Gouty arthritis is an inflammatory disease caused by the deposition of sodium urate crystals in and around the joints caused by long-term hyperuricemia (1). Uric acid is the final product of human purine metabolism. Uric acid in the human body maintains a dynamic balance under the action of the liver, kidneys and intestines. When the balance is lost, the serum uric acid level will increase (2). Hyperuricemia (>6.8mg/dL) is the main cause of gout and a risk factor for cardiovascular disease, kidney disease, metabolic syndrome and other diseases (3–6). Under physiological conditions, two thirds of uric acid is excreted from the kidneys and one third is excreted through the intestines (7). Hyperuricemia was divided into overproduction of uric acid and insufficient excretion (8, 9). In recent years, the hypothesis of “kidney overload” is increasingly recognized, suggesting that the types of hyperuricemia should be changed to renal excretion disorders and renal overload types, which including insufficient extrarenal excretion and excessive uric acid production (10). The extrarenal excretion of uric acid is mainly achieved through the intestinal tract. The current uric acid lowering drugs mainly include three categories: inhibiting the production of uric acid, promoting the dissolution of uric acid, and promoting the excretion of uric acid in the kidneys (11). Several drugs can inhibit the production of uric acid, such as allopurinol, febuxostat, and topiroxostat. Allopurinol reduces the synthesis of uric acid by inhibiting xanthine oxidase. However, allopurinol hypersensitivity syndrome (AHS), in which allopurinol has a fatal risk, warrants attention, and the incidence of AHS is higher in Asians, especially Han people (12). As a non-purine xanthine oxidase inhibitor, febuxostat is better than allopurinol in inhibiting the production of uric acid. However, it has been reported that febuxostat can increase the mortality of cardiovascular events in patients with gout. Other adverse reactions include muscle pain, elevated liver enzymes, etc. (11, 13). Recombinant uricase that promote the dissolution of uric acid, such as rasburicase, pegloticase, and pegloticase have a higher probability of infusion-related reactions such as rash, headache, and dyspnea (14, 15). Benzbromarone, probenecid, and lesinurad can promote the excretion of uric acid in the kidney. Benzbromarone inhibits the reabsorption of uric acid in the renal tubules to achieve the purpose of lowering uric acid, which can lead to the formation of uric acid kidney stones and liver toxicity (16). Probenecid and lesinurad reduces uric acid reabsorption by inhibiting the activity of renal uric acid transporter, but adverse reactions may occur in various systems (17). A clinical trial has shown that lesinurad monotherapy treats increased serum creatinine and the occurrence of renal-related adverse events (18). At present, the target of drugs for promoting uric acid excretion is mainly concentrated in the kidneys, which will increase the burden on the kidneys, especially for patients with chronic kidney disease. As the largest organ of the human body, the intestine has a huge potential for uric acid excretion, and it is hoped that it will become a safer and more effective target organ for lowering uric acid drugs. This article reviews the metabolic pathways of uric acid in the intestines and the possible therapeutic targets derived therefrom.

Uric acid is mainly synthesized in the liver, and a small amount is produced in the small intestine. It is the final product of human purine metabolism. Purine nucleotides generate adenosine, inosine and guanosine under the action of adenosine deaminase, adenosine is deaminated to form inosine, and inosine and guanosine are further converted into hypoxanthine and guanine, hypoxanthine Purine forms xanthine under the action of xanthine oxidase, and guanine deaminates to form xanthine. Xanthine is oxidized again by xanthine oxidase and finally produces uric acid ( Figure 1 ) (19, 20). In most mammals, uricase can oxidatively degrade uric acid into the soluble compound allantoin. In the process of human evolution, the gene encoding uricase has undergone inactivation mutations, resulting in a lack of uricase (21). It has been shown that two-thirds of the uric acid in the human body is excreted from the kidneys, one-third is excreted from the intestines and bile, and the proportion of uric acid excreted by bile is very small. The kidney regulates the excretion of uric acid through the reabsorption and secretion of proximal tubules, and this process is mainly achieved through uric acid transporters (22, 23). Uric acid transporter dysfunction plays an important role in the pathogenesis of hyperuricemia. Genome-wide association studies (GWAS) found that many genes related to hyperuricemia and gout. The genes encoding proteins referred to as uric acid transporter (24, 25), including URAT1, OAT4 and SLC2A9 that mediate the reabsorption of uric acid, and transporters such as ABCG2, OAT1, OAT2, OAT3, and MRP4 that mediate the secretion of uric acid ( Figure 2 ) (26).

The blood uric acid concentration is related to a variety of transporter-encoding genes. Among them, the uric acid transporter in intestinal epithelial cells transports uric acid from the blood to the intestinal lumen, which involves the participation of multiple transporters, mainly ABCG2 and SLC2A9 (27).

Intestinal microbes are composed of various microorganisms such as bacteria, fungi and viruses in the intestine. At least 100 trillion bacteria in the intestinal microecosystem live in the human intestines. They participate in host metabolism, immune regulation, and maintenance of internal environment homeostasis, etc. (49–51). Increasing evidences show that there are differences in the distribution of intestinal flora between gout patients and healthy people (52, 53). Studies have found that supplementing probiotics can improve uric acid levels. It is promising that probiotics may become a new direction for the treatment of gout and hyperuricemia (54–57). Current research suggests that the impact of intestinal flora on gout is mainly achieved through the following three aspects: participation in purine metabolism and decomposition of uric acid to reduce uric acid levels; metabolites produced by intestinal flora promote the excretion of uric acid ( Figure 3 ); participation in immune-inflammatory regulation of gout.

It has shown that intestinal flora has a regulatory effect on expression of uric acid transporters. Anserine, a natural carnosine derivative, shows an anti-hyperuricaemic effect, which was closely associated with an increasing abundance of clostridium and lactobacillus in the gut. Importantly, anserine-mediated regulation of uric acid transporters ABCG2, URAT1, and GLUT9 is dependent on intestinal flora (80). In addition, intestinal ABCG2 expression was significantly suppressed by gingko biloba leaf extract (GLE) administration, which is closely related to decreased populations of proteobacteria and deferribacteres at the phylum level. It is worth noting that GLE treatment did not affect ABCG2 expression, but treatment with the lysates of GLE-treated mouse stool significantly suppressed ABCG2 expression. These findings reveal a role for intestinal flora in regulating ABCG2 expression (81). Not only does the intestinal flora plays an important role in intestinal immune homeostasis, studies have also shown it can regulate uric acid transporters through its metabolites. In SCFAs treated rats, the expression and function of intestinal ABCG2 were increased. Similar results were also observed in mouse primary enterocytes and Caco-2 cells treated with SCFAs (82). These findings showed that microbiota has a regulatory effect on expression of uric acid transporters.

In keeping with in vitro and animal studies, data from large-scale metagenome genome-wide association studies (mgGWAS) for the oral microbiome revealed unequivocal human genetic loci associated with the oral microbiome, including uric acid transporter SLC2A9. SLC2A9 showed a strong correlation with species-level clusters belonging to oribacterium and lanchnoanaerobaculum in tongue dorsum samples (83). A previous study reported that oral cavity and stool bacteria overlapped in more than 45% of subjects (84). Interestingly, the tongue dorsum microbiota related gene SLC2A9 was correlated with the abundance of Bifidobacterium animalis in the gut (83). These results demonstrated that gut microbial diversity also has an impact on uric acid transporters.

Currently uric acid lowering drugs are mainly achieved through the kidneys, while the intestine is the second largest uric acid excretion organ. The decrease in intestinal uric acid excretion will increase the burden on the kidneys. At present, the intestinal excretion of uric acid has been used as a new direction for the treatment of gout and hyperuricemia, which can avoid side effects such as aggravating kidney damage and urinary tract stone formation. In summary, there is a bright prospect for drug and gut microbiota research targeting intestinal uric acid transporters to treat hyperuricemia and gout ( Figure 3 ). However, there are scarce studies about the association between intestinal flora and uric acid transporters, and the specific mechanism of the interaction between these need to be further elucidated.

HY, NL, and JC reviewed the literature and wrote the first draft. HY and JC reviewed the literature and finalized the manuscript. All authors have read and approved the final manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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