Gout and Diet: A Comprehensive Review of Mechanisms and Management

Gout is well known as an inflammatory rheumatic disease presenting with arthritis and abnormal metabolism of uric acid. The recognition of diet-induced systemic metabolic pathways have provided new mechanistic insights and potential interventions on gout progression. However, the dietary recommendations for gouty patients generally focus on food categories, with few simultaneous considerations of nutritional factors and systemic metabolism. It is worthwhile to comprehensively review the mechanistic findings and potential interventions of diet-related nutrients against the development of gout, including purine metabolism, urate deposition, and gouty inflammation. Although piecemeal modifications of various nutrients often provide incomplete dietary recommendations, understanding the role of nutritional factors in gouty development can help patients choose their healthy diet based on personal preference and disease course. The combination of dietary management and medication may potentially achieve enhanced treatment effects, especially for severe patients. Therefore, the role of dietary and nutritional factors in the development of gout is systematically reviewed to propose dietary modification strategies for gout management by: (1) reducing nutritional risk factors against metabolic syndrome; (2) supplementing with beneficial nutrients to affect uric acid metabolism and gouty inflammation; and (3) considering nutritional modification combined with medication supplementation to decrease the frequency of gout flares.


Introduction
Throughout history, gouty disease has always been strongly associated with abundant foods and immoderate alcohol intake. Gout is even known as the "king's disease" and symbolized social status in ancient times, as only the upper class could afford to consume wine and meats [1]. Nevertheless, gout currently has been well established as a global health problem and has gained attention due to its increasing incidence rate, multiple metabolic comorbidities, and high premature mortality [2]. Gout is well known as a phlogistic arthritis that is associated with hyperuricemia and elevation of urate in tissues. The increased urate causes the generation of monosodium urate (MSU) crystals, and MSU crystal deposition in and around the first metatarsophalangeal joint, knee, and fingers represents a clinical sign of gout [3]. The clinical symptoms of gout develop in several stages, including asymptomatic hyperuricemia, MSU crystal formation, intermittent gout and chronic gout [4]. Effective gout management mainly relies on the use of therapeutic strategies to control uric acid levels or achieve crystal dissolution. While current clinical principles based on medicinal management for gout have been well implemented [5], dietary modification and lifestyle changes have also been recommended for gout patients, since a suboptimal diet and obesity/diabetes-diseases of affluence contribute significantly to the risk of developing gout [5][6][7], increasing the burden of medical expenses. At present, dietary recommendations have been updated worldwide, and nutritional science for the management of gout has advanced dramatically [8,9]. Historical dietary recommendations for gouty patients tend to emphasize the concepts of "high-" and "low-" levels of the same nutrient, but the role of nutritional elements in gout is difficult to classify by a single beneficent or harmful criterion because problems of systemic metabolism arise when the balance between nutrient intake and consumption is disturbed. This means that although dietary management is considered to be an essential aspect of gout therapeutic strategies [2], a potential dietary mechanism in gout development is out of date or incomprehensive, and a systemic overview of dietary and nutritional factors of gout is needed for well-designed dietary management based on research practice. Moreover, studies have shown that dietary factors mainly focus on food classification, while diet-induced systemic metabolism is rarely mentioned in the progression of gout. It is worthwhile to comprehensively review the mechanistic findings of diets aimed at purine metabolism, urate deposition and gouty inflammation. Our acknowledgment of gout-related nutritional factors can provide a theoretical basis for on-target and comprehensive dietary guidelines for gout patients with different complications or at different stages. Purines are the basic components of nucleotides needed for building DNA and RNA within mammalian cells, and purine nucleotides, such as guano-sine-5 -triphosphate and adenosine triphosphate (ATP), are essential for regulating energy metabolism and intracellular functions, respectively. Disorders of purine metabolism are associated with considerable variations in the concentration of serum uric acid (SUA) because uric acid is the ultimate product of purine catabolism in humans. Purine source analyses show that nearly twothirds of purines in the body are endogenous, and the remaining purines that enter the body via foods are known as exogenous purines [10]. As a direct source of exogenous nucleotides and uric acid, dietary purines are vital for maintaining the balance of purine metabolism in mammalian cells by a coordinated process of de novo biosynthesis, the salvage pathway, and purine inter-conversion or degradation. As shown in Figure 1, these exogenous purines can be dephosphorylated into nucleosides in the body as part of the digestive course, accompanied by the oxidative release of free bases [11]. Subsequently, the degraded bases can be recycled into nucleotides in the tissues via the purine salvage pathway or wholly degraded into uric acid mainly within the liver or the small intestine [11,12]. Adenosine monophosphate (AMP) and guanine monophosphate (GMP) are usually the predominant forms of purine nucleosides derived from foods. The enzymatic degradation process uses deaminase and GMP reductase to convert AMP and GMP, respectively, to inosine monophosphate (IMP) [13]. AMP/GMP can also be dephosphorylated to generate adenosine/guanosine in a process catalyzed by nucleosidase. Both IMP and adenosine are then processed into inosine. The transformation of inosine to hypoxanthine is catalyzed by purine nucleoside phosphorylase, and eventually hypoxanthine utilizes the dual oxidation of xanthine oxidase (XO) to produce uric acid. Additionally, the conversion of guanosine into uric acid can be catalyzed by guanine deaminase following guanine formation by nucleotidase [13]. When purine overload in the body empowers the body's ability to manage it, excessive uric acid can accumulate in the bloodstream. This condition presenting with an elevated SUA concentration is known as hyperuricemia, and gout induced by hyperuricemia is deemed to be the metabolic disease linked to purines. All meats and edible plants contain purines, and some foods contain higher concentrations. Thus, overindulgent intake of a high-purine diet, including seafoods and animal offal, can trigger the excessive accumulation of purine metabolites, giving rise to the excessive accumulation of uric acid in the body [5]. In addition, some purine-free drinks can accelerate the promotion of purine degradation; for example, alcohol intake consumes large amounts of ATP to produce AMP in the liver, leading to the rapid occurrence of increased SUA levels [14]. The consumption of yeast-rich foods, such as bread and yeast drinks, can lead to a high colonization of Saccharomyces cerevisiae in the gut [15], which can gradually elevate the secretion of uric acid in the host. Figure 1. Potential mechanisms of diet-induced gout progression in humans. Diets provide abundant raw materials of purine, which is mainly metabolized in the liver, promoting uric acid production. Meanwhile, it can interfere with the intestinal environment, homeostasis, and urate transport to induce high levels of uric acid, leading to hyperuricemia and ultimately to gout. Additionally, gouty inflammation is caused by IL-1β production after the activation of NLRP3 by macrophages that ingest MSU crystals, and a second signal is required in humans by stimulating the activation of TLR signaling pathways that can be induced by diets. Moreover, neutrophil infiltration and diet-induced low-grade inflammatory states will exacerbate gouty inflammation. AMP, adenosine monophosphate. ASC, apoptosis-associated speck-like protein containing a caspase recruitment domain. GMP, guanine monophosphate. IL, interleukin. IMP, inosine monophosphate. LPS, lipopolysaccharide. MSU, monosodium urate. MyD88, myeloid differentiation factor88. NF-κB, nuclear factor kappa B. NLRP3, pyrin domain-containing protein 3. TLR, toll-like receptor. TNF, tumor necrosis factor. XO, xanthine oxidase.

The Excretion of Uric Acid
Under normal conditions, nearly 90% of uric acid is reabsorbed into the human body, and the remaining uric acid is excreted in the feces and urine [16]. When purines exceed the limit value for normal production and catabolism, the synthesis and excretion of uric acid are out of balance, and the circulating uric acid level is elevated. The kidneys are responsible for eliminating approximately two-thirds of circulating uric acid, with the remaining one-third excreted by the intestine and gut microbiota [12]. Diets could affect uric acid excretion by regulating the excretory function of the kidney and intestine. Because foods can come into contact with the intestinal tract and regulate intestinal homeostasis [17], dietary factors are involved in intestinal urate handling mechanisms. Endogenous uric acid from the bloodstream or as a constituent of saliva, bile, or peptic juices transfer from the enterocyte cytoplasm into the intestine tissues. In this process, enterocyte urate transporters are critical for maintaining urate homeostasis in the intestine, and an enterocyte-specific deficiency of these transporters, including ATP-binding cassette transporter G2 (ABCG2/BCRP) and NPT5 (SLC17A4), can impair the enterocyte urate transport process, which is also affected by exogenous metabolism, such as dietary fat and sugar [18]. Similarly, a study of 8709 participants suggested that high simple sugar exposure was found to interfere with the ability of SLC2A9 (encoding GLUT9) to mediate renal uric acid excretion without additive genotype-specific interaction [19]. After entering the intestinal tissue, uric acid can be degraded into nitrogen or CO 2 by the uricase activity found in the gut microbiota. The associations between diet-induced gut microbiota reconstruction and the progression of hyperuricemia/gout have been highlighted in recent research, as evidenced by the fact that long-term adherence to the typical Western diet caused an obvious reduction in the diversity of the gut microbiota, particularly those that degrade uric acid and produce metabolites known to benefit uric acid excretion [20]. For example, as a microbiota-derived metabolite, the short-chain fatty acid butyric acid was thought to promote intestinal uric acid excretion [21]; however, a fat-rich diet reduces the abundance of beneficial bacteria that produce short-chain fatty acids [20]. In addition, the diet is mainly designed to provide calories for energy expenditure, and the related energy metabolism and metabolites produced as a result of dietary modification can affect uric acid excretion. By way of illustration, a ketogenic diet converts energy metabolism substrates from sugars to fats with the production of large ketone bodies such as acetyl acetate and β-hydroxybutyrate (BHB) [22], which induce fluid acidification and cause uric acid precipitation. The production of BHB inhibits uric acid excretion by competing for binding sites of uric acid transporters.

Uric Acid Disturbance: Emphasis on Purines
Monosodium urate crystals formation occurs when the urate concentrations continue to rise beyond the point required for spontaneous generation (nucleation). The increased volume of MSU deposition can aggravate the progression of symptomatic gout [23]. Diets that contribute to excessive SUA levels can induce the formation and deposition of MSU crystals, and other factor changes, such as diet-induced fluid acidification and salt deposition, also promote the growth of urate crystallization [24]. Alcohol consumption and fasting can induce elevated lactic acid levels to decrease the local pH to create an acidic condition, which might be a risk factor for MSU deposition, as the increased concentrations of calcium ions in an acidic environment aggravate the decrease in MSU crystal solubility [25].

Gouty Inflammation
Some observations show that in some circumstances, uric acid can show antioxidant properties in the form of urate. However, soluble urate acts as a proinflammatory stimulus to fuel the maturation and production of interleukin (IL)-1β [26], thus strongly driving acute gouty inflammation and giving rise to chronic long-term inflammatory consequences of the disease. It is known that the pathogenesis of gouty inflammation involves the cleavage of C5 and generation of C5a and C5b-9 on the surface of urate crystals [27]. Urate crystal deposition is also extensively recognized as a danger signal for the influx of innate immune cells [28]. Mechanistically, MSU crystal-induced inflammatory gouty flares are caused by the activation of pyrin domain-containing protein 3 inflammasome (NLRP3) with consequent IL-1β secretion from macrophages and neutrophils, resulting in acute inflammatory responses, intense pain and joint swelling [28]. The initiation of NLRP3-dependent IL-1β activation includes a priming signal associated with nuclear factor κB (NF-κB) and a secondary signal of caspase-1 assembly activation; thus, MSU crystals alone are insufficient to induce IL-1β secretion. Additionally, other endogenous costimulatory factors, such as myeloid-related protein-8/-14 in phagocytes, can increase MSU crystals-mediated IL-1β secretion in a TLR-4-dependent pathway [27].
Diets also have a significant impact on the systemic phenotype of the innate immune system. For example, a Western diet or meat-based patterns intersect with a low-grade inflammatory response, which permanently biases the immune system toward a proinflammatory phenotype [29], fueling gouty inflammation. In contrast, the Mediterranean diet or vegetable-and fruit-based patterns have been reported to prevent systemic in-flammation and gouty flares [30]. A fiber-rich diet has been proven to rapidly resolve the urate crystal-mediated inflammatory response in a gout-like mouse model [31]. Diet intervention affecting the neutrophil inflammasome has been explored. For example, a ketogenic diet alleviates urate crystal-induced gouty flares by increasing BHB, which can block NLRP3/caspase-1-dependent IL-1β expression in neutrophils and urate crystal-activated macrophages, reducing inflammatory neutrophil recruitment [32].

Nutrient Element-Richness and Structure Determine the Role of Dietary Factors in Gout
A large amount of clinical evidence, shown in Table 1, indicated the close connection between adherence to the described dietary patterns and the risk of gout-related metabolic disorders, hyperuricemia, and metabolic syndrome. Commonly described dietary patterns, such as a high-carbohydrate diet, a high-protein diet, and a high-unsaturated fat diet, actually represent the proportional and structural collocation of dietary nutrient elements [33]. It has been shown that the beneficial dietary patterns against hyperuricemia usually contain a higher intake of vitamins, fiber, and unsaturated fatty acids and are often supplemented with appropriate amounts of minerals and high-quality protein, promoting a health state in which systemic metabolism is prone to disease improvement [34,35]. These observations can be explained by the fact that important nutrients in foods can be considered determinants of dietary factors in gouty development. For example, the Western diet is characterized by a high level of sugar, while fiber richness in the Dietary Approaches to Stop Hypertension (DASH) diet can increase satiety to reduce sugar intake from other high-energy foods and play a vital role in decreasing gout incidence [34]. Therefore, the influence of dietary factors on gouty disease is the effect of nutrient element-richness and structures on systemic metabolism. Understanding the potential mechanisms of nutrients, as shown in Figure 2, in gout development can facilitate an understanding of the overall nutritional balance needed for the prevention or treatment of gout. Note: data are from clinical trials that have been included in PubMed since 2012. A direct search was used to search for the following terms: "diet and uric acid" or "diet and gout" or "food and uric acid" or "food and gout". A total of 462 articles were obtained. After following these exclusion criteria-repetitive articles, acute trials, dietary supplements, combination of drugs and food, questionnaire survey, exercise interference, and mismatched intervention subjects-a

High Fat
Dietary fat is primarily metabolized into triglycerides within intestines and packaged as chylomicrons for delivery to peripheral tissues, where adipocytes further transfer triglycerides into free fatty acids (FFAs) for energy uptake and storage [67]. A small amount of FFAs can be absorbed by the liver tissue, together with lipids remaining in the chylomicron [67]. High-fat foods can evoke the pleasure of eating and promote the individual's desire to consume more energy-dense diets [68], which culminates in the overproduction of FFAs. Free fatty acids-mediated metabolic events initiate acute onset of gouty disease in the presence of MSU crystals deposited in the joint. The interaction of FFAs with TLR2 synergized with MSU crystals leads to the release of IL-1β induced by ASC/caspase 1 [69].
High fat consumption can cause excessive accumulation of triglycerides, inducing increased fat mass and obesity. It has been reported that overweight/obesity was connected with 60% of hyperuricemia cases in a clinical trial of 14,624 adults [70], possibly due to lipid metabolic disorder promoting purine metabolism by elevating XO activity [71]. Hypertrophy and hyperplasia of adipocytes are associated with higher oxygen consumption, which evokes hypoxic damage in other tissues, resulting in the chronic inflammation of obesity [72]. Nonalcoholic fatty liver disease and nonalcoholic fatty pancreatic disease subsequently occur when lipid overload occurs in the liver and pancreatic tissue, causing metabolic dysfunction in both and affecting acid-base balance. Metabolic acidosis further promotes hypercalciuria, low urine pH and hypocitraturia, predisposing patients to MSU crystal deposition and calcium renal stone formation [73]. In response to excessive FFAs circulation, insulin secreted from pancreatic β-cells upregulates the expression of renal urate transporters, including GLUT9 and URAT1, and decreases ABCG2 levels, promoting high SUA levels [18]. Uric acid conversely induces lipid accumulation and insulin resistance (IR), thereby forming a vicious cycle of uric acid and insulin [74].
Prior to the onset of IR and obesity, high fat intake has been found to upregulate the expression of reactive oxygen species (ROS) in adipose tissue and liver, along with the metabolic disturbance of adipocytes and the dysregulation of adipokine release [75], promoting or aggravating MSU-mediated NF-κB-dependent inflammation. For example, leptin levels secreted from adipose tissues were elevated in patients with gouty inflammation, and leptin can facilitate MSU-induced acute gout-related proinflammatory cytokine production in macrophages and synoviocytes [76]. The key adipocyte-derived chemokines McP-1 and LTB4 recruit proinflammatory macrophages to induce inflammation amplification, thus aggravating gouty inflammation [77]. Furthermore, a high-fat diet changes gut microbiota composition, leading to reduced microbiota diversity and an increased ratio of Firmicutes to Bacteroidetes and to the reduction of microbiota-derived beneficial metabolites such as butyric acid, which further aggravates gouty arthritis [20].

High Sugar
Sugars are the most abundant macromolecules in nature and can be classified according to their structure into monosaccharides, complex carbohydrates, and glycoconjugates [78]. They are the primary carbon source for ATP production and cellular biosynthesis. Sugars from diets can be absorbed as glucose, galactose or fructose in the liver portal circulation. The liver and gut normally process galactose and fructose into lactate, glucose and organic acids through gluconeogenesis, glycogenolysis, aerobic oxidation and other pathways [78]. High sugar consumption might initiate metabolic disease processes accompanied with hyperglycemia, IR, and fat accumulation. Moreover, high sugar intake in obese patients increases serum urate and decreases the percent of uric acid to creatinine clearance, indicating a close association between hyperuricemia and a high sugar diet [79]. Sugar-sweetened beverages containing high-fructose corn syrup and sucrose or almost equal amounts of fructose and glucose, which account for approximately one-third of added sugar consumption in the diets of American adults [80], have been thought to be closely connected with a high prevalence of hyperuricemia in Western countries [81].
Long-term high sugar consumption has been found to accelerate the accumulation of uric acid and promote MSU deposition in fly renal tubules, suggesting that a similar problem may occur in human excretory systems under dietary challenges [82]. In a follow-up study of 650 participants, the results confirmed that a high-sugar diet participates in kidney dysfunction and uric acid metabolism disorders [82].
The metabolic effects of sugar are distinct from those of starch principally because of the fructose component. Studies of dietary sugar intervention in animals and humans have demonstrated that overconsumption of fructose, but not glucose, can manifest multiple traits of metabolic syndrome [83][84][85], indicating that fructose might be responsible for high sugar-driven hyperuricemia and gout [86]. Fructose metabolism starts within the small intestinal tissue, where fructose can be absorbed by the facilitative hexose transporter GLUT5 (SLC2A5) and converted by ketohexokinase. Notably, exposure to high fructose increases the intestinal villus length to expand the surface area of intestinal cells that can absorb more nutrients from food [87], possibly aggravating high fructose-mediated metabolic disorders via overconsumption of nutrients. Excessive fructose consumption-induced gouty syndrome is related to the altered gut microbiota and its metabolites and induces inflammation and fatty acid disorders. Since high fructose intake induces the proliferation of mucusdegrading bacteria in the gut microbiota, decreased mucus glycoproteins can promote intestinal barrier damage and pathogen invasion [88].
Fructose-derived metabolites can be transferred from the intestinal tissues to the liver and systemic circulation, and the redundant fructose can also directly reach the hepatic tissue or enter the systemic circulation when the intestinal clearance capacity reaches an upper limit [89]. Fructose culminates the main rate-limiting step of glycolysis and is rapidly converted into ketohexokinase to generate fructose-1-phosphate, which is further metabolized into glyceraldehyde 3-phosphate and dihydroxyacetone phosphate. The acute fructose overload in the liver leads to ATP degradation and a decrease in ATP synthesis, both of which lead to an increase in AMP levels and stimulation of AMP deaminase activity, subsequently accelerating the formation of uric acid with consequent hyperuricemia. More notably, the costly fructose metabolism can also result in renal inflammation and fibrosis and form kidney stones due to calcium salt precipitation in high-fructose diet-fed mice [90]. Alarmingly, a normal physiological concentration of fructose in the kidney still causes a risk of defective elimination of uric acid and activation of renal inflammation by increasing the expression of intercellular adhesion molecule-1 in the serum and endothelial cells [91]. Therefore, carbohydrate restrictions, especially fructose intake, have been regarded as an efficient diet intervention for gouty patients to modulate the disease state. It has been shown that the intake of fructose-rich fruits could bring about a temporary upregulation of uric acid. However, the moderate consumption of these foods over a long time can facilitate the excretion of uric acid, which could be correlated with the alkalization of body fluids [92]. Therefore, it is always suggested that limiting fructose-rich soft drinks or reducing the consumption of high-fructose drinks rather than fruits is better for gout improvement.

High Protein
Proteins are biomacromolecules formed by folding long chains of amino acids, and dietary protein digestion in the gastrointestinal tract can provide amino acid dipeptides and tripeptides for cellular metabolism and protein synthesis in muscle or other tissues. High protein consumption is well known for its promotion of energy expenditure and urea synthesis. In addition, high dietary protein intake can also affect uric acid homeostasis, since protein digestion can generate several amino acids, such as glutamine, glycine and threonine, to induce purine synthesis, promoting the development of hyperuricemia [93]. A cohort study with 193,676 participants further revealed that higher nondairy animal protein consumption results in a disturbance of uric acid metabolism, including a reduced level of citrate and a higher level of uric acid and acidic urine, which subsequently promotes uric acid stone formation [94]. In addition, long-term high dietary protein intake has been shown to have adverse effects on uric acid elimination due to increased intraglomerular pressure and flow in kidney tissues [95]. The severity of glomerular damage has been significantly attributed to elevated SUA levels; hence, dietary recommendations for gouty patients often suggest that excessive protein intake should be restricted to avoid placing kidney tissue under undue stress.
Studies have also shown inconsistent effects of dietary proteins from different sources [96]. Overconsumption of animal proteins is linked to an elevated prevalence of gout, whereas overconsumption of plant protein (soybeans and soy products) or dairy product intake are associated with a reduced risk [8,96]. When compared with foods rich in plant proteins, an animal protein-rich diet promotes acidic urine production and uric acid stone formation [94]. Conversely, substitution of plant-based protein for a carbohydrate-rich diet can attenuate IR and compensatory hyperinsulinemia [97], thus improving the renal clearance of urate. Therefore, choosing appropriate dietary protein sources and controlling the amount of protein intake might represent an effective intervention for the improvement of gouty diseases.

Vitamins
Vitamins are essential trace elements that act as regulators of physiological and pathological functions, such as participating in immune responses, antioxidant activities and redox reactions. It has been demonstrated that an adequate intake of vitamin supplements or consumption of vitamin-rich fruits and vegetables seems to be a valid approach for hyperuricemia and gout treatment. Vitamins such as vitamin A, vitamin E, and vitamin C show beneficial effects against oxidative stress and inflammation, as well as effectively decreasing SUA levels [98][99][100], and the same uric acid-lowering effect also appears in a vitamin D-rich diet [101]. Additionally, vitamin E is also considered a membrane stabilizer that inhibits MSU crystal-induced hemolysis [102]. Many studies performed in humans and animals have shown that vitamin C (l-ascorbic acid) consumption can affect uric acid reabsorption and excretion to reduce SUA levels [100]. Both uric acid and vitamin C can be reabsorbed in the proximal tubule via anion-exchange transport, and vitamin C overload can competitively suppress the reabsorption of uric acid [103] in the filtrate. Meanwhile, its downregulation of URAT1 activity and/or Na + -dependent anion cotransporter could promote uric acid excretion [100]. The uricosuric function of vitamin C also appears to directly act on the glomerulus by reducing glomerular microvascular ischemia and increasing afferent arteriole dilation, thus increasing the glomerular uric acid filtration rate [104]. Furthermore, vitamin C reduces the incidence of gout by alleviating the NF-κB/NLRP3-related inflammatory response to MSU deposition [105].

Minerals
Minerals, including potassium, zinc, calcium, copper, iron, and selenium are micronutrients that are essential for body metabolism [73], and deficiencies or excesses of these micronutrients are potentially hazardous occurrences that might be involved in the development of gout. It is well known that dietary potassium consumption has obvious diuretic and natriuretic effects, and even a minor potassium insufficiency triggers an impairment in the kidney's capacity to secrete sodium chloride and retain sodium [106], resulting in renal dysfunction, while long-term routine potassium replenishment aggravates thiazide diuretic-mediated elevation of uric acid [107]. A similar facilitation effect was observed when iron accumulation triggers increased saturated transferrin-mediated XO activity [108,109]. Minerals also have a crucial role in maintaining acid-base balance. This has been attributed to keeping urine electrically neutral by regulating the secretion of anions such as chloride, sulfate, and phosphate in kidney tissues [73]. For instance, urinary calcium loss is a crucial risk factor that can trigger calcium stone formation and cause a uric acid excretion disorder [73]. Normal calcium intake can decrease the potential risk of kidney stone formation and is conducive to uric acid elimination in renal tissue [110,111].

Fibers
Dietary fibers refer to plant-derived carbohydrates that are resistant to hydrolyzation or assimilation in the upper gastrointestinal tract, and fibers trapped in the gut can increase intestinal viscosity and satiety, as well as reduce gastric emptying rate and regulate intestinal conduction [112]. Correspondingly, dietary fibers reduce the intake and absorption of high-energy food [113]. The consumption of dietary fibers can manage glucose and lipid metabolism to regulate energy balance [113,114]. More importantly, a lack of these fibers leads to a slower recovery of gut dysbiosis, and dietary fiber supplementation is able to improve the composition of the gut microbiota [115], suggesting a close connection between fiber and intestinal flora disorder in gout patients. The fiber fermentation process by gut microbiota accompanies the release of microbiota-driven metabolites (short-chain fatty acids, SCFAs) that show beneficial effects on the host's health [116]. After dietary fiber intake, acetate is the most abundant microbiota-derived SCFAs in the blood and can quickly resolve MSU-induced inflammation by promoting caspase-dependent apoptosis of neutrophils and the excretion of the anti-inflammatory IL-10 against LPS-induced inflammation [31]. Butyrate is another SCFAs mainly produced by microbiotal fermentation of indigestible fibers, and has been shown to improve lipid accumulation in the liver and pancreas, thereby reducing uric acid metabolism abnormalities by XO activation [71]. Butyrate can also decrease the activation of NF-κB induced by LPS and the translation or transcription of IL-1β by inhibiting histone deacetylases in human peripheral blood mononuclear cells [117]. Therefore, the consumption of more fiber-rich whole grains, vegetables and fruits is beneficial for regulating gastrointestinal homeostasis, reducing the intake of unhealthy foods and reshaping the gut microbiota. Meanwhile, the salutary metabolites produced by the microbiota-induced digestion of dietary fiber can regulate the inflammatory state of gouty patients and reduce uric acid production, all of which are conducive to the management of gout.

Recommended Nutritional Management and Its Combination with Drug Therapy
The close association of specific foods with SUA levels, as shown in Table 1, illustrates that the essential impact of food on health is ascribed to the synthesized effects of the nutrients from food, specifically the dominant or beneficial nutritional factors determining the final performance. Taking dairy products as an example, the increased intake of dairy products, especially those with low fat, can reduce the incidence of gout [8]. Late season skim milk, which contains higher levels of orotic acid than early season skim milk, has a preferential impact on the excretion of uric acid [118]. Moreover, glycomacropeptide and G600 milk fat addition in skim milk can greatly and effectively relieve joint pain and the frequency of gout flares [119].
The dietary management for gouty patients is commonly self-prescribed and centers around the control of purine sources, such as reduced consumption of purine-rich foods, which theoretically attenuates uric acid production; but patients often fail to adhere to recommendations in the long term due to the limited palatability of purine-free diets [34,37]. Although piecemeal modifications of the various yet limited numbers of nutrients often provide incomplete dietary recommendations [34], attention should be given to nutrient richness and structure to avoid the burden of inappropriate dosage. For example, the plasma concentrations of vitamin C saturation ranges daily from 200 to 400 mg, implying that exceeding the recommended supplemental dose has little effect on the consequences [120]. More importantly, taking high-dose and long-term supplements of vitamin C may be associated with adverse effects, and the resulting excessive uric acid excretion could elevate the risk of kidney stones in gouty patients [121,122]. As shown in Figure 3, recommended nutritional interventions should emphasize the necessity for appropriate supplementation of plant-derived fibers and dairy-derived protein and persuade patients to avoid high-compensation consumption of refined saturated fats and carbohydrates [34]. The typical dietary patterns include a DASH and Mediterranean diet, both of which are comprised of fruits, vegetables, and low-fat dairy products with reductions in total and saturated fats. Increasing evidence supports that consuming a DASH diet can continuously attenuate SUA in hyperuricemia patients and reduce the incidence of gout in participants [34,45]. Similar SUA-lowering effects have been observed in a research investigations of the Mediterranean diet [58]. Moreover, intervention with the DASH diet combined with adequate sodium and plant-derived protein shows more beneficial functions in reducing SUA levels [33,37]. Recommended food-derived nutritional interventions with anti-gouty mechanisms. Dietary management recommendations for gout patients include appropriate intake of fiber, minerals, and vitamins, as well as the selection of high-quality sugars, fats, and proteins, which are usually of plant origin. In addition, the consumption of products containing probiotics helps regulate intestinal homeostasis in patients with gout. ↑-increase; ↓-decrease; →-maintain; UA-uric acid; HQhigh-quality.
Most cases of dietary management related to uric acid reduction are reported in the nongouty population (as shown in Table 1). Dietary modification against gouty disease is commonly selected as an adjunct therapeutic strategy with medicinal drug therapy [10]; however, clinical trial data on the effects of dietary modifications combined with pharmacological interventions on gout are mostly lacking, as shown in Table 2. By way of illustration, colchicine and nonsteroidal anti-inflammatory agents (NSAIDs) have been used to treat acute gouty inflammation. Their combined use with dietary micronutrient supplementation can remedy micronutrient deficiency induced by NSAIDs and colchicine [123,124]. Allopurinol, a first-line drug used as a xanthine oxidase inhibitor against gout, requires high protein replenishment to facilitate renal clearance [125]. Therefore, our recommendation is for individuals to follow a healthy diet for prevention purposes, and for patients with mild gout, we recommend the DASH and Mediterranean diet, which focus on plant-based components. Additionally, we recommend a reduction in the consumption of high-fat foods (fast food and cream products), especially foods with trans fatty acids (such as margarine and butter), and for individuals to pay attention to the amount of nutrient supplements consumed. For patients with severe gout, dietary modification and medication should be combined, and health care providers should remind patients of food-drug interactions to achieve synergistic effects. •SUA significantly ↓ in the intervention groups •6 months after the intervention, SUA shows an elevation tendency in the low-purine diet + medication group and medication-only group •6 months after the intervention, SUA shows a continuous drop in the low-purine diet group Note: Data are from clinical trials that have been included in PubMed. A direct search was used to search for the following terms: "diet" or "food" with "drug" or "medicine" or "treatment" with "gout" or "hyperuricemia"; "diet" or "food" with commonly used clinical anti-gout drugs including "zurampic (lesinurad)", "colchicine", "febuxostat", "allopurinol", "probenecid", "aspirin", "pegloticase", "benzbromarone" and "etoricoxib". A total of 751 articles were obtained. After following these exclusion criteria-repetitive articles, dietary supplements, drug interactions, formulation improvement, exercise interference, nonmarket food and mismatched intervention subjects-a total of 7 articles showed the effect of the combination of diet and medication in the treatment of gout. ↑-increase; ↓-decrease; AUC-area under curve; C max -maximal plasma concentration; SUA-serum uric acid; T max -time to reach C max .

Conclusions and Future Perspective
Our study has shown the important role of diet in gout development and management and how dietary adjustments based on nutrient composition should be an important component of routine care for gout. Gout patients are commonly prone to choose health management by dietary modification because diet changes can instantly affect gout flares via multiple signaling pathways. Diet-induced systemic metabolic pathways, including purine, lipid, and glucose metabolism, as well as energy balance and gut microbiota changes, have provided new mechanistic insights and potential interventions for gout progression. Since foods are eventually metabolized into multiple nutrients for metabolic homeostasis in the body, dietary modification might represent an appropriate nutritional regulation for gout patients or for potential patients to effectively reduce the incidence of gout. The critical role of nutritional factors on gout development also supported the following recommended nutritional modification strategies: (1) reducing nutritional risk factors against metabolic syndrome; (2) supplementing with beneficial nutrients to affect uric acid metabolism and gouty inflammation; and (3) considering nutritional modification combined with medication supplementation to decrease the frequency of gout flares. Our consistent principle is that, in terms of diet, nutritional balance should be analyzed from the point of view of enrichments and structures of nutritional elements. Evidence supports that a low-fat, low-carb, plant-based dietary intervention is suitable for gouty patients; however, we need to pay specific attention to the golden rule of healthy dietary intake, that is, moderation. In addition, we advocate the combination of medications and dietary modification for gouty patients in therapy, and caution that they should note the impact of nutritional factors on drug pharmacokinetics and pharmacodynamics. However, many human studies focusing on the relationship of food and SUA levels often do not involve gouty patients. A limited number of clinical research studies explore food/nutrition and gout or anti-gout drugs, resulting in limited being drawn conclusions. In conclusion, the dietary mechanisms and nutritional basis provide scientific evidence for the prevention and improvement of gouty diseases, and dietary modifications based on effective regulatory mechanisms may be a promising strategy to reduce the high prevalence of gout.
Author Contributions: Y.X. and H.X. initiated the idea and performed the study. Y.Z. and S.C. wrote the manuscript. Y.Z., S.C., M.Y., Y.X. and H.X. discussed and revised the manuscript. H.X. has final responsibility for all parts of this manuscript. All authors have read and agreed to the published version of the manuscript.