Fluoride has been the leading preventive treatment for dental caries for almost a century, owing to its inhibitory effects on bacteria such as Streptococcus mutans and on its ability to promote enamel remineralization (Manchanda et al., 2022; Zaffarano et al., 2022). Fluoride may occur naturally in (or can be added to) drinking water and is added to hygiene products such as toothpaste, supplements, and mouthwashes. Severe cases of demineralization may warrant in-office applications of higher-concentration fluoride treatments such as varnishes, gels, and foams. Provided in severe cases in which restorative treatment is not feasible (including for children who will lose their primary dentition), silver diamine fluoride is a highly concentrated fluoride treatment that arrests dental caries (Duffin et al., 2022). It is well established that fluoride treatment exerts its anticaries effect by promoting the formation of fluorapatite, which incorporates into hydroxyapatite, the mineral component of tooth enamel. As fluorapatite is more acid-resistant than hydroxyapatite (pKa of 4.5 vs 5.5), enamel enriched with fluorapatite is able to withstand lower pH levels before demineralization occurs, thereby reducing caries incidence (Marquis et al., 2003).

Under caries conducive, low pH conditions, fluoride diffuses into S. mutans cells. Intracellularly, fluoride can inhibit key metabolic enzymes such as enolase, a glycolytic enzyme that catalyzes the conversion of 2-phosphoglycerate to phosphoenolpyruvate, a critical step in energy production and acid generation (Curran et al., 1994). Intracellular fluoride also interferes with the aciduricity of S. mutans by inhibiting the F₀F₁-ATPase proton pump, which exports protons to avoid cytoplasm acidification while acidifying the extracellular milieu (Li et al., 2022). As fluoride is not selective in inhibiting the enolase of S. mutans over that of other oral microbes, the ability to inhibit the S. mutans proton pump is a key attribute contributing to the anti-caries impact of this mineral. Fluoride has also been shown to inhibit S. mutans biofilm accumulation by reducing EPS production (Pandit et al., 2011). The dual-acting nature of fluoride, contributing to the remineralization of enamel and interfering with virulence and metabolism of S. mutans, contribute to its status as a particularly powerful anti-caries agent.

Hydrogen peroxide (H₂O₂) is a reactive oxygen species (ROS) that is widely incorporated into dentifrices and mouthwashes for its antimicrobial and whitening properties. Currently, a variety of oral hygiene products containing H₂O₂ are commercially available for oral debridement and whitening, including toothpastes and mouthwashes, with concentrations commonly ranging from 1.5% to 5% (Colgate® Optic white® Pro series stain prevention hydrogen peroxide toothpaste: colgate-palmolive, 2024; ACT whitening Mouthwash, 2025). Although clinical studies with topical H₂O₂ mouth rinses (1.5% to 3%) have demonstrated benefits in reducing dental plaque and gingival inflammation as compared to a placebo treatment (Hasturk et al., 2004; Muniz et al., 2020), H₂O₂ is not currently indicated for the treatment of dental caries.

Despite the fact that H₂O₂ is not marketed as an anticaries agent, laboratory studies have shown that H₂O₂ serves as an antagonistic weapon that suppresses caries associated microbes such as S. mutans. As a catalase negative gram-positive bacterium, S. mutans is highly susceptible to H₂O₂. Exposure to H₂O₂ results in DNA damage, protein oxidation, and disruption of membrane integrity, which collectively compromise cell viability and competitiveness (Storz and Imlay, 1999; Baldeck and Marquis, 2008; Kreth et al., 2008). Additionally, H₂O₂ suppresses S. mutans biofilm formation by interfering with quorum sensing, the bacterial cell-to-cell communication mechanism (De Furio et al., 2017). Elevated salivary H₂O₂ levels are associated with oral health and reduced caries risk, in part due to their inhibitory effects on S. mutans (Zhu and Kreth, 2012). H₂O₂ is endogenously produced by immune cells as well as by health-associated oral bacteria such as Streptococcus sanguinis, Streptococcus gordonii, and Streptococcus mitis via the pyruvate oxidase enzyme (Kreth et al., 2005; Zhu and Kreth, 2012; Fujishima et al., 2013; Yang et al., 2013; Redanz et al., 2018). Peroxigenic streptococci are overall more tolerant to the H₂O₂ they produce than S. mutans, making H₂O₂ a good anti-caries candidate (Redanz et al., 2018). Despite the promising findings for the efficacy of H₂O₂ against S. mutans, to date, there are no published clinical studies evaluating the role of topical H₂O₂ in the reduction of dental caries.

Chlorhexidine (CHX) is a broad spectrum bisbiguanide antiseptic. Due to its efficacy at inhibiting bacteria, fungi, and viruses, CHX was initially used as a disinfectant and later introduced into clinical dentistry after the discovery of its potent antiplaque and anti-gingivitis properties (Milstone et al., 2008; Brookes et al., 2020; Poppolo Deus and Ouanounou, 2022). In the United States, CHX is available only by prescription as a 0.12% chlorhexidine gluconate mouth rinse or as a chlorhexidine-thymol varnish (Rethman et al., 2011). The cationic molecule chlorhexidine bisbiguanide can passively diffuse through the bacterial cell wall, then bind to the negatively charged cell membrane. This binding compromises the membrane integrity, thereby increasing membrane permeability, ultimately resulting in the leakage of low-molecular weight molecules and cytoplasmic components. Clinically, CHX treatment is associated with good adherence, as the compound is able to bind to most oral surfaces including teeth, mucus membranes and salivary glycoproteins due to their negative charge, resulting in an activity period of up to 12 hours following application (Poppolo Deus and Ouanounou, 2022). CHX is also used preoperatively to reduce bacterial load and postoperatively following implant or periodontal surgeries to prevent plaque accumulation and promote wound healing when mechanical cleaning is limited (Rethman et al., 2011; Brookes et al., 2020; Poppolo Deus and Ouanounou, 2022). Common side effects of chlorhexidine include altered taste sensation, tongue discoloration, and tooth staining, which may discourage some from using this antiseptic regularly (Brookes et al., 2020).

The efficacy of CHX treatment in reducing S. mutans-associated caries remains a topic of debate. Similar to other bacteria, low concentrations (0.02%-0.06%) of CHX are bacteriostatic to S. mutans, while higher concentrations (0.12% or more) become bactericidal, when cytoplasmic coagulation and precipitation occur (Karpiński and Szkaradkiewicz, 2015). In vivo and in situ studies have provided evidence that CHX treatment can specifically reduce the recovery of viable S. mutans colonies and diminish biofilm thickness (Bowden, 1996; Ribeiro et al., 2007; Martínez-Hernández et al., 2020). However, a systematic review conducted by the American Dental Association found that use of a chlorhexidine mouth rinse did not result in a significant reduction in coronal caries (Rethman et al., 2011). In the case of root caries, the panel concluded that application of a chlorhexidine-thymol varnish may help reduce incidence in adults and elderly populations (Rethman et al., 2011). Despite its broad antimicrobial properties, chlorhexidine is not FDA-approved for the treatment or prevention of dental caries (Autio-Gold, 2008).

The trace metal Zinc (Zn) is an essential nutrient to all domains of life, functioning as a cofactor for critical enzymes (Andreini et al., 2008; Festa and Thiele, 2011; King, 2011; Ganguly et al., 2022). The Zn content in the human body fluctuates throughout the day based on factors including hormones, stress, trauma, infection, diet, and time of day, with estimates of salivary Zn concentrations ranging widely from 0.2 μM to 280 μM (Greger and Sickles, 1979; King, 2011; Lynch, 2011; King and Rousins, 2014; Sejdini et al., 2018). In spite of its essentiality, excess Zn is toxic to bacterial cells due to its ability to bind to non-cognate metalloproteins, thereby impairing their function (mismetallation), and due to interference with uptake of other essential metals, disrupting the critical balance of intracellular metals (Sandström, 2001; Holt et al., 2012; Shafeeq et al., 2013; Djoko et al., 2015; Lonergan and Skaar, 2019). Due to its antimicrobial and immunomodulatory characteristics along with its low toxicity to mammalian tissues, Zn has been incorporated into oral health products for decades, including over-the-counter toothpastes and mouthwashes. The concentration of Zn in such products ranges from 30 to 150 mM, and administration has shown to lead to several hours of elevated levels of Zn in the oral cavity (Harrap et al., 1984; Lynch, 2011; Fatima et al., 2016; Bowen et al., 2018; Delgado et al., 2018; Rahman et al., 2019). Supplemental Zn treatment has been marketed to improve numerous oral conditions, including formation of healthy enamel, reduction of halitosis, prevention of dental calculus formation, and bolstering of periodontal health (Khajuria et al., 2018; Uwitonze et al., 2020).

Despite the documented benefits of Zn as an antimicrobial agent, the role of this metal in the prevention of dental caries remains a subject of debate. Multiple in-vivo studies have found Zn treatment to be ineffective in altering dental plaque composition, plaque pH, or caries outcomes (Compton and Beagrie, 1975; Stephen et al., 1988; Giertsen, 2004; Parkinson et al., 2018). At the bacterial level, advances have been made in understanding the effects of Zn toxicity. For example, Zn treatment has been shown to reduce metabolic activity of cariogenic bacteria in vitro, inhibiting acid production by mutans streptococci and inhibiting ATPases, PTS (phosphoenolpyruvate:sugar phosphotransferase system) activity and alkali production (He et al., 2002; Phan et al., 2004). Recent work demonstrated that among oral streptococci, S. mutans demonstrates a high tolerance to Zn due to its unique zinc exporter, ZccE. In vivo studies using a rodent model showed that daily treatment with Zn modestly inhibited S. mutans oral colonization, but a mutant strain lacking ZccE was highly susceptible to Zn treatment, resulting in a significant impairment in oral colonization (Ganguly et al., 2022). Thus, combinatorial approaches with Zn and compounds that target ZccE activity hold promise in eliminating the advantage that S. mutans holds over other oral microbes when exposed to excess Zn.

Prebiotics were first defined by Gibson & Roberfroid in 1995 as “nondigestible food ingredients that beneficially affect the host by selectively stimulating the growth and/or activity of one or a limited number of bacterial species already resident in the colon, and thus attempt to improve host health” (Gibson and Roberfroid, 1995). In 2017, the International Scientific Association for Probiotics and Prebiotics (ISAPP) redefined prebiotics as “a substrate that is selectively utilized by microorganisms conferring a health benefit” encompassing non-food substances and effects beyond the gastrointestinal tract (Gibson et al., 2017). Recent years have seen the incorporation of prebiotics into dental care products to improve oral health and to potentially supplement or replace fluoride (Suresh et al., 2021; Luo et al., 2024). Candidate prebiotics include oligosaccharides, inulin, amino sugars, sugar alcohols, arginine, urea, and nitrates, as all of these molecules exhibit the potential to inhibit caries-associated microbes or to promote the growth of beneficial oral commensal species (Koopman et al., 2015; Zeng et al., 2016; Chen et al., 2020; Agarwal et al., 2022; Zeng et al., 2022). A growing number of conventional and natural-product-based oral hygiene products now contain prebiotics, though their efficacy remains under investigation (Suresh et al., 2021). Among these, sugar alcohols and arginine are the most included compounds (Zheng et al., 2017; Alhumaid and Bamashmous, 2022).

Sugar alcohols, such as erythritol, maltitol, sorbitol, and xylitol, have been researched for their inclusion in oral health products due to their properties as prebiotics, caries inhibitors, and non-cariogenic sugar substitutes (Runnel et al., 2013; Thabuis et al., 2013; Falony et al., 2016; Cocco et al., 2017; Rafeek et al., 2019). Xylitol, in particular, has been extensively studied and included in a wide range of dental products, including toothpastes, mouthwashes, chewing gums, and candies (Alhumaid and Bamashmous, 2022). In S. mutans, xylitol has been shown to interfere with PTS activity, thereby inhibiting acid production and becoming toxic once it accumulates in the cytoplasm of oral bacteria. Importantly, clinical studies showed that xylitol can reduce the abundance of some cariogenic oral streptococci in saliva while not affecting the prevalence of commensal streptococci who may be unable to metabolize xylitol (Trahan et al., 1985; Makinen et al., 1995; Trahan et al., 1996; Bahador et al., 2012; Runnel et al., 2013) (Soderling and Pienihakkinen, 2020). Despite the poisoning effect that xylitol exerts on S. mutans by interfering with PTS activity, recent work has shown that some gut microbes are able to metabolize xylitol; the impacts of this sugar alcohol on the short chain fatty acid composition of gut microbes is likely to have implications in overall health of the host, further expanding the impact of this prebiotic (Xiang et al., 2021).

Arginine is another widely studied prebiotic compound that has been added to oral care products (Zheng et al., 2017; Wolff and Schenkel, 2018; Luo et al., 2024). Arginine favors the metabolism and competitiveness of commensal bacteria in the oral microbiome by producing ammonia, which neutralizes the acids produced by S. mutans in the oral cavity (Agnello et al., 2017; Huang et al., 2017). Also, arginine itself inhibits growth, metabolism and proteins important for S. mutans virulence (Chakraborty and Burne, 2017). Clinical studies have shown that arginine supplementation negatively affects dental plaque build-up and disrupts established cariogenic bacterial biofilms (Sharma et al., 2014; Huang et al., 2017; Gloag et al., 2021) while also inhibiting growth of Candida, a fungus that interacts synergistically with S. mutans in cariogenic conditions (Koopman et al., 2015).

Collectively the human oral cavity can host over 700 potential bacterial species, with any given individual typically harboring between 100–200 species (Dewhirst et al., 2010). When oral microbial homeostasis is disrupted, cariogenic organisms such as S. mutans can become overabundant, leading to increased biofilm accumulation, reduced oral pH, and elevated caries incidence (Lemos et al., 2019; Spatafora et al., 2024). Probiotics are considered to be live microorganisms that, when administered directly to the intended environment, provide a health benefit to the host (Gibson et al., 2017). While frequently used for treatment of gut microbiome dysbiosis, probiotic use in the oral environment is a relatively new practice that continues to evolve and improve. In the oral environment, beneficial commensal streptococci are known for their ability to produce hydrogen peroxide and are therefore often included in oral probiotic formulations (Redanz et al., 2018) (Burton et al., 2013b). Several Lactobacillus species have demonstrated the ability to impair S. mutans biofilm formation via suppression of the genes coding for Gtfs (gtf) (Wasfi et al., 2018). Clinically, the effects of L. reuteri chewable tablets were shown in one study to reduce caries incidence in children with mixed dentition (Stensson et al., 2014). Unlike the other agents discussed in this review, probiotics are often marketed separately from existing oral hygiene products, such as dentifrices and mouth rinses, and at the current time, relatively few of these products are available on the market or have undergone extensive clinical testing. As such, probiotic supplements may not be monitored for safety, as the Generally Regarded as Safe (GRAS) label, designated by the Food and Drug Administration (FDA), applies only to substances added to food (Burdock, 2000).

Clinical studies examining probiotic efficacy in children with early childhood caries (caries in children in primary dentition) have thus far yielded conflicting results (Di Pierro et al., 2015; Hasslöf et al., 2022; Staszczyk et al., 2022). However, some promising oral probiotic candidate organisms emerged from these studies. For example, treatment with Streptococcus salivarius via a lozenge decreased S. mutans prevalence after 3 months in caries-active children (Burton et al., 2013a). Alternatively, a blend of strains of Streptococcus uberis, Streptococcus oralis, and Streptococcus rattus provided as chewable tablets decreased overall caries incidence with consistent use after 3 months (Hedayati-Hajikand et al., 2015). Notably, these effects appeared to be dependent on the ability of the probiotic organism to colonize the treated environment, which may prove challenging in cases where S. mutans is already established. If treatment is pursued early in life, a child’s oral microbiome may be more receptive to the introduction of beneficial organisms before the community eventually stabilizes as the subject ages. Adult oral microbiomes are typically more stable, and beneficial effects of probiotic treatment may require additional supplementation to favor their implantation in the microbiome, as short-term treatment may result only in temporary colonization (Petersson et al., 2011; Romani Vestman et al., 2015). Ultimately, while oral probiotics show potential for caries prevention, their long-term efficacy remains uncertain as the microbes may have requirements (e.g. nutritional) that must be provided to exert their beneficial function. Further research will provide guidance regarding how to sustain probiotic benefits and to identify strains with consistent colonization and cariostatic properties (Lopes et al., 2024; Garcia et al., 2025).