Uric acid (UA) is synthesized primarily in the liver, intestine, and vascular endothelium. Hyperuricemia (HUA) occurs when UA production exceeds its excretion, a condition regarded as a metabolic disorder. It is generally defined as a serum urate level exceeding 7.0 mg/dL in men or 6.0 mg/dL in women (1). The well-documented consequence of hyperuricemia is an increased risk of gout and the formation of kidney stones. Approximately 20% of the United States population is affected by hyperuricemia (2). Statistically, the prevalence of hyperuricemia is significantly higher in men than in women (3, 4). The etiology of hyperuricemia is multifactorial, encompassing a range of acquired factors. These primarily include increased purine consumption due to dietary intake of meat, alcohol, high-fructose corn syrup, and certain medications such as cyclosporine, low-dose aspirin, and diuretics. Additionally, rare genetic factors can contribute to the condition, including hypoxanthine-guanine phosphoribosyl transferase (HPRT) deficiency and phosphoribosyl pyrophosphate (PRPP) synthase overactivity. Furthermore, myeloproliferative disorders and environmental exposures, such as lead poisoning, temperature fluctuations, and physiological stress, may also lead to elevated uric acid levels (5).

In healthy individuals, approximately 25% of uric acid is excreted through the gastrointestinal tract, in contrast to its renal excretion. Exposure of the gut microbiota to uric acid (UA) may alter the composition of the microbiota (6). Gut microbiota and their metabolites can reduce serum uric acid (SUA) levels by promoting purine and UA catabolism, modulating intestinal UA transporter proteins, enhancing UA excretion, and regulating intestinal barrier permeability to mitigate chronic inflammation (7). Probiotics is a topic of much debate in contemporary scientific discourse. Probiotics are health-promoting products, typically lactic acid-producing bacteria introduced through fermented foods, such as Lactobacillus and Bifidobacterium (8). These bacteria have been shown to benefit human health by preventing or treating diseases and restoring the balance of intestinal flora through mechanisms such as antimicrobial action, enhancement of the integrity of mucosal barriers, and immunomodulation (9, 10). Clinical findings confirm the positive effects of probiotics on gastrointestinal disorders (e.g., inflammatory bowel disease, diarrhea) and immune disorders (e.g., HIV), and studies have also demonstrated the efficacy of probiotics for the treatment of conditions such as obesity, insulin resistance syndrome, type 2 diabetes mellitus, and non-alcoholic fatty liver disease (8, 11). Prebiotics are defined as non-viable food components that confer a health benefit to the host associated with the microbiota modulation. This definition is regarded as the most authoritative to date by the Food and Agriculture Organisation of the United Nations (FAO) (12). It is hypothesized that prebiotics have the capacity to modify the gut microbiota, with distinct prebiotics promoting the proliferation of various gut-colonizing bacteria. However, these alterations are frequently constrained at the level of individual strains and species, rendering them challenging to predict a priori (13). The World Health Organization (WHO), the Food and Agriculture Organization (FAO), the European Food Safety Authority (EFSA), the International Scientific Association for Probiotics and Prebiotics (ISAPP), and other organizations have provided comprehensive classifications of edible prebiotics and probiotics for reference (13, 14).

Despite numerous studies investigating how probiotics and prebiotics modulate the gut microbiota in patients with HUA, extensive cross-sectional studies still fail to assess the risk of HUA prevalence in populations consuming these supplements. Therefore, this study aims to analyze the relationship between probiotic and prebiotic supplements and the prevalence of HUA in U.S. adults. This analysis utilizes data from the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2018 and evaluates whether potential confounders affect this association.

This study is a comprehensive, large-scale, cross-sectional investigation of the association between prebiotic and probiotic consumption and the development of hyperuricemia in US adults. To ensure independence of the association between exposure and outcome, several covariates were included in the analyses, including age, sex, race, BMI, PIR, education level, alcohol consumption status, hypertension, diabetes, and chronic kidney disease. The results of the logistic regression models showed that both the prebiotic- and probiotic-related models calculated ORs of less than 1 regardless of the inclusion of covariates, but only the probiotic-related models were statistically different after testing (crude model: OR = 0.54, 95% CI [0.34, 0.83], p = 0.008; adjusted model 1: OR = 0.58, 95% CI [0.36, 0.89], p = 0.019). This finding shows that probiotic intake may reduce the incidence of hyperuricemia. After we classified the intake of prebiotics and probiotics in detail, further logistic regression analysis suggested that the prebiotic-related model still showed no significant difference but that the protective effect of probiotics alone on hyperuricemia still existed after excluding the impact of prebiotic intake. In addition, the results of the ROC curves we constructed demonstrated the importance of probiotics in the model for predicting hyperuricemia, but unfortunately, the predictive power of the model was shown to be the same, with no significant decrease after removal.

Many experts believe that beneficial gut bacteria provide the host with various nutrients, prevent infections, and regulate immunity, which improves host health (9, 13). Studies have shown that specific gut microbiota can regulate the synthesis and catabolism of purines and uric acid (UA) (6), and conversely, changes in bacterial composition may contribute to the progression of hyperuricemia (20, 21). The prevailing view is that prebiotics and probiotics may alter the gut flora to some extent, thereby reducing the development of hyperuricemia; however, there are fewer extensive cross-sectional studies in this area. In this study, which included 7,176 subjects, logistic regression modeling and calculation of odds ratios confirmed that probiotics play a beneficial role in preventing the development of hyperuricemia and that this effect is not confounded by prebiotic intake.

The preventive effect of probiotics on hyperuricemia may be due to their modulation of the gut flora in favor of the internal environment, which plays a regulatory role in uric acid and purine metabolism (21–24) as a recent study published in CELL has clearly demonstrated the important role of the gut flora in anaerobic uric acid metabolism (25). Several studies have also suggested possible mechanisms in the pathways or influencing metabolism factors. Lactobacillus, Bifidobacterium, and Saccharomyces cerevisiae have been used safely and effectively as probiotics for a long time and are the most studied probiotics (26). Using these probiotics alters the abundance of the gut flora, disrupting the existing balance and shifting the internal environment in a more favorable direction (23, 24, 27). Furthermore, certain probiotics modulate uric acid levels by altering the metabolic balance of amino acids, unsaturated fatty acids, etc. (20, 28, 29) and affect extrarenal excretion by inhibiting the transport process of urate transport proteins (e.g., SLC22A11, SLC17A3, and SLC2A9) in the gut (6, 22, 30). Regulation of uric acid oxidase (uricase), xanthine oxidase (XO), and xanthine dehydrogenase (XDH) activities by different bacterial strains also impair purine absorption and alter the balance of the intestinal flora, which can attenuate or exacerbate hyperuricemia. This has been demonstrated by experimental results with strains of Lactobacillus fermentum JL-3 (31), Lactobacillus rhamnosus Fmb14 (32), L. plantarum (33), and others.

Besides the metabolic factors mentioned above, scientists such as Kim and Hou have suggested that uric acid has a dual role as an antioxidant and an inflammatory promoter, suggesting that immune function is also crucial in the pathogenesis of hyperuricemia and gout (27, 29). A study using a uric acid oxidase knockout (Uox-KO) mouse model with experimentally observed intestinal immune dysregulation and impaired intestinal barrier demonstrated that impaired intestinal integrity contributes to the pathogenesis of HUA. Also, it proposed that the gut microbiota profoundly influences purine nucleotide catabolism and CD4+ Th17 cell infiltration by disrupting amino acid (AA) metabolism, in which CD4+ Th17 cells play an essential role in HUA and gout inflammation (6).

Most studies consider prebiotics to be alternatives to probiotics or additional supplements that stimulate the growth and activity of beneficial bacteria in the gastrointestinal tract, with natural products such as inulin and lactose being essential sources of prebiotics (10). The mechanism of action of prebiotics is not fully understood, with articles suggesting that the health-promoting effects of prebiotics are related to bifidobacteria (26, 34). Meta-analyses have also been conducted to investigate the effects of prebiotics on metabolites such as short-chain fatty acids (SCFAs), but with mixed results (35–37). In our study, the regression models constructed with or without adjustment for covariates yielded OR values less than 1, but the tests were not statistically different, which may indicate that the effect is relatively weak, requires prolonged administration, accumulates in the body at higher concentrations, or is affected by other confounding factors that were not included, such as different intestinal conditions.

Among the subjects enrolled in our study, hyperuricemia tends to have demographic characteristics such as older age, male predominance, a higher proportion of Non-Hispanic White participants, higher BMI, lower PIR, also slightly lower educational level, and more smoking preference, and in terms of disease state, it may be more likely to be comorbid with underlying conditions such as HBP, DM, and CKD. These characteristics are consistent with previous studies of hyperuricemia in the NHANES database (38, 39) and highlight the importance of controlling for covariates when assessing the relationship between probiotic intake and HUA. Several studies further discussed the association between diseases; for example, Krishnan (40) found a non-linear association between hyperuricemia and glomerular function, with prevalence increasing with decreasing glomerular function and that an eGFR of 60 mL/min/1.73 m² appears to be the threshold for a dramatic increase in the prevalence of gout; and several reviews have further examined hypertension, diabetes mellitus, chronic kidney disease and hyperuricemia, and it is generally accepted that hyperuricemia is strongly associated with these diseases and may even be an independent risk factor (41–43). However, a report from a scientific workshop organized by the National Kidney Foundation also points out that these associations need to be supported by additional clinical studies and that routine treatment of hyperuricemia in patients with hypertension, nephropathy, or metabolic syndrome/type 2 diabetes mellitus is not recommended at present (44).

Discussing these factors above, combined with epidemiological studies related to hyperuricemia and gout, can confirm the significant influence of age, gender, race, education level, BMI, etc., on hyperuricemia (45). Meanwhile, there are also some machine learning studies confirming the significant influence of poor lifestyle, abnormally high biochemical indices such as creatinine, lipids, and glucose, as well as hypertension, heart failure, diabetes mellitus, and end-stage renal disease, and other underlying diseases have a notable influence on adverse clinical outcomes in hyperuricemia (46). Therefore, our study also constructed a disease prediction model, calculated AUC values, and plotted ROC curves. The results showed that the value of factors such as age, sex, ethnicity, BMI, HBP, and CKD in predicting hyperuricemia was remarkable. Unfortunately, although the AUC values obtained before and after the addition of probiotics differed and showed better predictive performance, this effect was not statistically significant (AUC: 0.7877 versus 0.7886, Z = 1.626, p = 0.104). This result suggests that probiotics are not suitable for inclusion in a prediction model for hyperuricemia. Fortunately, there was no significant interference between probiotic consumption and these disease predictors after subgroup analyses.

As with most studies, our study has several limitations. First, we selected data from 2011 to 2018 for cross-sectional analyses to examine associations between prebiotics, probiotics, and hyperuricemia outcomes in the US adult population. This design limited our ability to determine temporality and causality. Second, the data collected were self-reported, which may introduce recall bias and affect the accuracy of the information. Third, the pathogenesis of hyperuricemia is complex, and our study did not adjust for all possible confounders, such as unspecified medication use, dietary habits, or genetic predisposition. These limitations suggest that further longitudinal studies with more controlled variables are needed to understand the relationship between probiotics and hyperuricemia better.

Our study suggests that probiotic consumption is associated with a reduced risk of hyperuricemia in the US adult population but is not suitable for inclusion in disease prediction models, in contrast to the notable effect of prebiotics on hyperuricemia. However, this finding needs to be confirmed in future longitudinal prospective studies.