zhang, Mass, et al. ²⁰²²). Therefore, the relationship between fructose and HUA may be influenced by differences in research samples and the diversity of fructose sources. The “individualized” interference of population characteristics, manifesting in differences in health baselines, regional lifestyle patterns, and genetic backgrounds, leads to divergent UA metabolic responses to fructose across populations. In terms of fructose source diversity, natural fructose—coexisting with components like dietary fiber—exerts weaker metabolic impacts, whereas processed fructose, because of its high dosage and synergistic effects with other ingredients, more readily elevates UA levels. Therefore, further research is needed to determine whether a high‐fructose diet is likely to induce HUA.

4.2.2. High‐Purine Diet

Purines are natural substances found in nearly all foods, and their content and type significantly influence UA levels. The intake of foods with high purine content, such as seafood, meat, and alcoholic beverages, increases the nucleic acids in the body, leading to excessive levels of the metabolite UA, which contributes to the development of HUA (Liu et al. 2020). This can also alter the structure and diversity of the gut microbiome. Huang et al. (Sheng‐Nan et al. ²⁰¹⁵) found that feeding quail high‐purine feed made by mixing ordinary feed with 15 g/kg dried yeast powder induced HUA and changed the structure of the quail's gut microbiome. They also discovered that the contents of intestinal flora metabolites, such as lipopolysaccharides (LPSs) and XOD, were positively correlated with blood UA levels. Therefore, the intake of high‐purine foods can contribute to the development of HUA not only by increasing UA levels but also by modifying the gut microbiome composition.

Cao et al. (2017) found that in a mouse model of diet‐induced HUA, excessive nucleic acid intake caused elevated UA levels, which subsequently altered the structure and diversity of the gut microbiome. Similarly, Liu et al. (2020) established a rat model of high‐purine diet‐induced HUA and used 16S rDNA sequencing to analyze changes in intestinal microorganisms, identifying Vallitalea, Christensenella, and Insolitispirillum as being correlated with HUA. To further explore the role of intestinal bacteria in high‐purine‐induced HUA, the intestinal microorganisms Bifidobacterium and Lactobacillus in mice were analyzed through 16S rDNA sequencing. Additionally, fecal microbiota transplants from hyperuricemic rats to normal rats were performed to compare UA levels. The results revealed that fecal microbiota from hyperuricemic rats caused a significant increase in UA levels in recipient rats, indicating that the gut microbiota plays an important role in HUA induced by a high‐purine diet. Moreover, individual genetic differences can influence serum uric acid levels following purine intake. A large‐scale prospective study on the basis of the Korean KoGES‐HEXA cohort (44,053 participants) systematically evaluated the association between red and processed meat consumption and the risk of developing HUA. The results showed that among individuals with high genetic risk, higher intake of red and processed meat was associated with a significantly increased risk of HUA, with relative risks of 2.72 for men and 3.28 for women. These findings suggest a significant interaction between dietary factors and genetic susceptibility.

4.2.3. High‐Fat Diet

Long‐term intake of high‐fat foods can increase UA levels and induce HUA. Yu et al. (2018) found that feeding rats a high‐fat diet containing 10% yeast extract for 6 weeks successfully induced HUA, leading to changes in the gut microbiome. The changes observed in Anabaena and Bifidobacterium species were consistent with findings by Guo et al. (2016). Additionally, Hsu et al. (2019) showed that rats on high‐fat diets had significantly higher body weights and UA levels compared to those on regular diets, with Lactobacillus plantarum GKM3 potentially reducing UA levels by altering the intestinal microflora composition. Sun et al. (2020) observed that C57BL/6 mice fed a long‐term high‐fat diet developed proteinuria, increased blood urea nitrogen and creatinine, kidney dysfunction, and increased tubular cell apoptosis. These findings indicate that a high‐fructose, high‐creatinine, and high‐fat diet is associated with proteinuria, creatinine accumulation, renal dysfunction, and increased apoptosis of renal tubular cells. Therefore, limiting high‐fat diet intake can help prevent HUA. A high‐fat diet can induce obesity, trigger insulin resistance, and impair renal UA excretion. Meanwhile, fatty acids and inflammatory cytokines secreted by adipocytes activate hepatic xanthine oxidase, promoting UA synthesis. Recent studies indicate that saturated fats may indirectly elevate UA by exacerbating metabolic disorders and inflammatory responses, whereas unsaturated fats might exert positive effects on UA regulation by improving the metabolic microenvironment—though specific mechanisms require further validation.

5. Overview of Gut Microbiome

The intestinal flora consists of a diverse array of microorganisms that colonize the human gut and play an essential role in regulating energy and metabolism (Tran et al. 2015). Structural changes or imbalances in the gut microbiome can lead to metabolic disorders (Ding et al. 2022; Li, Li, et al. ²⁰²³; Shen et al. ²⁰²⁴). The use of the intestinal microbiome as an entry point to explore the pathogenesis of diseases has become a new area of focus, particularly for metabolism‐related conditions, such as easing the symptoms of irritable bowel syndrome and HUA (Angelucci et al. 2019; Bian et al. ²⁰²⁰; Liu et al. ²⁰²⁰; Xie et al. ²⁰²³).

According to the gut–renal axis theory, dysbiosis damages the intestinal barrier, leading to increased intestinal permeability. This allows various toxins to enter the bloodstream and reach the kidneys, potentially triggering inflammation (Nakai et al. 2006). Recent studies have found that this inflammation can affect the expression of UA transporter proteins, which may lead to increased serum UA levels. Additionally, changes in the gut microbiome have been shown to directly influence UA metabolism. An extensive literature review has revealed that modulating the structure of the gut microbiome may have a therapeutic effect on HUA (Nomura et al. 2013).

6. The Relationship Between Intestinal Microbes and HUA

HUA, a disorder in purine metabolism, is often associated with elevated levels of pro‐inflammatory factors, oxidative stress, and dysregulation of the intestinal microbiome (Xu et al. 2019; Yu et al. ²⁰¹⁸). Emerging research has demonstrated that the ecological imbalance of the gut microbiome is closely linked to HUA. The intestine plays a critical role in the excretion of UA, accounting for one‐third of its elimination (Shao et al. 2017). Additionally, resident gut microorganisms are essential in metabolizing the UA secreted into the intestine. The gut microbiome also produces metabolites, such as SCFAs, that can influence host metabolism and overall health. Long‐term consumption of high‐fructose, high‐purine, and high‐fat foods alters the structure and composition of the intestinal microbiome, which in turn affects the gut's role in purine and UA metabolism and excretion, leading to elevated blood UA levels (Xu et al. 2019). Conversely, elevated UA levels can induce chronic inflammation in the body and intestinal tract, changing the internal environment and further affecting the composition and abundance of the gut microbial community. This creates a bidirectional and mutually reinforcing relationship between the intestinal microbiome and HUA.

Interestingly, certain bacterial genera that increase in hyperuricemic animal models may correlate positively with higher blood UA levels. This suggests that targeted modulation of the gut microbiome may be a promising therapeutic strategy for managing HUA and related metabolic disorders. In patients with gout, Guo et al. (2016) observed an increased abundance of Enterococcus faecalis and E. xylanolytica, whereas Bifidobacterium pusillus and B. pseudostreptococcus were significantly reduced. In contrast, Bifidobacterium pusillus and Bifidobacterium pseudostreptococcus were found in lower abundance by 16S rDNA sequencing. Shao et al. (2017) analyzed 26 fecal samples from patients with gout using nuclear magnetic resonance hydrogen spectrometry and high‐throughput sequencing. They discovered that the diversity of fecal flora was significantly reduced in gout patients compared to healthy individuals, whereas pathogenic bacterial taxa such as Mycobacterium spp., Zygomonas spp., and Anaerobic cordyceps. were significantly more abundant. For more information on the characteristics of the gut microbiome in patients with HUA, refer to Table 1.

TABLE 1.

Characteristics of intestinal microbiome in the hyperuricemia organism.

Study design	Contributing factor	Characterization of intestinal microorganisms	Causality (correlation vs. causation)	References
Human	Gout	Mycobacterium spp., Zygomonas spp., and Anaerobic cordyceps were significantly more abundant	Correlation	Shao et al. (2017)
Human	Gout	Bacteroides caccae and Bacteroides xylanisolvens are enriched, yet Faecalibacterium prausnitzii and Bifidobacterium pseudocatenulatum are depleted	Correlation	Guo et al. (2016)
Animal (wistar rat)	10% yeast extract for high‐fat feeds	There was a significant decrease in the genera Prevotella, Extremophilic archaea, and Lactobacillus; and an increase in the number of Aspergillus spp. that can secrete xanthine dehydrogenase to convert purines to uric acid	Correlation	Hsu et al. (2019)
Animal (wistar rats)	Yeast feeds and a high‐purine diet	Vallitalea, Christensenella, and Insolitispirillum were enriched	Causation (Fecal microbiota transplantation)	Liu et al. (2020)
Animal (c57BL/6 rat)	Uox‐KO mice	After co‐housing with Uox‐KO mice, the abundance of Ileibacterium, Anaerotruncus, and Roseburia significantly increased in the wild‐type mice	Causation (co‐housing experiment)	Song et al. (2022)
Animal (quails)	Yeast feed	There were changes in the abundance of Mycobacterium anisopliae, Mycobacterium thickum, and Mycobacterium anisopliae and inflammatory changes in the cecum tissue	Correlation	Agus et al. (2021)

In summary, the gut microbiome is related to the pathogenesis of HUA and may become a new target for the alleviation and treatment of HUA and related diseases in the future. With continuous advancements in research on the relationship between HUA and gut microbiome, its pathogenesis has been further elucidated, and the characterization of gut microbiome has emerged as a new target for treatment strategies. Armour et al. (2019) studied 2000 human fecal flora samples and found that changes in α‐diversity, β‐diversity, and β‐dispersity were specifically correlated with rheumatoid arthritis. They constructed a regression model on the basis of changes in microbial function, which accurately differentiated the disease from other conditions. This approach could offer a new diagnostic method for diagnosing patients with HUA or gout on the basis of differences in fecal microbiota composition. This emerging evidence underscores the therapeutic promise of microbiota‐targeted interventions, such as probiotics, dietary modulation, and fecal microbiota transplantation (FMT). This suggests that, in the future, microbiota‐based biomarkers may be developed as non‐invasive tools for early diagnosis or risk stratification of HUA and gout. Moreover, integrating gut microbiome profiling into personalized treatment strategies may open new avenues for precision medicine approaches targeting metabolic disorders.

7. Mechanisms of Action of Gut Microbiome in Alleviating HUA

The gut microbiome may alleviate HUA by restoring intestinal microbial diversity and directly acting on intestinal epithelial cells or producing metabolic byproducts to promote the expression of tight junction proteins (e.g., ZO‐1 and occludin). Elevated levels of tight junction proteins help inhibit the transmission of endotoxins and inflammatory factors within the intestinal tract, thereby reducing the inflammatory response (Liang et al. 2022; Singh et al. ²⁰²⁴). Relevant studies have shown that SCFAs produced by gut microbiome can inhibit XOD activity, SCFAs produced by gut microbiota primarily inhibit xanthine oxidase (XOD) activity through indirect mechanisms, including regulating the inflammation‐oxidative stress axis, reprogramming metabolic pathways, activating antioxidant networks, and synergistically reducing XOD‐activating substrates and pro‐inflammatory signals via microbiota‐host interactions, suggesting that modulating the microbiome to increase SCFA production could lower UA levels. Studies have also shown that probiotics can effectively reduce UA levels in patients with HUA by regulating the gut microbiome (Table 2).

TABLE 2.

Studies on the mechanism of action of probiotics in alleviating hyperuricemia.

Mechanism	Probiotics	Action effect	References
Inhibit the activity of XOD	109 CFU/mL Lactobacillus plantarum UA149	Decreased serum UA levels	Cao, Liu, et al. (2022)
	5 × 109 CFU/mL Lactobacillus rhamnosus CCFM1130, CCFM1131, and Lactobacillus royale CCFM1132	The XOD activity and UA levels in the liver and serum of hyperuricemia mice were significantly decreased	Xu et al. (2022)
	3 × 109 CFU/mL Lactobacillus paracasei MJM60396	Reduced XOD activity by 81%	Kilstrup et al. (2005)
	Lactobacillus paracasei X11 and Lactobacillus plantarum Q7	Decreased XOD and ADA levels	Lee et al. (2022), Ma et al. (2016)
Promote purine degradation or metabolism	Lactobacillus gasseri PA‐3	Through the uptake and degradation of inosine, guanosine, and adenosine in the gut as well as the uptake of IMP, GMP, and AMP	Stow and Bronk (1993), Yamada et al. (2018)
	109 CFU/kg/day Lactobacillus DM9218	Degradation rate of nucleotides and nucleosides	Wang et al. (2019)
	Lactobacillus shortcombicus DM9218	Absorption of inosine and guanosine reduces UA	Buzard et al. (1952)
Repair the gut barrier and regulate the gut microbiota	108 CFU Lactobacillus fermentum JL‐3	Improve the structure and function of gut microbiome and maintain a stable state of intestinal microbial community	Wu et al. (2021)
	Lactobacillus paracasei MJM60396	Increases the expression of ZO‐1 in intestinal epithelium and blocks and protects the intestinal barrier	Yamada et al. (2016)
	Lactobacillus rhamnosus GG produced soluble proteins p40 (0.1–1.0 μg/mL), and p75 (0.1–1.0 μg/mL)	Repair the damage caused by hydrogen peroxide to the barrier function and tight junction function of Caco‐2 cells	Seth et al. (2008)
	2 × 108 CFU Akkermansia muciniphila	The expression of intestinal compact junction proteins claudin, occluding and ZO‐1 increased by 70.35%, 179.16% and 155.02%, respectively, which reduced intestinal permeability	Zhang, Liu, et al. (2022), Zhang, Mass, et al. (2022)
Accelerate UA excretion	Lactobacillus paracasei MJM60396	Increased the expression of kidney urate excretion transporters OAT1 mRNA and OAT3 mRNA, and decreased the expression of urate reabsorption proteins URAT1 mRNA and GLUT9 mRNA	Yamada et al. (2016)
	1 × 108 CFU/mL Lactobacillus rhamnosus Fmb14	It inhibited the expression level of URAT1 in the kidney and promoted the expression of ABCG2 in the colon	Zhao, Jiang, et al. (2022), Zhao, Chen, et al. (2022)
	Lactobacillus plantarum Dad‐13, Lactobacillus plantarum Mut‐7, and Lactobacillus casei OL‐5	Up‐regulated ABCG2 gene expression and accelerated uric acid excretion	Handayani et al. (2018)

Furthermore, the intestinal microbiome influences the renal excretion of UA. As shown in Figure 4, the gut microbiome can inhibit the expression of GLUT9 and URAT1 transporter proteins in renal proximal tubular cells, which are responsible for UA reabsorption (Arakawa et al. 2020). Conversely, the gut microbiome can promote the expression of transporters such as ABCG2, OAT1, and OAT3, which facilitate UA excretion (Zhao, Jiang, et al. ²⁰²²). This helps inhibit the reabsorption of urate by proximal renal tubular cells, promoting its elimination from the body. Additionally, the intestinal microbiome enhances UA excretion by promoting the expression of ABCG2 in the intestinal area and inhibiting the expression of GLUT9, further supporting its role in lowering UA levels (Mancikova et al. 2016).

FIGURE 4.

Mechanism of action of probiotics in reducing UA through the renal tubule.

7.1. Inhibition of XOD Activity

XOD is a key enzyme in UA synthesis, catalyzing the oxidation of hypoxanthine to xanthine, and then to UA. The intestinal microbiome plays an important role in alleviating HUA through its ability to inhibit UA production, leading to a reduction in UA levels. As illustrated in Figure 3, the proposed mechanism involves the gut microbiome inhibiting the activity of XOD, a key enzyme in the UA production pathway, thereby reducing UA synthesis. Furthermore, intestinal microbes may directly absorb, utilize, or degrade purine analogs, such as nucleotides, nucleosides, and purine bases within the gut, preventing their absorption by intestinal epithelial cells (Du, Wang, et al. ²⁰²⁴; Wei et al. ²⁰²²).

Inhibition of XOD activity is a proven method to reduce serum UA levels. Certain inflammatory factors or endotoxins, including LPSs and superoxide anions, can stimulate and increase XOD activity (Cao, Liu, et al. ²⁰²²; Ishii et al. ²⁰¹⁴). Interestingly, some probiotic strains have been shown to inhibit UA production by improving intestinal barrier function and reducing LPS permeability, which in turn affects XOD expression and activity. For example, L. plantarum UA149, when administered to rats with HUA, significantly decreased XOD content and UA production, leading to lower serum UA levels. Similarly, Lactobacillus rhamnosus CCFM1130, CCFM1131, and Lactobacillus royale CCFM1132 were found to significantly reduce XOD activity and UA levels in the liver and serum of mice with HUA (Xu et al. 2022). Oral administration of Bifidobacterium bifidum also significantly inhibited the increase in XOD activity induced by UV irradiation in mice, possibly by reducing hydrogen peroxide production and oxidative damage (Cao, Bu, et al. ²⁰²²). Other probiotic strains, such as Lactobacillus paracasei X11 and L. plantarum Q7, have demonstrated the ability to decrease both XOD and ADA levels in mice (Lee et al. 2022; Ma et al. ²⁰¹⁶). L. paracasei MJM60396 was shown to reduce XOD activity by 81% (Kilstrup et al. 2005). In a 2‐month randomized, double‐blind, placebo‐controlled clinical trial, 160 patients with gout received febuxostat in combination with either a daily dose of 3 × 10¹⁰ CFU of a multi‐strain probiotic powder (containing Lactobacillus paracasei Zhang, L. plantarum P‐8, L. rhamnosus Probio‐M9, Bifidobacterium lactis Probio‐M8, and B. lactis V9) or a placebo. The probiotic group showed a significant reduction in serum uric acid levels and a lower frequency of acute gout flares compared to the placebo group. However, only about half of the participants responded positively to probiotic intervention, as evidenced by reductions in serum UA, gout flare rate, and XOD levels. In contrast, non‐responders showed no significant difference from the placebo group, suggesting that individual responses may be closely linked to baseline gut microbiota composition (Zhao et al. 2024). Although some clinical studies have observed the adjunctive effects of probiotics in lowering serum uric acid levels among gout patients, their efficacy in individuals with hyperuricemia (HUA) remains insufficiently validated. Future large‐scale, long‐term prospective studies specifically targeting the HUA population are needed to clarify the clinical value of probiotic interventions.

Current studies focus on probiotics' ability to inhibit XOD activity and expression, as this can effectively reduce UA generation (Liu et al. 2024). Unlike drug therapy, probiotic interventions offer a gentle, side‐effect‐free treatment for HUA. The variability in probiotic efficacy and strain‐specific responses may lead to inconsistent individual reactions to the same strain, with the effectiveness of a specific strain potentially hindered by host factors like gut microbiota composition, metabolic status, and environmental influences, thus limiting universal applicability. Although the specific mechanisms by which probiotics inhibit XOD are still under investigation, their metabolites seem to play a key role. Further research in this area may lead to the development of novel probiotic‐based approaches for managing HUA and related metabolic disorders.

7.2. Degradation and Absorption of Purines in the Intestine

Purines in the human body exist mainly as purine nucleotides, purine nucleosides, and purine bases. Because of the absence of the uricase gene in humans, purine material is ultimately excreted from the body as UA. During purine metabolism, purine nucleotides are converted into purine nucleosides by nucleosidases, and purine nucleosides are converted into purine bases by purine nucleoside phosphorylase. These bases are then transformed into xanthines by XOD or ADA, and subsequently oxidized to UA by XOD (Cheng et al. 2022; Wei et al. ²⁰²²). Therefore, the degradation and uptake of purines by probiotics represents an important area of research for reducing UA levels. It has been demonstrated that some lactic acid bacteria can utilize purines, reducing intestinal absorption and, consequently, UA production (Yamada et al. 2016, 2017).

For instance, L. paracasei MJM60396 and Lactobacillus formosanus MJM60662 showed 100% degradation of inosine, guanosine, and adenosine in vitro, with the former also achieving 100% degradation of these compounds in lysates. Lactobacillus gasseri PA‐3 can reduce UA production by uptaking and degrading inosine, guanosine, and adenosine in the intestine, as well as by uptaking IMP, GMP, and AMP, thereby reducing the intestinal absorption of these and related purines in rats and exerting a UA‐lowering effect (Huang et al. 1993; Salati et al. ¹⁹⁸⁴; Yamada et al. ²⁰¹⁸). This strain has also been found to utilize nucleosides directly, which supports its UA‐lowering potential in the humans' intestinal tract (Kuo et al. 2021; Li et al. ²⁰¹⁴). In a randomized, double‐blind, placebo‐controlled clinical trial, researchers evaluated the uric acid‐lowering effect of yogurt containing Lactobacillus gasseri PA‐3 in patients with HUA and/or gout. A total of 88 participants were enrolled, with the intervention group consuming probiotic yogurt daily for 12 weeks. The results showed a significant reduction in serum UA levels in the intervention group compared to the placebo group, with no serious adverse events observed (Yamanaka et al. 2019). In vitro studies have shown that Ligilactobacillus salivarius CECT 30632 can completely degrade inosine (100%) and guanosine (100%), and partially degrade uric acid (50%). A subsequent randomized, double‐blind, placebo‐controlled pilot clinical trial evaluated the effects of this probiotic strain in patients with HUA and gout. The results demonstrated that oral administration of the probiotic for 6 consecutive months significantly reduced serum UA levels and the frequency of gout attacks, with no serious adverse events reported (Rodriguez et al. 2023). These findings indicate good safety and tolerability, providing preliminary clinical evidence supporting the potential application of probiotics in HUA management.

Several strains such as Lactobacillus DM9218, Lactobacillus Royce TSR332, and Lactobacillus fermentum TSF331 have been shown to produce nucleoside hydrolases, which can degrade purine substances in food and reduce their intestinal absorption, thereby lowering serum UA levels (Wang et al. 2019). Li et al. (Vitetta and Gobe 2013) investigated the UA‐lowering effect of Lactobacillus DM9218, isolated from Chinese kimchi, and found that it was able to compete with rat intestinal epithelial cells for nucleosides in food. The cell‐free extract of this bacterium was able to degrade nucleosides, which was hypothesized to occur through purine nucleosidase activity, thus reducing UA levels. Wang et al. (2019) identified the inosine hydrolase gene in Lactobacillus shortcombicus DM9218 and expressed it in Escherichia coli . These results demonstrated that the modified E. coli had the ability to degrade inosine, further supporting the potential of probiotics in managing UA levels.

Therefore, probiotics can absorb nucleosides by competing with intestinal epithelial cells and degrade purine substances in the human intestinal tract by utilizing self‐produced purine nucleosidase. This process reduces the nucleoside content in the intestinal tract and inhibits the intestinal absorption of nucleosides, ultimately leading to a reduction in UA levels. Such competitive and enzymatic actions suggest a promising microbial mechanism for mitigating purine load and managing HUA.

7.3. Regulation of Gut Microbiome Homeostasis and Restoration of the Intestinal Barrier

The gut microbiota constitutes the largest and most complex micro‐ecological community within the human body, playing an indispensable role in preserving host health and physiological balance (Ma et al. 2019; Xiong et al. ²⁰²²). This intricate system comprises more than 1500 microbial species, including not only bacteria but also viruses and other microorganisms. The intestinal barrier, meanwhile, serves as a multifaceted defense mechanism, safeguarding the gastrointestinal tract from both endogenous and exogenous threats. It consists of physical, chemical, immune, and microbial elements, each performing distinct protective functions. Any disruption of the gut barrier has been associated with the onset of a range of diseases, such as irritable bowel syndrome, nonalcoholic fatty liver disease (NAFLD), type 2 diabetes, insulin resistance, and inflammatory bowel diseases (Chang et al. 2025; König et al. ²⁰¹⁶; Turner ²⁰⁰⁹). The integrity and composition of gut microbiota are intimately linked to barrier function and the progression of these disorders. A balanced microbial community helps inhibit pathogenic invasion and translocation, enhances mucosal barrier strength, and limits toxin uptake, thereby contributing to intestinal health (Paolella et al. 2014). Furthermore, it supports immune function by stimulating the secretion of antimicrobial agents (Mills et al. 2019). Conversely, an imbalance in the gut microbiota, known as dysbiosis and 111, has been demonstrated to increase vulnerability to hypertension, gastrointestinal disorders, cardiovascular and metabolic diseases, as well as neuropsychiatric conditions such as anxiety, depression, and even cancer (Afzaal et al. 2022).

The functional balance of gut microbiome not only supports barrier integrity but also profoundly influences the host's metabolism of a wide range of endogenous compounds, including UA. One‐third of UA in the human body is excreted through the intestine and is influenced by the composition of the gut microbiota (Yin et al. 2022). Research has shown that maintaining or restoring a healthy microbiota can help modulate UA levels, partly through the action of specific enzymes such as urease and allantoinase produced by certain gut microbes. These enzymatic processes convert UA into metabolites that are more easily utilized or excreted by the host (Han et al. 2020; Méndez‐Salazar and Martínez‐Nava ²⁰²²; Ramazzina et al. ²⁰¹⁰; Wu et al. ²⁰²¹). Therefore, strategies that regulate the balance of the gut microbiota not only help restore the intestinal barrier but also play a critical role in the management of metabolic processes and in preventing an accumulation of metabolic waste products.

Transplantation of feces from HUA rats into normal rats resulted in a significant increase in serum UA levels in the normal rats, along with marked changes in the diversity and abundance of the gut microbiome in the HUA rats (Cheng et al. 2022). This suggests a potential link between gut microbiome and HUA. Microbiomic studies comparing the fecal flora characteristics of patients with gout and healthy individuals have shown that gout patients have lower flora abundance and diversity, with a significant increase in pathogenic bacteria such as S. danielsii and Corynebacterium. In a study of fecal transplants in HUA mice, it was found that fecal transplants restored the abundance of genera like those of thick‐walled bacteria, those of Bacteroidetes, and Aspergillus, demonstrating the modulatory effect of gut microbiome on HUA (Han et al. 2020). L. paracasei X11 increased the abundance of Faecalibaculum in the intestines of HUA mice, reduced the relative abundance of Bacteroides and Aspergillus species, and restored the normal Firmicutes‐to‐Bacteroidetes ratio to Bacteroides abundance. L. fermentum JL‐3 improved the structural and functional alterations of the gut microbiome in mice induced by UA, maintaining a stable state of the intestinal microbial community, which helped alleviate HUA (Wu et al. 2021). Additionally, a macrogenomic analysis of fecal samples from gout patients and healthy individuals showed that the abundance of SCFA‐producing strains was higher in healthy individuals than in patients with gout (Cheng et al. 2022; Yuan et al. ²⁰²²). The ethical feasibility of FMT for human HUA requires rigorous donor screening, long‐term risk monitoring, and informed consent, whereas clinical feasibility is constrained by the lack of standardized protocols, host microbiota heterogeneity, and competition with existing therapies. Although animal studies demonstrate its potential to modulate the microbiota, human application must address ethical concerns about the irreversibility of microecological intervention and validate therapeutic consistency and cost‐effectiveness in clinical trials.

HUA is also associated with intestinal permeability. Excessive intake of fructose has been shown to inhibit the expression of intestinal tight junction proteins, leading to dysregulation of the gut microbiome. This triggers inflammation and increases intestinal permeability, allowing inflammatory factors and toxic metabolites, such as LPS, to pass from the intestinal lumen into the portal vein. This can activate inflammatory factors and trigger related inflammation (Cho et al. 2021; Softic et al. ²⁰¹⁸). Lv et al. (2020) found that HUA mice exhibited pro‐inflammatory effects because of dysregulated intestinal immunity and suggested that the combined disruption of intestinal immunity and intestinal ecology impaired the intestinal barrier, allowing microorganisms to enter from the circulatory system. Therefore, it is inferred from animal models that gut flora and gut barrier are closely related to HUA.

Treatment with L. paracasei MJM60396 significantly increased the expression of intestinal epithelial ZO‐1 and occludin, thereby protecting the intestinal barrier (Yamada et al. 2016). Lactobacillus species have been shown to promote tight junction protein expression and activate the Toll‐like receptor 2 signaling pathway (Karczewski et al. 2010). Furthermore, L. rhamnosus GG was found to produce P40 and P75 soluble proteins, repairing the damage to tight junction function and barrier integrity in Caco‐2 cells caused by hydrogen peroxide through the mitogen‐activated protein kinase pathway. This intervention reduced UA permeability and attenuated inflammatory responses (Seth et al. 2008). After intervention with Akkermansia muciniphila , the expression of intestinal tight junction proteins—claudin, occludin, and ZO‐1—was significantly increased by 70.35%, 179.16%, and 155.02%, respectively, compared to the model group mice. Additionally, after pasteurization of A. muciniphila , the expression of these proteins increased by 56.48%, 93.52%, and 66.09%, further reducing intestinal permeability and inhibiting the permeability of inflammatory factors (Zhang, Liu, et al. ²⁰²²).

These studies indicate that probiotics can regulate UA levels by modulating the diversity of the gut microbiome, adjusting the ratio of the gut microbiome, and repairing the intestinal barrier in HUA animals. Probiotics have the potential to serve as the basis for the early diagnosis of HUA, and a better understanding of the relationship between the gut microbiome and HUA can provide a theoretical foundation for the dietary treatment of HUA. However, further research is needed to investigate the underlying mechanisms by which probiotics regulate the gut microbiome and repair the intestinal barrier to reduce UA levels.

7.4. Impact on UA Excretion

Transporter proteins, such as OAT1, OAT3, multidrug resistance protein (MRP) 2, MRP4, nicotinate phosphoribosyl transferase 1, ABCG2, and others, have not yet been fully identified in relation to UA excretion (Table 3) (Lu et al. 2017). The effect of probiotics on UA excretion has not been fully explored. However, research suggests that probiotics may affect UA excretion by influencing the expression of urate transporters, promoting the expression of urate excretion transporter proteins, and inhibiting the expression of urate reabsorption proteins. Additionally, probiotics may directly degrade UA, converting it into more soluble substances such as allantoin, which facilitates increased UA excretion and reduced serum UA levels (Zhang et al. 2021).

TABLE 3.

The role of transfer proteins.

Protein	Primary expression site	Role in uric acid handling	References
Organic Anion Transporter 1 (OAT1)	Kidney proximal tubule (basolateral membrane of tubular epithelial cells)	Uptakes urate from blood (interstitium) into renal tubular cells via urate–dicarboxylate exchange, facilitating urate secretion into the urine. Knockout of OAT1 in mice modestly reduces urate excretion, indicating its role in renal urate secretion	Sun et al. (2021)
Organic Anion Transporter 3 (OAT3)	Kidney proximal tubule (basolateral membrane); also in other tissues (e.g., choroid plexus) at lower levels	Functions similarly to OAT1, mediating uptake of urate (and other organic anions) from blood into renal proximal tubule cells in exchange for dicarboxylates. By importing urate into the cell, OAT3 enables subsequent apical efflux into urine. OAT3 knockout also slightly decreases urate excretion, confirming its role in net urate secretion	Sun et al. (2021)
Multidrug Resistance–Associated Protein 2 (MRP2)	Liver hepatocytes (canalicular membrane) and intestinal enterocytes (brush border); also in the kidney proximal tubule (apical brush‐border membrane)	ATP‐dependent efflux pump for organic anions. MRP2 can transport conjugated anions (e.g., bilirubin glucuronides, drug metabolites) into bile or urine. In vitro studies show MRP2 can transport urate, suggesting it may contribute to urate excretion into bile or urine. However, in vivo, its role in renal urate secretion appears limited or redundant (no clear decrease in urate excretion has been observed with MRP2 dysfunction)	Chai et al. (2015), Chung and Kim (2021)
Multidrug Resistance–Associated Protein 4 (MRP4)	Kidney proximal tubule (apical membrane); also in other tissues (e.g., apical membrane of colon, liver, and blood–brain barrier)	An ATP‐driven efflux transporter that exports urate and other organic anions across the apical membrane. MRP4 in the renal tubule cells pumps urate into the urine, acting as a unidirectional urate efflux pump for urinary excretion. It likewise may contribute to intestinal secretion of urate. In vitro, human MRP4 transports urate (and cyclic nucleotides, drug metabolites, etc.) efficiently. In MRP4‐deficient mice, urinary urate export is diminished (though compensatory mechanisms exist)	Benn et al. (2018), Tanner et al. (2017)
ATPBinding Cassette G2 (ABCG2)	Intestinal epithelium (apical membrane, especially colon) and kidney proximal tubule (apical lumenal membrane). Also expressed in other barrier tissues: e.g., liver canalicular membrane, placental syncytiotrophoblast, blood–brain barrier	High‐capacity urate exporter that actively secretes uric acid out of cells. In the gut, ABCG2 mediates direct intestinal excretion of urate into feces (accounting for a significant fraction of urate elimination). In the kidney, ABCG2 on proximal tubule cells transports urate into the urine (complementing renal secretion). ABCG2 thus provides an alternative route for uric acid disposal (“extrarenal” excretion via intestine) and works in tandem with renal transporters to prevent urate accumulation	Benn et al. (2018), Eckenstaler and Benndorf (2021)
Glucose Transporter 9 (GLUT9)	Primarily expressed in the liver and kidney, especially abundant in the epithelial cells of the renal proximal tubules	Functions as a basolateral uric acid efflux transporter in proximal tubular cells, transporting intracellular uric acid into the blood, thus mediating uric acid reabsorption. Kidney‐specific deletion of GLUT9 leads to increased uric acid excretion and elevated urine UA/creatinine ratio	Auberson et al. (2018), Chung and Kim (2021)
Urate Transporter 1 (URAT1)	Primarily expressed in the epithelial cells of the renal proximal tubules. It is localized on the apical brush border membrane of these cells and serves as one of the main transporters responsible for uric acid reabsorption in the renal tubules	URAT1 mediates the reabsorption of filtered uric acid from the tubular lumen into cells via an organic anion/uric acid exchange mechanism. It is the predominant transporter on the apical side of the proximal tubule. Loss of URAT1 impairs uric acid reabsorption, leading to increased urinary uric acid excretion. URAT1 and GLUT9 work synergistically—URAT1 is localized apically, and GLUT9 basolaterally—together facilitating the transport of uric acid from the urine back into the bloodstream	Chung and Kim (2021), Halperin Kuhns and Woodward (2021)

An increasing number of probiotic strains, which are able to regulate host metabolism and prevent chronic diseases without harmful side effects, have been characterized (Kuo et al. 2021; Li et al. ²⁰²²). For instance, the probiotic Lactobacillus ingluviei has been shown to influence UA excretion by affecting the expression of ABCG2, a UA transporter protein; Lactobacillus ingluviei is informative in its mechanistic studies (Angelakis et al. 2012). L. rhamnosus BFE5264 and L. plantarum NR74 upregulated the expression of ABCG1 and ATP‐binding cassette subfamily A member 1 at the cellular level (Yoon et al. 2013). Pasteurization of A. muciniphila resulted in a 63.84% and 72.81% reduction in the expression of URAT1 and GLUT9, respectively, and a 146.17% increase in the expression of ABCG2 (Zhang, Liu, et al. ²⁰²²). L. paracasei MJM60396 was also found to significantly increase the expression of urate excretion transporter proteins OAT1 mRNA and OAT3 mRNA while decreasing the expression of urate reabsorption proteins URAT1 mRNA and GLUT9 mRNA in the kidneys of mice, thereby enhancing UA excretion (Lee et al. 2022; Yamada et al. ²⁰¹⁶). Similarly, L. rhamnosus Fmb14 inhibited the expression of URAT1 in the kidney and promoted the expression of ABCG2 in the colon (Zhao, Chen, et al. ²⁰²²).

Yasiri and Seubsasana (2020) found that L. fermentum SF121 directly degraded UA, facilitating its excretion and decreasing the activity of XOD, collectively lowering serum UA levels in mice. Additionally, L. fermentum JL‐3 was found to directly degrade UA, as its byproducts contained allantoin, suggesting that this bacterium may produce uricase. L. plantarum Dad‐13, L. plantarum Mut‐7, and Lactobacillus casei OL‐5 produce urease, which maintains activity under appropriate environmental conditions (Fadda et al. 2010; Handayani et al. ²⁰¹⁸). However, it is important to note that humans naturally lack uricase, the enzyme responsible for converting uric acid to allantoin, which may pose challenges for the direct clinical translation of uricase‐producing probiotics. Although microbial degradation of UA into allantoin represents a promising strategy, its long‐term efficacy, safety, and metabolic consequences in humans require further investigation. Specifically, it remains to be clarified whether exogenous microbial uricase activity can function effectively in the human gut environment and whether the resulting allantoin can be safely metabolized or excreted without adverse effects. Therefore, although the ability of certain Lactobacillus strains to degrade UA is encouraging, future studies should focus on validating these findings in human subjects and exploring the regulatory pathways involved.

These findings indicate that some probiotics can directly break down UA, likely through the production of uricase, converting UA into soluble allantoin for excretion from the body. Furthermore, probiotics can reduce UA levels by inhibiting the expression of urate reabsorption proteins and promoting the expression of urate excretion transporter proteins. However, the specific mechanisms through which probiotics influence URAT expression remain unclear and warrant further investigation (Fujita et al. 2023; Vázquez‐Ávila et al. ²⁰¹⁸). In this regard, hypothetical pathways could be proposed: probiotics may regulate URAT gene expression through metabolites such as SCFAs, or indirectly influence its activity by reshaping the gut microbiota structure. Additionally, ongoing research in this field is exploring interactions between specific strains (e.g., Lactobacillus reuteri , Bifidobacterium) and URAT subtypes (URAT1, GLUT9, etc.), which offer potential clues for mechanistic elucidation (Kuo et al. 2021).

8. Conclusions and Future Insights

The gut microbiome, which colonizes the human gut, plays a crucial role in the onset and progression of HUA. Changes in the composition and metabolism of the gut microbiota result in abnormalities of uric acid degradation, increasing uric acid generation. Therefore, exploring disease mechanisms and therapeutic targets through the lens of the gut microbiome has become a key focus of global research. Current research employs specific probiotic strains (e.g., Lactobacillus plantarum ) to promote SCFA production for UA synthesis inhibition and microbiota structure regulation, or utilizes high‐fiber/polyphenol diets to reshape gut microecology for UA metabolism improvement, whereas fecal microbiota transplantation explores restoring dysbiotic intestinal environments with healthy donor microbiota to intervene in HUA. These approaches focus on strategies like probiotic colonization, diet‐induced microbiota metabolic reprogramming, and whole‐microbiota transplantation to target the composition and function of gut microbiota, thereby influencing UA production, excretion, and systemic inflammatory status to intervene in HUA progression.

This review systematically analyzes the multifaceted roles of the gut microbiota in the pathogenesis of HUA, highlighting current research on its involvement in reducing UA production, promoting purine degradation, regulating amino acid transport, and enhancing UA excretion. Probiotic intervention has emerged as a promising adjunctive therapy because of its good safety profile and high patient acceptability. However, most existing studies are based on animal models, and clinical evidence remains limited. Moreover, the efficacy of probiotics may vary depending on specific strains and the host's baseline gut microbiota composition. Therefore, future research should prioritize large‐scale, long‐term clinical trials in HUA populations to evaluate the sustained effects of probiotics on serum UA levels and elucidate their underlying mechanisms. In parallel, studies utilizing humanized mouse models or non‐human primates are warranted to better mimic the human gut environment and enhance the translational relevance of findings. From a broader perspective, deepening our understanding of the regulatory role of the gut microbiome in HUA may not only facilitate the development of novel, safe, and targeted therapies, but also offer theoretical and practical insights for the prevention and management of related diseases such as gout and chronic kidney disease.

Author Contributions

Junyu Yang: conceptualization (equal), visualization (equal), writing – original draft (equal), writing – review and editing (equal). Jiali Chen: visualization (equal), writing – original draft (equal), writing – review and editing (equal). Zhenmin Liu: supervision (equal), writing – review and editing (equal). Yezhi Qu: writing – review and editing (equal). Xiqing Yue: writing – original draft (equal), writing – review and editing (equal). Bo Yuan: conceptualization (equal), funding acquisition (equal), investigation (equal), project administration (equal), supervision (equal), writing – review and editing (equal). Mohan Li: supervision (equal), writing – original draft (equal), writing – review and editing (equal).

Conflicts of Interest

The authors declare no conflicts of interest.

Yang, J. , Chen J., Liu Z., et al. 2025. “The Role of the Intestinal Microbiome in the Pathogenesis and Treatment of Hyperuricemia: A Review.” Food Science & Nutrition 13, no. 10: e70982. 10.1002/fsn3.70982.

Data Availability Statement

No new data were generated or analyzed in this review. Data supporting the findings of this study are available in the referenced works.