Gout: Global Burden, Pathogenic Mechanisms, and the Emerging Role of Urolithins in Alleviating Hyperuricemia

Gout: Global Burden, Pathogenic Mechanisms, and the Emerging Role of Urolithins in Alleviating Hyperuricemia

Gout affected ~55 million people globally in 2020 (22.5% prevalence rise over 30 years), with 3x higher rates in men than women and a projected 96 million cases by 2050 (shifting to low-/middle-income countries). Its pathogenesis involves genetics, gut microbiota imbalance, and elevated uric acid (excess production via xanthine oxidase or poor excretion). Urolithins (from fruit/nut ellagitannins metabolized by gut microbes) show promise: Urolithin C lowers serum uric acid (SUA) better than A/B in mice via enhancing renal excretion; Urolithin A reduces plasma uric acid by inhibiting hepatic xanthine oxidase. This work underscores gout’s global burden and urolithins as potential natural interventions.

A Fascinating Dive into a Growing Global Health Challenge and Nature’s Potential Solution

Imagine waking up one morning with a sudden, searing pain in your big toe—so intense that even the weight of a bedsheet feels unbearable. This is not just a random ache; it could be a telltale sign of gout, a form of inflammatory arthritis that has plagued humanity for centuries, yet its prevalence continues to surge worldwide like an unwelcome tide. Once dismissed as a “disease of kings” linked to excessive indulgence in rich foods and wine, gout is now a global health concern affecting millions across all walks of life, from high-income nations to low- and middle-income countries. As its footprint expands, scientists and researchers are racing to unravel its complex origins—from genetic codes to the hidden world of gut microbes—and discover effective ways to combat it. Among the most promising breakthroughs? Urolithins, natural compounds derived from everyday fruits and nuts, which are stepping into the spotlight as potential allies in the fight against high uric acid, the root cause of gout. Let’s delve into the latest science behind gout’s global rise, its complex pathogenesis, and how these tiny molecules produced in the gut may hold the key to better management.


According to a recent annual review article titled Gout: one year in review 2025, published in the journal Clinical and Experimental Rheumatology, approximately 55 million people worldwide were living with gout in 2020. The age-standardized prevalence of the condition stood at around 660 cases per 100,000 individuals, marking a 22.5% increase over the past three decades. In 2020, the global prevalence of gout among men was roughly three times higher than that among women, and this prevalence tended to rise as age increased. Looking ahead, it is projected that the number of people with gout will climb to 96 million by 2050—a shift that suggests the burden of gout may shift from high-income countries to low- and middle-income nations over the next 30 years. On a global scale, the United States has seen the highest increase in gout prevalence, at 90.6%, followed by Australia (45.9%) and Canada (30.3%).



1. The Pathogenic Mechanisms of Gout

The article Gout: one year in review 2025 highlights that genetic factors play a pivotal role in the onset and progression of gout. There is a strong genetic correlation in uric acid levels between populations in Europe and East Asia, with no significant differences observed between the two groups. However, a notable distinction exists: individuals of European descent tend to have higher uric acid levels in cardiovascular tissues, whereas those of Asian descent show higher uric acid concentrations in immune and respiratory system tissues—such as the nasal mucosa.

Additionally, emerging evidence points to changes in the gut microbiota (which includes bacteria, fungi, mycoplasmas, viruses, and archaea) as a factor influencing the development and progression of gout. A separate study further supports this, revealing that compared to healthy control subjects, individuals with gout exhibit reduced richness and diversity in their gut microbiota. This imbalance in gut microbes contributes to the pathogenesis of gout by affecting purine metabolism, uric acid excretion, and the activation of the NLRP3 inflammasome.


The pathological process of gout is characterized by elevated uric acid levels in the early stages and the onset of inflammation in the later stages. Elevated uric acid levels primarily stem from either excessive uric acid production or insufficient uric acid excretion. The production of uric acid is closely linked to xanthine oxidase (XO), an enzyme that catalyzes the conversion of hypoxanthine and xanthine into uric acid. Abnormal increases in XO activity or elevated XO expression levels can lead to overproduction of uric acid.



2. Urolithins in Improving Hyperuricemia

Back in 2016, researchers from the University of Washington published a study in Nature Medicine showing that urolithin A can promote mitophagy (the process of removing damaged mitochondria) and extend the lifespan of Caenorhabditis elegans (a type of roundworm) by 45%. This discovery established urolithin A as the first naturally occurring compound scientifically recognized for its ability to enhance mitophagy. In 2019, the first human clinical trial involving urolithin A demonstrated its anti-aging effects, specifically by significantly boosting the body’s overall fatty acid oxidation—a key indicator of mitochondrial function. The remarkable potential of urolithin A in optimizing mitochondrial metabolic efficiency has since drawn significant attention from researchers in the fields of longevity science and health.


2.1 The Existence and Formation of Urolithins

Urolithins are not widely found in nature in their direct form; instead, they are catabolites derived from ellagitannins. Ellagitannins, in turn, are a class of plant polyphenols present in various fruits (e.g., pomegranates, strawberries) and nuts (e.g., walnuts). Most ellagitannins enter the colon, where they are primarily metabolized by colonic microbes to form urolithins.

A study using Iberian pigs as a model explored how ellagitannins are converted into urolithins, shedding light on the intestinal production process of different urolithin types. The process unfolds as follows: first, ellagitannins are metabolized by gut microbiota in the body to form ellagic acid. Next, one lactone ring of ellagic acid is removed, producing tetrahydroxyurolithin. Subsequent removal of hydroxyl groups from tetrahydroxyurolithin then leads to the formation of urolithin A, urolithin B, and urolithin C. Analyses of plasma and urine samples revealed that urolithin A glucuronides and sulfates (the primary in vivo forms of urolithin A) are the major metabolites, while urolithin C glucuronides and sulfates, along with urolithin B glucuronides and sulfates (urolithin C and urolithin B are two types of bile acids that mainly exist in the body as glucuronides and sulfates), serve as minor metabolites.



2.2 Research on Urolithin C in Reducing Uric Acid

On September 1st, a Chinese research team published a study in the Journal of Agricultural and Food Chemistry showing that urolithin C can alleviate renal dysfunction by inhibiting the ROS-p38/ERK MAPK axis, thereby improving hyperuricemia.

Studies conducted on hyperuricemic mice demonstrated that urolithin C can significantly lower serum uric acid (SUA) levels—and its effectiveness in this regard is superior to that of both urolithin A and urolithin B. The research employed a hyperuricemic mouse model and a uric acid-induced human renal tubular epithelial cell model to investigate the mechanism by which urolithin C reduces uric acid. The mechanistic findings revealed that urolithin C relieves hyperuricemia by enhancing renal uric acid excretion, while also mitigating renal oxidative stress and fibrosis.

Furthermore, urolithin C inhibits uric acid-induced activation of the p38/ERK MAPK pathway by reducing the production of reactive oxygen species (ROS). Additional experiments confirmed that urolithin C improves the expression of renal uric acid transporters and fibrosis markers by inhibiting the p38/ERK MAPK pathway. Collectively, the in vitro and in vivo results indicate that urolithin C can promote renal uric acid excretion by correcting the imbalance in the expression of uric acid transporters.



2.3 Research on Urolithin A in Reducing Uric Acid

Earlier studies have evaluated the antihyperuricemic effects of urolithin A in cultured hepatocytes and a mouse model of hyperuricemia. In the cultured hepatocyte experiments, a 100 µM concentration of the compound was used to assess its ability to inhibit uric acid production in hepatocytes without causing cellular damage. The results showed that ellagic acid, urolithin A, and urolithin B all significantly reduced uric acid production in AML12 hepatocytes in a dose-dependent manner. At a concentration of 100 µM, urolithin A exhibited a stronger inhibitory effect than both ellagic acid and urolithin B.

Given that the in vitro antihyperuricemic effect of urolithin A was more potent than that of urolithin B, researchers focused solely on investigating urolithin A’s antihyperuricemic effects in a mouse model of hyperuricemia induced by purine bodies. In these mice with purine body-induced hyperuricemia, oral administration of urolithin A significantly suppressed the elevation of plasma uric acid levels and hepatic xanthine oxidase (XO) activity. Moreover, DNA microarray results indicated that urolithin A—like allopurinol, a potent XO inhibitor—can induce downregulation in the expression of genes associated with hepatic purine metabolism. Therefore, the uric acid-lowering effect of urolithin A is at least partially attributed to its ability to inhibit purine metabolism and uric acid production by suppressing XO activity in the liver.


As gout continues to evolve into a more pressing global health issue, understanding its mechanisms and identifying natural, effective interventions becomes increasingly critical. Urolithins, with their diverse forms and proven ability to target hyperuricemia through multiple pathways—from enhancing renal excretion to inhibiting key enzymes—offer a promising avenue for future research and potential therapeutic development. By bridging the gap between nature’s bounty and scientific innovation, these compounds may one day play a vital role in easing the burden of gout for millions worldwide.


References
  1. Punzi, L., Scagnellato, L., Galozzi, P., et al. Gout: one year in review 2025. Clin Exp Rheumatol. 2025; 43(5):799-808.
  2. Espín, J. C., Larrosa, M., García-Conesa, M. T., et al. Biological Significance of Urolithins, the Gut Microbial Ellagic Acid-Derived Metabolites: The Evidence So Far. Evidence-Based Complementary and Alternative Medicine. 2013; 2013:270418.
  3. Adachi, S.-i., Sasaki, K., Kondo, S., et al. Antihyperuricemic Effect of Urolithin A in Cultured Hepatocytes and Model Mice. Journal of Agricultural and Food Chemistry. 2020; 25(21):5136.
  4. Han, Q., Nan, C., Peng, K., et al. Urolithin C Ameliorates Hyperuricemia by Mitigating Renal Dysfunction through ROS-p38/ERK MAPK Axis Suppression. Journal of Agricultural and Food Chemistry. 2025; [In Press].
  5. He, A., Wang, J., Feng, Y., et al. Terminalia chebula Retz. extract relieves gout arthritis by inhibiting xanthine oxidase, the uric acid transporter, and NLRP3 inflammasome activation. Journal of Ethnopharmacology. 2025; 119848.
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