Diabetes mellitus (DM) is a chronic metabolic disorder characterized by persistent hyperglycemia resulting from insufficient insulin secretion or impaired insulin action, often accompanied by disturbances in glucose, lipid, and protein metabolism (Dale Abel et al., 2024; Yameny, 2024). According to the latest report by the International Diabetes Federation (IDF), 537 million adults worldwide are living with diabetes, a number projected to rise to 783 million by 2045. Type 2 diabetes mellitus (T2DM) is the most prevalent form, accounting for over 90% of all diabetes cases (Schulze and Hu, 2022).T2DM is closely related to obesity (Chandrasekaran and Weiskirchen, 2024), insulin resistance (IR) (Penno et al., 2021), chronic inflammation (Rohm et al., 2022), and oxidative stress (Andreadi et al., 2022; Caturano et al., 2023), which, if not effectively controlled, can lead to complications such as cardiovascular and cerebrovascular diseases, nephropathy, retinopathy, and neuropathy, posing a serious threat to human health (Ali et al., 2022).

The human microbiota plays a significant role in the development and progression of T2DM, involving not only changes in the composition and function of the gut microbiota (Zhou et al., 2022) but also dysbiosis of the oral microbiome (Kumari and Gnanasundaram, 2021). The oral microbiota, as the second most abundant and diverse microbial community in the human body after the gut, comprises approximately 700 microbial species and forms a complex ecological network (Caselli et al., 2020). As a major gateway to the body, the oral microbiota influences both local and systemic health. Its dysbiosis may provoke oral inflammation, compromise mucosal barriers, and allow microbial products into circulation, fueling chronic inflammation and immune imbalance that contribute to diabetes and its complications (Suarez et al., 2020).

In recent years, an increasing number of studies have focused on the association between oral microbiota and diabetes mellitus (Kumari and Gnanasundaram, 2021). For instance, endotoxemia caused by Porphyromonas gingivalis infection has been shown to significantly increase the risk of insulin resistance and diabetes in animal models (Li et al., 2024), suggesting that oral microbiota dysbiosis may directly contribute to the development of diabetes. Additionally, several epidemiological studies have demonstrated that the composition of the oral microbiota is closely associated with glycemic control and systemic inflammation in patients with diabetes (Negrini et al., 2021; Zeng et al., 2024). These microbial profiles are further influenced by lifestyle factors, including diet, smoking, oral hygiene practices, and metabolic status (Shaalan et al., 2022; Mohammed et al., 2024).

Given the complex and dynamic nature of the oral microbiota under diabetic conditions, a systematic review is needed to summarize current evidence. This review investigates differences in oral microbiota composition and diversity in individuals with T2DM and explores potential mechanisms by which oral dysbiosis may influence disease onset and progression.

T2DM is a rapidly growing chronic metabolic disease worldwide, with more than 500 million patients currently affected by metabolic disease and T2DM accounting for over 90% of these cases (Rasouli et al., 2023). In the human oral cavity, the complex and diverse microbial community has a profound impact on health. Oral flora interacts with host metabolic status through multiple mechanisms, including inflammatory responses, insulin resistance, and immunomodulation (Lee et al., 2021).When oral microorganisms enter the systemic circulation via swallowing or gingival microdamage, they may serve as risk factors for triggering or exacerbating metabolic disorders (Jia et al., 2023).Currently, routine screening for T2DM relies mainly on blood glucose testing, which has limitations, especially during the early asymptomatic stage (Ortiz-Martínez et al., 2022). In recent years, oral microecology, due to its close association with glucose metabolism, has been regarded as an auxiliary screening and early risk prediction tool (Liu et al., 2021). The relative abundance of certain salivary taxa has been shown to significantly differentiate T2DM from nondiabetic individuals with good sensitivity and specificity (Shrivastava et al., 2025). Notably, oral flora is more stable in the short term and easier to sample than intestinal flora, making it a promising source of noninvasive biomarkers. Focusing on oral samples, this review aimed to summarize the characteristic changes of oral flora in patients with T2DM and to deepen the understanding of the possible relationship between T2DM and oral health.

A total of 34 studies with 2,062 patients with T2DM were included. Fourteen studies demonstrated correlations between specific phyla of oral microbiota and T2DM (Cortelli et al., 2014; Kampoo et al., 2014; Janem et al., 2017; Latti et al., 2018; Chen et al., 2020; Kori et al., 2020; Shi et al., 2020; Sun et al., 2020; Gao et al., 2022; Guo et al., 2023; Li et al., 2023; Rasouli et al., 2023; Soundaram et al., 2024; Tang et al., 2025). All of the 34 studies examined associations between specific genera and T2DM (Hintao et al., 2007; Kamaraj et al., 2011; Adeyemi et al., 2019; Kumar et al., 2012; Al Mubarak et al., 2013; Zhou et al., 2013; Cortelli et al., 2014; Kampoo et al., 2014; Kumar et al., 2014; Shenoy et al., 2014; Mohammadi et al., 2016; Rezazadeh et al., 2016; Janem et al., 2017; Long et al., 2017; Ogawa et al., 2017; Schmalz et al., 2017; Hsaine et al., 2018; Latti et al., 2018; Chen et al., 2020; Kori et al., 2020; Matsha et al., 2020; Shi et al., 2020; Sun et al., 2020; Almeida-Santos et al., 2021; Gao et al., 2022; Lu et al., 2022; Sabancı et al., 2022; Guo et al., 2023; Li et al., 2023; Rasouli et al., 2023; Wang et al., 2023; Gu et al., 2024; Soundaram et al., 2024; Tang et al., 2025), and 17 analyzed species-level changes in patients with T2DM (Hintao et al., 2007; Al Mubarak et al., 2013; Zhou et al., 2013; Mohammadi et al., 2016; Long et al., 2017; Ogawa et al., 2017; Hsaine et al., 2018; Chen et al., 2020; Matsha et al., 2020; Shi et al., 2020; Gao et al., 2022; Lu et al., 2022; Sabancı et al., 2022; Li et al., 2023; Gu et al., 2024; Soundaram et al., 2024; Tang et al., 2025). Notably, 14 studies reported significant differences in oral microbiota composition between patients with T2DM and healthy controls (Hintao et al., 2007; Al Mubarak et al., 2013; Kampoo et al., 2014; Kumar et al., 2014; Shenoy et al., 2014; Mohammadi et al., 2016; Rezazadeh et al., 2016; Ogawa et al., 2017; Hsaine et al., 2018; Latti et al., 2018; Chen et al., 2020; Almeida-Santos et al., 2021; Guo et al., 2023; Wang et al., 2023), suggesting that certain oral microorganisms may be associated with an elevated risk of developing T2DM. In terms of phylum, several studies reported significant differences in the abundance of Firmicutes, Bacteroidetes, and Proteobacteria compared to healthy controls (Cortelli et al., 2014; Shi et al., 2020; Tang et al., 2025). At the genus level, significant differences were reported for Streptococcus, Prevotella, and Porphyromonas in patients with T2DM compared to healthy individuals. In addition, Streptococcus emerged as an important focal point, with 18 studies demonstrating its association with the progression of T2DM (Hintao et al., 2007; Al Mubarak et al., 2013; Kampoo et al., 2014; Rezazadeh et al., 2016; Janem et al., 2017; Long et al., 2017; Ogawa et al., 2017; Schmalz et al., 2017; Shi et al., 2020; Almeida-Santos et al., 2021; Gao et al., 2022; Lu et al., 2022; Sabancı et al., 2022; Li et al., 2023; Rasouli et al., 2023; Wang et al., 2023; Gu et al., 2024; Soundaram et al., 2024), highlighting its relevance in this area of research. In terms of diversity, 15 studies analyzed the Alpha diversity of oral flora in patients with T2DM (Cortelli et al., 2014; Kampoo et al., 2014; Kumar et al., 2014; Rezazadeh et al., 2016; Chen et al., 2020; Kori et al., 2020; Shi et al., 2020; Almeida-Santos et al., 2021; Gao et al., 2022; Sabancı et al., 2022; Guo et al., 2023; Rasouli et al., 2023; Wang et al., 2023; Gu et al., 2024; Soundaram et al., 2024), with some heterogeneity in the results. Three studies reported significantly higher diversity (Kumar et al., 2014; Almeida-Santos et al., 2021; Soundaram et al., 2024), while no significant differences were observed in six studies (Kumar et al., 2014; Rezazadeh et al., 2016; Shi et al., 2020; Sabancı et al., 2022; Rasouli et al., 2023; Gu et al., 2024). These discrepancies may reflect the influence of multiple underlying factors. Periodontal status may act as an important effect modifier, as active inflammation can alter microbial community richness and evenness in divergent ways depending on disease severity and treatment history (Griffen et al., 2012). Similarly, glycemic control has been shown to shape oral ecological conditions: poorly controlled hyperglycemia favors the dominance of acidogenic taxa and may lead to reduced diversity, whereas in some cases the concurrent colonization of opportunistic species could manifest as apparent diversity gains (Latti et al., 2018). In addition, the use of antidiabetic medications, particularly metformin, has been associated with shifts in microbial composition through both immunomodulatory and metabolic pathways, further contributing to heterogeneity across studies (Gu et al., 2021). Beyond these biological influences, methodological factors such as sampling site, sequencing depth, and the choice of diversity indices may also have contributed to the variability observed.

At the phylum level, 14 studies analyzed changes in patients with T2DM. Firmicutes consistently showed a higher abundance and was the phylum most closely associated with T2DM. In contrast, Proteobacteria showed a significant decrease in several studies, while Bacteroidetes displayed inconsistent trends, with some studies reporting reduced abundance and others finding no significant differences. These results are consistent with previous findings; for example, Tokman et al. reported that an increase in Firmicutes may be strongly associated with chronic low-grade inflammation and metabolic disturbances in patients with T2DM (Bahar-Tokman et al., 2022).Some strains in this phylum can produce metabolites such as short-chain fatty acids during carbohydrate metabolism. These metabolites may not only alter oral ecology by affecting the mucosal barrier and local pH but also modulate host immune responses and insulin sensitivity, thereby promoting diabetes progression (Molinsky et al., 2025).

At the genus level, the oral flora of patients with T2DM showed changes in the abundance of several key taxa. Notably, Streptococcus was repeatedly reported to be elevated in most studies. This genus is widely present in normal oral ecology and has a strong ability to metabolize sugar, rapidly proliferating and producing acidic metabolites in high-sugar environments, thereby lowering oral pH and promoting the development of dental caries and periodontal disease (Ali et al., 2021).Patients with T2DM provide favorable conditions for Streptococcus enrichment due to decreased salivary flow rate and altered salivary composition, which may constitute an important mechanism driving the oral flora toward pathogenicity. In addition, the genus Porphyromonas (particularly P. gingivalis) also showed a trend of increased abundance in several studies (Gu et al., 2024). P. gingivalis is a key causative agent of periodontal disease and represents the core of the “oral–systemic inflammatory axis.” It secretes virulence factors such as lipopolysaccharides (LPS) and proteases that activate the host immune system and induce systemic inflammatory responses, which in turn may promote insulin resistance (Reyes, 2021; Murugaiyan et al., 2024). Its enrichment in the T2DM population suggests that this genus may not only contribute to oral disease but may also participate in the systemic regulation of T2DM progression. Prevotella is another genus frequently reported in T2DM studies, though its trends vary. Some studies found an increase in its abundance in the oral or intestinal flora of patients with T2DM, potentially linked to its ability to ferment carbohydrates and produce butyrate (Zhang et al., 2021). In contrast, other studies reported a decrease. These differences may reflect ecological roles of Prevotella in different oral sites, disease stages, or comorbid contexts and may also be influenced by factors such as diet and oral hygiene.

At the species level, changes in specific bacteria provide more precise insights into the relationship between oral flora and T2DM. Streptococcus mutans, the main causative agent of dental caries, was significantly increased in patients with T2DM. The hyperglycemic environment favors the growth of S. mutans, and the acidic substances it produces further damage tooth enamel, creating a vicious cycle (Brito et al., 2021). Similarly, periodontal pathogens such as Porphyromonas gingivalis and Treponema denticola were also increased in most studies. These species exacerbate systemic inflammatory responses by triggering periodontal inflammation and releasing inflammatory mediators, which in turn impair glycemic control and insulin sensitivity (Liu et al., 2024). Although trends for other species such as Fusobacterium nucleatum were less consistent, their role in oral dysbiosis should not be overlooked. F. nucleatum may aggravate oral disease progression by promoting biofilm formation and enhancing the invasiveness of other pathogenic bacteria.

Research indicates that metabolic dysregulation in diabetes mellitus (DM) exacerbates inflammation and promotes microbial dysbiosis in the subgingival microbiome, which is a key factor in the progression of periodontitis in diabetic patients. Hyperglycemia elevates glucose levels in saliva, providing a nutrient-rich environment for cariogenic bacteria in the dental biofilm. Studies have shown that saliva in patients with DM contains higher levels of glucose, urea, and total protein, while exhibiting lower calcium levels and acidic pH (Verhulst et al., 2019), which further support the growth of pathogenic bacteria. These dysbiotic shifts in the oral microbiome are not only associated with local tissue destruction but also contribute to systemic inflammation. Cytokines such as interleukin-1e (IL-1leu), tumor necrosis factor-s (TNF-r-s), and the receptor activator of nuclear factor κa ligand (RANKL) have been implicated in mediating periodontitis in diabetic patients. Additionally, interactions between advanced glycation end products (AGEs) and their receptor (RAGE) exacerbate inflammation and periodontal tissue destruction (Mealey and Oates, 2006; Taylor et al., 2013). Recent studies suggest that diabetes may enhance the pathogenicity of the oral microbiome through IL-17-mediated pro-inflammatory mechanisms. These immune disruptions in DM lead to dysbiosis in the subgingival microbiome, predisposing individuals to periodontitis. Moreover, these dysbiotic shifts may also affect the gut microbiome via the oral–gut pathway, contributing to systemic inflammation and insulin resistance, thereby linking oral health to broader metabolic dysfunction in diabetic patients (Li et al., 2023).

Emerging evidence suggests that antidiabetic medications, particularly metformin, may influence hostuence,lys.r interactions beyond glucose regulation. Metformin has been shown to modulate the gut microbiota by enriching beneficial taxa such as Akkermansia muciniphila and other short-chain fatty acid producers, while reducing potentially pathogenic bacteria. Although direct evidence of its impact on the oral microbiota is limited, preliminary findings indicate distinct microbial signatures in patients with T2DM receiving metformin therapy, possibly mediated by reduced systemic inflammation, improved immune balance, and altered salivary metabolic profiles. In contrast, evidence regarding the microbiome-related effects of other antidiabetic drugs, such as DPP-4 and SGLT2 inhibitors, remains scarce. Longitudinal and interventional studies are needed to clarify whether these agents exert protective, neutral, or adverse effects on the oral microbial ecosystem and metabolic outcomes (Hung and Hung, 2020).

This study has several methodological limitations. Different detection methods (e.g., PCR, 16S rRNA gene sequencing) significantly influence the interpretation of results, as each technique has distinct advantages and inherent biases. PCR can precisely amplify target microbial DNA but is restricted to known species and may overrepresent certain taxa, whereas 16S rRNA sequencing provides broader community profiles but with limited resolution and lower sensitivity for low-abundance microbes. These methodological differences may contribute to inconsistencies in reported abundance and limit comparability across studies. In addition, most included studies were cross-sectional in design, which restricts causal inference. Another important limitation is the inconsistent handling of key confounders, including oral hygiene, diet, smoking, and metformin use. Quality assessment revealed that 21 studies did not adequately control for these factors, which may introduce systematic bias and obscure whether observed microbial changes are attributable to T2DM itself or to external influences. To address these issues, future studies should adopt prospective cohort designs, use standardized microbiome sequencing technologies, and apply rigorous statistical methods to control for confounders. Considering lifestyle, metabolic status, and oral environmental factors will further strengthen the validity and reliability of conclusions.

This systematic review identified significant changes in the oral flora of patients with T2DM across 34 studies. These changes were observed at the phylum, genus, and species levels, with the most consistent increases reported for the phylum Firmicutes, the genus Streptococcus, and the species Porphyromonas gingivalis. Total oral bacterial load was generally higher in patients with T2DM, while bacterial diversity showed heterogeneous patterns across studies. Given the strong association between oral flora and T2DM, future research should prioritize clarifying causal relationships. In addition, maintaining good oral hygiene may contribute to both the prevention and management of diabetes.