Kidney stones are a common urologic disorder that imposes a significant burden on global public health (Thongprayoon et al., 2020). The global incidence of kidney stones has increased in recent decades, particularly in Western countries and several emerging economies (Romero et al., 2010). In recent years, the diagnosis of kidney stones has gradually increased, driven by changes in lifestyle, dietary habits, and advancements in medical technology (Dai et al., 2019; Ferraro et al., 2020). Studies indicate that ~50% of individuals with kidney stones will experience recurrence within 5–10 years of the initial episode (Siener, 2021). For patients with kidney stones, taking appropriate preventive measures can effectively reduce the probability of recurrence (Fontenelle and Sarti, 2019). Understanding the epidemiologic characteristics of kidney stones and their risk factors is crucial for developing effective prevention and treatment strategies, ultimately reducing the public health burden.

Oral microbiome diversity refers to the variety and abundance of microorganisms, including 56 bacteria, fungi, and viruses, in the oral cavity (Berg et al., 2020). Among the various microbial habitats in the human body, the oral microbiota stands out as one of the most intricate and densely colonized communities (Baker et al., 2024). The diversity of the oral microbiome is essential not only for maintaining oral health, but it also has a significant association with overall systemic wellbeing (Graves et al., 2019). Increasing evidence suggests that an imbalanced oral microbiota may not only lead to oral diseases but also be linked to systemic conditions such as cardiovascular disease, diabetes, and respiratory infections (Wang et al., 2024; Hosomi et al., 2022; Crestez et al., 2024). However, there are fewer direct studies on the oral microbiota and kidney stones, but there are some studies in related fields that provide insights. Research has demonstrated that dysbiosis of the oral microbiota is associated with the advancement of chronic kidney disease, particularly among individuals suffering from periodontitis (Yasuno et al., 2024). Patients with infectious urinary tract stones frequently experience oral health issues, particularly among the elderly and immunocompromised individuals. An imbalance in the oral microbiota may exacerbate urinary tract infections by increasing pathogenic bacteria in the mouth (Jones-Freeman et al., 2021).

Although direct studies on the oral microbiota and kidney stones are limited, existing evidence indicates that a healthy oral microbiome plays a key role in the host's overall health (Wade, 2013). Population-based studies are essential to explore the relationship between oral microbiota and kidney stones, aiming to promote human health and elucidate the underlying mechanisms. Accordingly, we utilized data from the 2009–2011 and 2011–2012 cycles of the National Health and Nutrition Examination Survey (NHANES), a large-scale population-based dataset, to examine the relationship between oral microbiome diversity and the occurrence of kidney stones.

This study investigated the association between oral microbiome diversity and kidney stones using data from a large, population-based survey in the United States. Surprisingly, alpha diversity was negatively associated with kidney stone risk. To ensure the reliability of the results, we conducted the corresponding sensitivity analysis assessment using restricted cubic spline curves and subgroup analysis.

Our study suggests that participants with high oral microbiome diversity were more likely to be young, male, less educated, not hypertensive, unmarried or living alone, and habitual smokers. These demographic and lifestyle factors are linked to a higher risk of kidney stone formation. It is well known that hypertensive patients have increased excretion of calcium and oxalate, which are key factors in stone formation (Poore et al., 2020). In addition, smoking may lead to oxidative stress and renal tubular damage, which may promote stone formation (Tsermpini et al., 2022; Caliri et al., 2021). Thus, the observed association between oral microbial diversity and these risk factors highlights the need for further studies in the future to investigate the potential mechanistic links between the oral microbiota and the pathogenesis of kidney stones. However, after controlling for these potential confounders in our multivariate regression model, the inverse relationship between oral microbiome diversity and the risk of kidney stones remained statistically significant. This suggests that oral microbiome diversity is not solely driven by these baseline characteristics in renal stone pathogenesis and may play an independent protective role rather than being associated with traditional risk factors. The observed paradox therefore highlights the complexity of host-microbiome interactions and emphasizes the need for further mechanistic studies to explore potential causal pathways linking oral microbial ecology to kidney stone formation.

Our results suggest that both the Shannon-Weiner index and Simpson Index are protective factors against the pathogenesis of kidney stones (OR < 1). This suggests that higher oral microbial diversity may contribute to reducing the risk of kidney stone formation. Although the two indices differ in their mathematical expression, they both capture fundamental aspects of species richness and evenness. Interestingly, the heat map shows a positive correlation between the two. This suggests that they are internally consistent and that individuals with higher overall microbial diversity may have more favorable microbial environments, thereby mitigating stone pathogenesis. Previous studies have demonstrated that dysbiosis can elevate oxidative stress and chronic low-grade inflammation, both of which are established risk factors for kidney stone formation (Mostafavi Abdolmaleky and Zhou, 2024). Furthermore, certain microbial metabolites may influence urine composition, including oxalate and citrate levels, thereby directly impacting the risk of stone formation (Gao et al., 2022). Thus, the observed association between higher oral microbial diversity and lower risk of kidney stones may reflect a more balanced microbial ecosystem that helps to maintain host metabolic and immune homeostasis. These findings warrant further investigation of the functional role of specific microbial taxa on diversity-related protective effects.

The model constructed in this study to assess the association between oral microbial diversity and the risk of kidney stones showed an AUC of about 0.696 on ROC analysis, indicating that the model had an acceptable discriminatory power (Zhang et al., 2015). Despite the “highly accurate” criterion, this predictive performance is still informative in epidemiologic studies, suggesting a potential role of oral microecology in kidney stone formation, considering that the occurrence of kidney stones may be influenced by a combination of environmental, genetic, and lifestyle factors.

Previous research has examined the link between the oral microbiome and mortality, establishing a negative association, which provides a basis for our current study (Yang et al., 2024). Existing research suggests that the oral microbiota plays a crucial role in overall body health (Santacroce et al., 2023). Oral microbiota diversity is often considered an indicator of good health and can impact systemic health by enhancing the immune system, modulating inflammation, and participating in metabolic processes (Wang et al., 2024). Imbalances in the oral microbiota may impact kidney health by promoting systemic inflammation, thereby increasing the risk of chronic kidney disease. This imbalance may be transmitted via the bloodstream, triggering a systemic immune response that subsequently affects kidney function and stone formation (Mizutani et al., 2022).

Caution should be exercised in interpreting the negative correlation association between the oral microbiome and kidney stones because the oral microbiome has specific characteristics in particular diseases. First, the oral microbiota interacts with the gut microbiota via the mouth-gut axis (Tan et al., 2023). Pathogenic bacteria in the oral cavity may reach the gut through swallowing, thereby influencing gut microbiota diversity (Wu et al., 2024). The gut microbiota is closely linked to urinary metabolites (e.g., calcium, oxalic acid, and uric acid), and alterations in these metabolites may indirectly influence kidney stone formation (Al et al., 2023). A study confirmed that gut microbiota diversity influences the absorption of calcium and oxalic acid, subsequently affecting urinary oxalic acid levels, a key factor in kidney stone formation (Yuan et al., 2023). Second, the oral microbiota influences kidney health through immune regulation, and oral microbial diversity may promote immune tolerance, preventing excessive immune responses (Liu et al., 2022). Studies have shown that imbalances in the oral microbiota are linked to elevated systemic inflammation, which may promote kidney stone formation (Knauf et al., 2019). Another study confirmed that pathogenic bacteria in the oral cavity may enter the bloodstream, triggering an immune response that affects kidney immune function and metabolism (Guo et al., 2022). In addition, several studies have revealed the role of the oral microbiota in mineral metabolism in the body. The oral microbiota may influence systemic metabolism via metabolites, such as short-chain fatty acids, which are critical for stone formation. Short-chain fatty acids have been shown to reduce the risk of stones by inhibiting oxalic acid absorption in the gut or promoting its excretion (Blaak et al., 2020).

Emerging evidence indicates that certain oral microbial taxa may actively contribute to systemic health and potentially affect the development of kidney stones (Xu et al., 2025). For instance, genera such as Streptococcus, Prevotella, and Veillonella are frequently detected in individuals with greater oral microbial diversity and have been associated with the regulation of inflammatory pathways (Li et al., 2022; Chen et al., 2023). Some of these microbes are known to produce short-chain fatty acids (SCFAs), which exert systemic anti-inflammatory effects and may help preserve renal homeostasis (Fusco et al., 2023). Others may alter the local pH or produce ammonia, potentially disrupting the systemic acid-base balance (Weiner and Verlander, 2019). Additionally, changes in the oral microbiota may affect nitric oxide metabolism or urea recycling, thereby indirectly influencing urinary composition, including oxalate, citrate, and calcium levels (Bryan et al., 2022; Rosier et al., 2024). These mechanisms offer potential explanations for the observed protective association between greater oral microbial diversity and reduced kidney stone risk.

Consequently, we hypothesized that higher microbial diversity is generally associated with better health, as diverse microbial communities can better maintain ecological balance and inhibit pathogenic bacterial growth. In the context of kidney stones, oral microbiota diversity may reflect stronger systemic immune responses and metabolic stability, thereby reducing the risk of stone formation. The oral microbiota may indirectly influence renal metabolic processes by affecting the gut microbiota, immune system, and hepatic and renal metabolism, thus contributing to kidney stone formation or prevention.

To the best of our knowledge, this is the first study to explore the relationship between oral microbiome diversity and kidney stones in a large, population-based sample. The strengths of this study include, among others, our inclusion of a nationally representative sample of U.S. adults, as well as innovative sensitivity analyses for different indicators and subgroups and dose-response relationships. However, we have to recognize some limitations. First, our study was an observational design and cannot demonstrate a causal and temporal difference between oral microbiome diversity and kidney stones. Second, the consideration of covariates may be incomplete. Third, although NHANES collects information about kidney stones through professionally trained personnel, it does not, however, detail stone composition or frequency of stone episodes, which could introduce potential bias. Therefore, further prospective designs and causality studies are needed to confirm our findings.

In this study, we found an inverse relationship between oral microbiome diversity and kidney stone risk observed in alpha diversity. This reveals the complexity of host-microbiome interactions, and further mechanistic studies are necessary to elucidate these complex roles in the future.