Elucidating the role of gut microbiota dysbiosis in hyperuricemia and gout: Insights and therapeutic strategies

Abstract

Hyperuricemia (HUA) is a condition associated with a high concentration of uric acid (UA) in the bloodstream and can cause gout and chronic kidney disease. The gut microbiota of patients with gout and HUA is significantly altered compared to that of healthy people. This article focused on the complex interconnection between alterations in the gut microbiota and the development of this disorder. Some studies have suggested that changes in the composition, diversity, and activity of microbes play a key role in establishing and progressing HUA and gout pathogenesis. Therefore, we discussed how the gut microbiota contributes to HUA through purine metabolism, UA excretion, and intestinal inflammatory responses. We examined specific changes in the composition of the gut microbiota associated with gout and HUA, highlighting key bacterial taxa and the metabolic pathways involved. Additionally, we discussed the effect of conventional gout treatments on the gut microbiota composition, along with emerging therapeutic approaches that target the gut microbiome, such as the use of probiotics and prebiotics. We also provided insights into a study regarding the gut microbiota as a possible novel therapeutic intervention for gout treatment and dysbiosis-related diagnosis.

Key Words: Gut microbiota; Dysbiosis; Gout; Hyperuricemia; Inflammation; Intestinal barrier; Probiotics; Prebiotics; Fecal microbiota transplantation

Core Tip: Current research highlights the relationship between gout and gut microbiota composition. Gout patients have significantly different microbial profiles than healthy individuals, with changes in specific bacterial taxa. These alterations may increase uric acid production and purine metabolism, potentially worsening the disease. Traditional gout treatments influence gut microbiota while emerging approaches aim to rebalance the gut ecosystem using probiotics and prebiotics. This gut-centric view offers a novel perspective for developing new gout management strategies. Microbiome-focused treatments show promise, emphasizing the vital role of gut health in managing this metabolic condition and revealing new treatment opportunities.

TO THE EDITOR

Gout, a type of inflammatory arthritis, is a significant global health concern. Also known as the ‘disease of kings’, its prevalence has increased in recent years, affecting an estimated 1%–4% of adults in developed countries[1]. Hyperuricemia (HUA), marked by an increase in the serum level of uric acid (UA), serves as the foundation of gout pathophysiology. This condition occurs when the serum levels of urate exceed the physiological solubility of about 6.8 mg/dL (404 μmol/L); although it does not always indicate gout, it is regarded as a primary risk factor in most populations[2]. Furthermore, HUA is even more prevalent than gout, affecting 20%–25% of adults in certain groups[3]. The kidneys remove almost all UA from the blood, with the rest eliminated through the intestinal tract[4]. The human intestinal tract contains various microorganisms, which collectively form the gut microbiota. In HUA and gout patients, intestinal microbiota dysbiosis is linked to abnormal urate degradation and systemic inflammation, which highlights the need for further research on this topic.

The abundance of Bacteroides is high in gout patients, whereas that of Faecalibacterium is relatively low. These species can change the composition of the microbiota in individuals with gout, worsening disease progression or affecting recovery[5,6]. Dysbiosis can influence the intestinal immune system and increase the permeability of the gut–barrier, allowing microbial products to enter the bloodstream and cause systemic inflammation, which exacerbates the inflammatory state of gout[7-9]. The analysis of the gut microbiota is now regarded as a promising approach for treating HUA. It can reverse HUA in the intestine by affecting purine and UA catabolism, enhancing the excretion of UA, and regulating the inflammatory response in the intestines[10-13]. HUA may also reduce the function of the intestinal barrier, inducing a systemic inflammatory response, and changes in the gut microbiota may affect serum UA through changes in host metabolites[7]. Thus, the increase in the number of inflammation-associated microbiota in HUA also enhances the inflammatory characteristics of gout[7]. This article focused on the role of gut microbiota in gout development and showed a way to use it in gout treatment, offering a promising strategy to manage HUA.

CONTRIBUTION OF THE GUT MICROBIOTA TO HUA

The gut microbiome significantly contributes to the development of HUA through several mechanisms. It facilitates the catabolism of purines and UA; bacteria such as Escherichia coli and Proteus secrete xanthine dehydrogenase (XDH) for oxidative purine catabolism[14]. This enzyme is required for breaking down purines, thus reducing the levels of UA. Additionally, Lactobacillus and Pseudomonas synthesize enzymes that degrade UA to urea, reducing purine absorption and UA levels in the intestine[15]. These enzymes catalyze the conversion of UA into urea, a less harmful substance, thus reducing the risk of HUA. However, not all gut microbiota have protective effects. Escherichia and Shigella secrete xanthine deaminase, which converts hypoxanthine and xanthine to UA and increases serum UA levels.

While specific gut flora and their enzymes act in the catabolism and excretion of purines and UA, gut microbiota metabolites, such as short-chain fatty acids (SCFAs), also regulate the excretion of UA[16]. Acetate, succinate, and glucose provide energy to intestinal epithelial cells, which in turn enhance the excretion of UA and thus alleviate HUA[16]. However, metabolites such as acetate and succinate can increase the production of interleukin (IL)-1β, thus increasing inflammation[17]. The gut microbiota alters the intestinal transporters that are involved in the clearance of UA. Adenosine triphosphate-binding cassette subfamily G2 plays a crucial role as a transporter for secreting urate in the intestine[17], and its expression is upregulated in nephrectomized rats, indicating the importance of this transporter in the excretion of UA during renal dysfunction[18].

The gut microbiota plays a crucial role in chronic inflammation associated with HUA. Dysbiosis increases intestinal permeability, which promotes the translocation of bacteria or their products, such as lipopolysaccharide (LPS), into the bloodstream[8]. High serum levels of LPS induce chronic inflammation, thus increasing the risk of HUA[19]. This information on the underlying mechanisms can provide insights into the complexity of HUA and the potential for targeted interventions[20].

Changes in the gut microbiota composition of patients with HUA

Extensive studies related to the gut microbiota have been conducted in the context of HUA and gout, both in human and animal models. The findings have revealed substantial changes in microbial diversity and abundance. Human studies have shown a decrease in alpha diversity and observed species in gout patients than in healthy controls[5,21,22]. At the phylum level, this is characterized by an increase in Bacteroidetes, Firmicutes, and Actinobacteria and a decrease in Proteobacteria[12]. Changes at the genus level include an increase in Prevotella, Bacteroides, Barnesiella, and Parasporobacterium and a decrease in Faecalibacterium, Coprococcus, and Alistipes in gout patients[5,6]. Gout patients' gut microbiomes show a deficiency in microbes carrying the allantoinase gene (which converts UA to urea) but an abundance of microorganisms with the XDH gene[5,23]. These changes are associated with reduced production of SCFAs and alterations in purine metabolic pathways[24].

Méndez-Salazar et al[25] compared the taxonomic composition of the gut microbiota between gout patients with and without tophi. They found that compared to gout patients with tophi, those without tophi had a greater abundance of Ruminococcus, Akkermansia, Bacteroides, and Phascolarctobacterium in the gut microbiome and the lowest richness of other genera at the genus level. These findings suggested that the composition of the gut microbiota is different in gout patients with and without tophi, which may have implications for disease progression. Compared to healthy controls, patients with tophaceous gout showed a higher abundance of the phylum Proteobacteria and the genera Escherichia and Shigella. The abundance of Proteobacteria was greater in tophaceous gout patients than in healthy controls; the patients exhibited a further increase in the abundance of Escherichia and Shigella, Sarcina, Rikenellaceae, and Lachnospiraceae. In 2019, Xi et al[26] reported a dramatic increase in the growth of Proteobacteria, especially Escherichia and Shigella, in the gut microbiota of urate oxidase knockout mice. Thus, these bacteria can substantially affect the severity of gout.

Animal studies have provided valuable insights, but their findings are often supplementary and inconsistent with current human studies. Despite increased research on alpha diversity in HUA models[27], comparable evidence in human studies remains limited[28]. Phylum-level changes are characterized by an increase in Firmicutes, Actinobacteria, and Proteobacteria but a decrease in Bacteroidetes[7]. At the genus level, some changes include an increase in the abundance of Bacteroides, Clostridium, and Parabacteroides but a decrease in the abundance of Prevotella and Lactobacillus[26]. Biochemically, it is necessary to focus on a hyperuricemic animal model that shows an increase in the concentrations of UA, blood urea nitrogen, creatinine, and total cholesterol, as well as the levels of the inflammatory markers TNF-α and IL-1β[7,28]. These findings indicate that gout and HUA substantially disrupt the composition, function, and richness of the gut microbiota.

These findings also provide new information for developing diagnostic and therapeutic strategies for the microbiome of gout patients and indicate that the application of gut microbiota is a promising strategy for treating HUA and gout[12].

Management of HUA

The classical choice of drugs used for treating acute gout includes nonsteroidal anti-inflammatory drugs (NSAIDs), which can effectively relieve pain and inflammation[29]. However, NSAIDs are most likely to disrupt the balance of the gut microbiome, contributing to the growth of gram-negative bacteria and the inhibition of gram-positive bacteria[13]. As a result, inflammatory pathways are activated through Toll-like receptor 4, and proinflammatory cytokines are released. Allopurinol, the most common xanthine oxidase inhibitor, can effectively decrease UA levels[30]. Allopurinol treatment can increase the abundance of Bifidobacterium and decrease the abundance of anaerobes in the gut microbiota[11]. Additionally, it can significantly decrease the abundance of Bilophila, which causes the onset of systemic inflammation[31]. These changes in the gut microbiota indicate that allopurinol may have therapeutic effects on gout. Another UA-lowering drug is benzbromarone, a uricosuric agent that acts by inhibiting the significant apical UA exchanger in the human proximal tubule urate anion transporter-1[32]. Benzbromarone treatment can alter the gut microbiota, characterized by an increase in Bifidobacterium and suppression of Butyricimonas[11]. Febuxostat, a non-purine inhibitor of xanthine oxidase, is used to lower UA levels in patients with HUA and gout. Febuxostat can partially restore the diversity of the gut microbiota in untreated gout patients[10]. Febuxostat-treated gout patients exhibited improved purine metabolism in their gut microbiome compared to untreated and regular gout patients. Moreover, animal experiments have shown that febuxostat alters the dysbiosis of the gut microbiota, modulates gut microbiota metabolites, and suppresses microinflammation[33]. As febuxostat can restore the diversity of the gut microbiota, it may be further investigated for its therapeutic effects on gout.

Gout treatment is complex, with the main challenges related to low rates of urate-lowering therapy initiation and continuation, along with the side effects of traditional drugs. These side effects include gastrointestinal toxicity, tolerance, allopurinol hypersensitivity syndrome, nephrotoxicity, and contraindications in patients with other prevalent comorbid conditions[34-36]. About 40% of gout patients are affected by chronic kidney disease and a decrease in glomerular filtration rate[37]. Even the use of NSAIDs, colchicine, and uricosuric medications has limitations[38]. Therefore, safer treatment methods that can effectively intervene in gout development are urgently needed.

Probiotics and prebiotics in gout treatment

Novel information on the role of the gut microbiota in the pathogenesis of gout has increased interest in natural products, including probiotics and their biotherapeutic counterparts in faecal microbiota transplantation (FMT). These methods function by inhibiting purine metabolism and inflammatory factors, modulating the expression of transporters, and protecting the integrity of the intestinal barrier. They also increase the number of bacteria related to the production of SCFAs, promote SCFAs production, and reduce XDH activity in the serum and liver[39]. Among all dietary supplements, Bifidobacteria and Lactobacilli are the most popular probiotics used in functional foods. Among the newly identified probiotics, Faecalibacterium prausnitzii (F. prausnitzii), Akkermansia muciniphila, and Clostridium spp, also have promising effects[40].

Recent clinical studies have shown that the gut microbiota can regulate purine metabolism and inflammation, which indicates its importance as a target for the prevention and treatment of gout. In 2023, Zhao et al[41] conducted a study on 40 male participants (20 gout patients and 20 healthy controls) to assess the role of probiotics in gout treatment. Gout patients were found to have lower microbial diversity and microecological disturbance. Changes at the level of gut bacteria, for example, in F. prausnitzii, Bacteroides uniformis (B. uniformis), and Lachnospira eligens, induced disruption of the metabolic pathway associated with UA and purine metabolism, which in turn affected metabolites such as cholate and cholesterol. The key differential species were highly positively or negatively correlated with UA concentration, indicating that they can serve as probes for the treatment and prevention of gout. This study established an important relationship between gut microbiota composition and gout, which might act as a reference for investigating interventional efficacy in future studies[41].

In another randomized, double-blind clinical trial conducted in 2022, Zhao et al[41] examined the role of gut microbiota in gout management following probiotic supplementation. The study included 120 volunteers and compared the effects of probiotic yogurt supplemented with Limosilactobacillus fermentum (L. fermentum) GR-3 to those of conventional yogurt over two months. They found that L. fermentum GR-3 was significantly associated with reduced UA levels and inflammation in at-risk individuals[42]. Metabolomic analysis revealed positive anti-inflammatory responses to the consumption of probiotics, indicating that modulation of the gut microbiota involving F. prausnitzii and B. uniformis can decrease UA levels in patients with gout. These findings further support the effectiveness of probiotics in gout therapy.

An animal study revealed that diets containing probiotics can reduce HUA by affecting the intestinal flora. For example, Lactobacillus fermentans JL-3 can alleviate HUA-induced intestinal microbiota dysbiosis and effectively decrease UA levels in mouse models[43]. Similarly, the probiotic strain DM9218 was found to increase fructose-induced HUA by reducing serum UA levels and hepatic xanthine oxidase activity and regulating intestinal dysbiosis[44]. Furthermore, probiotics containing urate-decomposing bacteria can decrease the level of UA in the serum of hyperuricemic animal models and modulate hypertension and kidney disease[45].

Additionally, probiotics containing certain strains, particularly those of the genus Lactobacillus, are efficacious in treating HUA. While Lactobacillus reuteri and L. fermentum decrease the synthesis of UA using purines, Lactobacillus brevis DM9218 and Lactobacillus gasseri PA3 efficiently degrade the metabolic intermediate products of purines[46-48]. Based on these studies, probiotic-based therapeutic strategies should be considered for treating HUA and the conditions related to this disease. Although probiotics are effective under certain pathological conditions, the protective effects of these agents, especially when they are taken at minimal concentrations, are not known; thus, further research is needed to improve the curative benefits of probiotic medications.

Prebiotics

Prebiotics increase the relative numbers of Lactobacillus and Bifidobacterium species, which promote the production of SCFAs, such as butyrate and propionate[49]. For example, fisetin can reverse changes in Bacteroides and Firmicutes in hyperuricemic mice, indicating that it decreases serum UA levels by modulating the gut microbiome[50]. Li et al[48] showed that polysaccharides from Enteromorpha prolifera (EPP) attenuated the level of serum UA while increasing the diversity of gut microbiota. These findings indicated that EPP administration is associated with an increase in the relative abundance of Alistipes and Parasutterella, which are negatively correlated with high levels of UA[48]. Guo et al[51] conducted a comparative analysis to determine the inulin-mediated role in HUA and the composition of the gut microbiota in urate oxidase gene knockout mice. They found that inulin supplementation significantly reduced UA and inflammatory marker levels; inulin also strengthened the intestinal barrier by increasing the expression of tight junction proteins[51].

In 2024, Asuncion et al[52] assessed the therapeutic efficiency of Poecilobdella manillensis (P. manillensis) (Leech) protein extract on HUA in mice. The results indicated that this extract reduced UA levels and improved renal function while modulating the composition of the gut microbiota. Treatment with this extract might influence sphingolipid and galactose metabolism. These results further implied that the protein extract of P. manillensis may be a drug candidate for managing HUA due to its multifaceted effects on UA metabolism, kidney function, and gut microbial ecology[31].

FMT

FMT is a procedure involving the transfer of fecal microbes from a healthy donor into the gastrointestinal tract of a recipient with disturbed microbiota. The mechanisms underlying the actions of FMT are probably related to the reconstitution of balanced microbiota, and therefore, are crucial for therapeutic effects; however, these mechanisms are not clear[53,54]. Considering that gut microbiota dysbiosis is associated with gout, FMT might be an effective method of treating this disease. In a study conducted in 2022, Xie et al[55] found that washed microbiota transplantation significantly decreased serum UA levels, relieved gout symptoms, and restored intestinal barrier function in patients with gout. Other studies have demonstrated that fecal transplantation can help reverse HUA and lower renal inflammation in mice[56]. These results indicate that FMT might be a promising treatment option for gout as it directly addresses the imbalance in microbiota.

To summarize, probiotics and prebiotics can effectively treat gout through intestinal microbial modulation. Since most studies have been performed in animals, the efficacy of this new treatment in alleviating symptoms needs to be investigated by conducting human trials involving gout patients.

Conclusion and future directions

The study on gut microbiota dysbiosis in individuals with gout and HUA has attracted much attention because of the complex interplay of gut microbial communities in the pathogenesis and development of illnesses. The considerable changes in the composition, function, and number of particular bacteria associated with the development of gout and HUA are under investigation, and the data can provide new insights into disease mechanisms and new therapeutic approaches. Key findings from human and animal studies have shown consistent patterns of dysbiosis in gout patients and hyperuricemic models, primarily involving changes in major bacterial phyla and genera, with functional modifications related to purine metabolism, SCFAs production, and the inflammatory response.

Several important directions for future research and development have emerged. A well-designed human clinical trial is needed to evaluate the efficacy of microbiome-targeted interventions for treating gout with respect to their effect on clinically relevant endpoints, UA, and inflammation. Personalized treatment strategies for gout based on the makeup of the microbiome of each person should be developed using the capabilities of high-throughput sequencing and machine-learning tools for deducing microbial signatures associated with susceptibility to gout or response to treatment. Future research should focus on elucidating the complex relationships between the gut microbiome and gout pathogenesis, particularly examining specific metabolites and signaling pathways involved in microbiota-host interactions related to UA metabolism and inflammation. Microbiome studies offer promising avenues for developing novel therapeutic agents, including designer probiotics, UA degradation methods, and targeted prebiotics that selectively promote beneficial bacteria growth. In the future, microbiome data analysis and other omics technologies need to be combined to gain deeper insights into the systemic effects of gut microbiota dysbiosis in gout patients.