Gut microbiota capable of metabolizing uric acid and purines may play a key role in reducing gout diagnoses, and although the findings from new retrospective and prospective studies suggest key roles in how such microbiota could be exploited, human interventional trials to date have been disappointing.

Those were some of the messages from a session at the Gout Hyperuricemia and Crystal Associated Disease Network Annual Research Symposium (G-CAN) 2025 in Chicago.

There are some 150 known species of microbes that inhabit the human gut, and they are “phenomenal biochemists. They metabolize everything that we put in our mouth. They transform it; they get energy. They get carbon [and] nitrogen, and they make metabolites that influence our health,” Federico E. Rey, PhD, a professor of bacteriology at the University of Wisconsin–Madison, said during his presentation.

And it isn’t just bacteria. Yeast can colonize the human gut, sometimes transiently, and they may manipulate uric acid levels in the intestine and possibly even systemically, according to Rey. Meanwhile, bacteria metabolize flavonoids into compounds that may prevent atherosclerosis and complex plant polysaccharides into short-chain fatty acids that affect the immune system, gut motility, insulin sensitivity, and blood pressure. In mice, microbiota also metabolize uric acid secreted into the gut, generally increasing purine concentrations in the gut and reducing circulating uric acid levels. They can also produce detrimental metabolites such as trimethylamine N-oxide, which is associated with impaired kidney function and inflammation, according to Rey.

These discoveries may open opportunities for personalized nutrition to help modulate some of the symptoms associated with gout, Rey said. “There are thousands of metabolites that bacteria make that influence all aspects of our biology. What is really exciting to me and frustrating at the same time is that because each of us has a unique community, we can all eat [the same thing], and the abundances of each one of these metabolites will vary. Some of us may not make any of dihydroxyl benzoic acid. Some of us make a lot of butyrate, some of us make very little.”

That has prompted searches for microbes that deplete uric acid or purines from the gut, and Rey believes that such actions affect inflammation and transport of purines to the kidneys.

Purine levels are lower in germ-free mice than in conventional mice; they also have higher levels of waste products from uric acid metabolism, such as allantoin. “So those sort of give us a hint that maybe microbes [represent] a new way to break down uric acid,” Rey said. His group conducted an experiment in which fecal samples from 15 healthy humans were used to colonize 15 germ-free mice. When they measured metabolites, they found up to a threefold difference in circulating uric acid levels between the animals. “These mice are genetically identical. These mice have all eaten the same food, yet we see a threefold change from the ones with the lowest to the highest in the levels of uric acid. I think there’s a lot of knowledge to uncover here,” he said.

One known mechanism of modulating uric acid levels in the blood is metabolism of uric acid and purines, and probiotics with uricase activity have been found to lower uric acid levels in preclinical and some clinical studies.

Such pathways are highly regulated in microbes. “Bacteria having the presence of these genes in the gut doesn’t mean that these genes are being expressed and that those proteins are degrading uric acid,” Rey said. Microbes have specific nutrient needs that can also interfere with normal function, and adding glucose can dampen degradation of uric acid. “And you can imagine that these signals don’t just take place in a petri plate. They also play out in the gut of a human or a mouse,” he said. Researchers are working to identify signals and how they play out in living systems.

Meanwhile, some researchers have turned to probiotics as a potential solution, but clinical studies have been disappointing, according to Rey. “The bottom line is if you put a bacterium or probiotic that has a capacity to hydrolyze purines or uric acid in a mouse, typically you see a decrease in uric acid. When we try to do the same thing in humans, it doesn’t work that great,” said Rey, who referenced a meta-analysis illustrating the general failure. One potential issue is that the production of probiotics is not standardized. “In the lab, we can do a lot of things to make sure that the bacteria we’re giving are viable. It’s a very different situation when someone takes it at home or when the probiotic sits 2 months in the store before someone buys it,” he said.

Effect of Fiber Intake on Gout Risk

Sharan Rai, PhD, a research fellow at Massachusetts General Hospital and Harvard Medical School, Boston, discussed a couple of studies related to microbiota and the risk for gout.

The first study examined the impact of long-term dietary fiber intake on the risk for incident gout. “As fiber is a substrate for gut microbial fermentation that produces beneficial, anti-inflammatory metabolites, it may also therefore have a role in modulating the risk of gout,” Rai said during her presentation at G-CAN 2025.

Rai and her colleagues studied 80,175 women in the prospective Nurses’ Health Study, which relied on self-reported data and cumulatively averaged responses from questionnaires completed at baseline and every 4 years for diet and every 2 years for lifestyle factors. The researchers used US Department of Agriculture sources to calculate the intake of cereal fiber, fruit fiber, vegetable fiber, and legume fiber for each individual and divided fiber intake into five quintiles.

Over a follow-up of more than 2.2 million person-years, there were 1117 incident cases of gout. Those in the highest quintile of fiber intake had a lower risk for a gout diagnosis than those in the lowest quintile (hazard ratio [HR], 0.69; 95% CI, 0.56-0.87). There was no significant difference in gout diagnosis among the other quintiles when compared to the lowest quintile. When the researchers limited the analysis to cereal fiber, there was a statistically significant decrease in the risk for gout in all quintiles of cereal fiber intake above the lowest, and the risk was lowest in the quintile with the highest intake (HR, 0.61; 95% CI, 0.50-0.76). Fruit and legume fiber did not have strong associations with gout risk, although fruit fiber trended toward a reduction in risk in the two quintiles with the highest intake.

“This supports the hypothesis that greater dietary fiber intake, which can support the growth of human gut purine-degrading bacteria and other gut microbiota that affect urate homeostasis, may help to prevent gout,” Rai said. Limitations of the study included the retrospective, self-reported nature of dietary data and that participants have higher economic status and are predominantly White than the general population.

Effect of the Presence of Urate-Metabolizing Bacterial Genes on Serum Urate Levels

Rai also presented a study that examined the relationship between urate-metabolizing bacterial genes and serum urate levels in a human population. Some gut bacteria have a highly preserved cluster of genes that encode enzymes that degrade urate in anaerobic conditions. It’s been unknown how well these specific bacterial genes correlate with serum urate levels in humans who do not have functional genes for enzymes that degrade urate.

The researchers analyzed stool and plasma samples collected between 2016 and 2019 from 935 men and women participating in the third generation of the Framingham Heart Study, stool and plasma samples collected between 2012 and 2013 from 296 men participating in the Men’s Lifestyle Validation Study (a substudy of the Health Professionals Follow-Up Study), and stool and plasma samples collected between 2013 and 2014 from 207 women participating in the Mind Body Study (a substudy of the Nurses’ Health Study II).

They looked for the presence of five recently characterized urate-metabolizing genes and linked them to urate metabolite assays from the serum samples. Genetic analyses revealed the five genes to be present in 15 separate bacterial species. In 48 instances of these urate-metabolizing genes across the 15 bacterial species, there were eight that were correlated with serum urate level in two of the cohorts and 20 that were correlated with serum urate in at least one cohort. There were also several instances in which the genes were significantly and inversely correlated with serum urate levels. There were also some differences between sexes that the researchers plan to investigate in future studies.

“This translational proof-of-concept study does show that greater abundance of some of these genes is significantly correlated with lower urate in three human cohorts, and these gut species identified may be particularly relevant to hyperuricemia and gout, for example, through their capacity for anti-inflammatory short-chain fatty acid production. And finally, these findings do continue to support the potential modulation of urate by the gut microbiome in humans,” Rai said.

In comments to Medscape Medical News about the bacterial genes study, co-author Robert Terkeltaub, MD, noted the importance of its use of diverse American cohorts, given that most research on dysbiosis and gout comes out of China and because gut microbiome diversity is lower in patients with gout than in control populations. “One key point was that [Rai] used American cohorts, and that also there were sex differences in the results. Sharan Rai’s work is very important because she showed that there’s positive and negative correlations in these American cohorts with the serum urate level amongst bacteria that differently consume urate,” said Terkeltaub, professor emeritus of medicine at the University of California San Diego and president of G-CAN.

Is Risk for Gout Tied to Antibiotic Use?

Natalie McCormick, PhD, an instructor in medicine at Harvard Medical School, presented research tying the risk for gout to antibiotic use. She noted that in previous research, uricase-deficient mice that were given antibiotics targeting anaerobic bacteria had reduced uric acid metabolism, and when these findings were applied to humans in an analysis of electronic health records, researchers found that exposure to clindamycin, which has anaerobic coverage, was associated with a 30% increased risk for incident gout over 5 years compared with exposure to trimethoprim/sulfamethoxazole, which has limited effect on anaerobic bacteria.

To replicate these findings and extend them to patients with chronic kidney disease (CKD), McCormick and her colleagues conducted a target trial emulation to compare the rates of gout flares among patients in British Columbia, Canada, who were treated with clindamycin vs trimethoprim/sulfamethoxazole, both in those with and without CKD. Over 3 months in more than 600,000 patients, there was a higher risk for incident gout in the clindamycin group (rate ratio [RR], 1.78; 95% CI, 1.52-2.07), which translated to 2.2 additional gout flares per 1000 person-years (95% CI, 1.4-2.8). Among those with CKD, the association was stronger (RR, 3.71; 95% CI, 2.17-6.34), and this translated to 27 additional flares per 1000 person-years (95% CI, 16-37). Among those without CKD, the RR was 1.61 (P for interaction = .003)

“We’ve been able to replicate the findings…and provide further translation of the experimental findings to clinical endpoints in humans, showcasing a dual role for bacterial purine metabolism, both in terms of direct urate homeostasis, as well as reduced gut inflammation through the generation of butyrate and other short-chain fatty acids,” said McCormick.

However, she noted that such effects could also be due to the ablation of other commensal gut bacteria, which help maintain the anaerobic environment and butyrate and acetate levels that can affect inflammation.

The findings “might be able to guide selection of antibiotic therapy in patients with gout or at higher risk of gout, especially those with baseline CKD. Some other implications are evidence from at least the population level that many antibiotic prescriptions are potentially inappropriate and [are potentially overused],” McCormick said.

Difficult-to-Apply Antibiotic Findings to the Clinic

Despite the encouraging findings described by McCormick, it remains challenging to translate them to the clinic, Terkeltaub said. He pointed to another promising approach, which employs generally regarded as safe bacteria, typically lactobacilli, that have been engineered to affect purine metabolism and have oxygen-dependent uricase that can function in the aerobic conditions of the small bowel. “There are studies of varying quality, from very poor to reasonable, in human beings. They find some degree of uric acid lowering in most of those clinical studies,” he said.

Recently, researchers genetically manipulated the nonpathogenic probiotic Escherichia coli Nissle 1917 strain, first identified by Alfred Nissle in a German soldier in 1917 and since shown to be generally protective against pathogenic bacteria and to have favorable effects on some gastrointestinal conditions. The researchers engineered the bacteria to express cluster of genes that together degrade uric acid to pyruvate and lead to the generation of adenosine triphosphate and anti-inflammatory short-chain fatty acids. When fed orally to hyperuricemic mice, the strain not only reduced the serum uric acid level but also associated kidney injury triggered by the elevated uric acid burden. “Even after they stopped the feeding, there was a persistence of this effect of the probiotic for many weeks. It’s not as easy in human beings because of the resistance to invasion colonization by the existing communities of organisms including human gut Enterobacteriaceae,” Terkeltaub said.

An approach that is increasingly used in studies is to put bacterial genes that anaerobically metabolize urate and other purines into nonpathogenic strains such as E coli Nissle 1917 and test them as probiotics. “Logically, it’s the next stage in clinical development of probiotics, with greater promise than other probiotic delivery vehicles such as yogurt,” Terkeltaub said.

Fecal microbiota transplantation, which has been tried in China, is limited due to patient acceptance, according to Terkeltaub. “People had one treatment as part of [a] trial, but they just didn’t want to have it again. It wasn’t a well-accepted therapeutic approach.”

Rey, Rai, and McCormick did not make any financial disclosures. Terkeltaub reported consulting for Crystalys, Shanton, Atom Bioscience, Arthrosi, Novartis, and Scilex.

Jim Kling is a writer based in Bellingham, Washington.