Recent insights in the oral microbiome have brought new understanding of its critical role in maintaining oral health. The microbiome and the human body function as an integrated superorganism, affected by genetics as well as lifestyle factors such as sugar consumption, tobacco smoking, oral hygiene, and use of antibiotics.¹ A rich, diverse, and balanced oral microbiome in symbiosis with the host is associated with health, while persisting environmental stress may induce a dysbiotic shift resulting in caries, periodontal diseases, or candidiasis (Fig 11-1). Therefore, measures to promote a balanced microbiome to maintain (primary prevention) or restore oral health (secondary prevention) have gained evolving interest in recent years. The most established methods to interfere with the drivers of dysbiosis towards caries are daily exposure to fluoride, regular oral hygiene practices, reduced intake of sucrose, and stimulation of saliva.² In addition, regular ingestion of pre-, pro-, and synbiotics, as defined in Table 11-1, may exert beneficial effects on general and oral health. Prebiotics interfere primarily with events associated with the caries process while probiotics have been linked to treatment of both caries and periodontal disease, as well as with bad breath and Candida overgrowth. This chapter will briefly review the role and evidence of using prebiotic supplements and probiotic bacteria in preventive dentistry. An immediate remark is that these strategies are adjuncts, rather than alternatives, to the established knowledge and can boost the effect of the common evidence-based preventive technologies.

Table 11-1 Common definitions of prebiotics, probiotics, and synbiotics

Oral prebiotics

Arginine

Arginine is a naturally occurring amino acid in parotid saliva and probably the most investigated prebiotic for oral care. Arginine is hydrolyzed into ammonia through the arginine deiminase system (ADS) pathway by major commensal (health-associated) members of the oral microbiota, such as Streptococcus sanguinis, Streptococcus gordonii, Streptococcus parasanguinis, and Streptococcus mitis. In addition, certain Lactobacillus and Actinomyces strains are ADS-positive.⁶ The ammonia production from arginine metabolism offers ecological, such as pH increase, and bio-energetic advantages to ADS-positive bacteria and favors their growth.⁷ Arginine may also increase the penetrability of the biofilm through interference with the bacterial production of exopolysaccharides that glue the matrix community together.⁸ The relationship between the ADS activity and caries has been evaluated in adults as well as in children, and one example is shown in Fig 11-2. In this study, the ADS activity in saliva and plaque was significantly higher in caries-free young adults (DMFT [decayed, missing, or filled teeth] = 0) compared to those with at least four active caries lesions.⁹ Furthermore, a recent systematic review based on seven studies concluded that low ADS activity in saliva and plaque could be a potential caries risk indicator for adults, while this relationship was inconclusive in children.¹⁰

One important question is, however, whether arginine interventions can modulate the composition of the oral microbiota and actually prevent caries. Studies have suggested that the use of a 1.5% arginine toothpaste with and without fluoride twice daily for 2 to 8 weeks may induce a health-associated microbial shift in volunteers and in caries-active individuals,^11,12 thereby confirming findings from multi-species biofilm models in vitro.¹³ In clinical trials, arginine has been added to toothpaste and mint confection and the anti-caries effects have been compiled in several systematic and narrative reviews (Table 11-2). The studies were conducted on permanent teeth in schoolchildren, middle aged adults, or elderly patients, and the vast majority compared a fluoride toothpaste with 1.5% w/w arginine vs a standard fluoride toothpaste. Collectively, evidence suggested that arginine in combination with calcium bases and fluoride provided a superior reduction of caries increment and progression compared with fluoride alone.¹⁴ The prevented fraction ranged from 15% to 25% but the confidence in the effect estimates was very low.^14,15 The downgrading was motivated because only a few trials, with low risk of performance bias, were available. There was also an obvious risk of publication bias since studies were conducted and, in many cases co-authored, by employees of the industry. Thus, further independent studies according to the principles of good clinical practice are needed to gain knowledge and avoid downgrading and perception of low trust. Large clinical randomized trials are very expensive to perform, but the industry should limit their involvement solely to financial support.

Table 11-2 Summary of reviews on arginine toothpaste with caries lesion as the endpoint

Many foods are rich in arginine, and arginine is generally regarded as safe for use in toothpaste. Recently, a novel toothpaste formula containing 1.5% L-arginine and zinc (0.96% zinc oxide and zinc citrate) was claimed to provide superior effects on the reduction of the amount of plaque, presence of gingivitis, and oral malodor compared with a regular fluoride toothpaste.¹⁹ However, not all subjects may benefit from arginine supplements. Zaura et al²⁰ recently categorized the salivary microbiome, metabolome, and the biochemical properties of saliva from young healthy adults into five ecological types. Three of the five ecological types were termed “adaptive” while two were “specialized,” either saccharolytic (pro-caries) or proteolytic (pro-periodontal diseases).²⁰ Enhancing pH recovery by generating alkali from prebiotic supplements such as arginine would theoretically be highly beneficial in the former group, whereas an additional arginine may lead to unwanted effects in individuals with an already predominantly proteolytic microbiome. This illustrates that the concept “one size for all” is untrue concerning preventive strategies. Hence, individually tailored measures are called for in the future.

Urea

Urea is formed in the liver and naturally occurs in saliva. Some common oral bacteria, for example Streptococcus salivarius, Actinomyces naeslundii, and Haemophilus species, have the capacity to convert urea to ammonia/ammonium and bicarbonate that may increase pH in dental plaque.⁶ Consequently, clinical studies have associated reduced levels of urease in plaque with increased caries activity.^9,22 The clinical effect of urea as a caries preventive agent has been investigated in two clinical trials^23,24 in which schoolchildren were supplied with sugar-free chewing gums supplemented with urea for daily use during 3 years. However, the results were disappointing as no major effects on caries increment were obtained compared with non-urea controls. It is nevertheless possible that the results were somewhat biased by the stimulation of saliva through the mechanical chewing itself. A possible drawback for wider implementation of urea-containing products could be its unattractive name and the commonly perceived unpleasant taste.

Xylitol

Xylitol is a five-carbon sugar substitute with anti-caries properties but its clinical use has been accompanied by scientific controversies over the past decades. Recent systematic reviews have displayed contrasting conclusions on its efficacy, from “effective”²⁵ to “uncertain.”²⁶ The question is whether xylitol can be regarded as an oral prebiotic. Studies on the gut microbiota have shown that some polyols, including xylitol, can be absorbed by passive diffusion and reach the large bowel and increase the number of bifidobacteria in humans.²⁷ In the oral environment, xylitol cannot be fermented by bacteria and may therefore hamper the metabolic activity in the oral biofilm and reduce the low-pH stress. The in vivo effect on the oral microbial communities, however, remains to be established.

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