Saliva
The precious body fluid
Dominick P. DePaola, DDS, PhD, Guest Editor
Adequate salivary flow and its unique composition of proteins are essential to the maintenance of oral tissues. Saliva is a glandular secretion that is in constant contact with the hard and soft tissues of the mouth. Many functions have been ascribed to saliva, including its role as a lubricant that coats the mucosa and helps protect the oral tissues against mechanical, thermal and chemical irritants.1 Other functions include its buffering capacity; acting as an ion reservoir that facilitates the remineralization of teeth; antimicrobial activity, involving secretory immunoglobulin A, lysozyme, lactoferrin and myeloperoxidase; agglutination, resulting in the clearance of bacterial cells; pellicle formation; initiation of digestion through 
-amylase; providing a solvent and acting as a medium where tastants derived from foods are presented to taste buds; and acting as a medium for moistening dry foods to aid swallowing.1 All of these functions are largely protective of the oral environment.
Over the years, the dental and research communities have examined the most appropriate ways to use saliva to provide maximum protection against caries and soft-tissue diseases. Perhaps the best testimony for the importance of saliva in oral health is the destruction of oral tissue that occurs when saliva and salivary flow are compromised by physiological or pathological states or through medications and treatment.
In recent years, it has become clear that saliva contains specific proteins and RNA molecules encoded by genes that can be monitored in different states of health and disease, and, thus, saliva can be used as a diagnostic tool.2 Salivary diagnostics have the potential to be used in health surveillance because saliva can be collected simply and noninvasively, and it contains biomarkers that act as proxies for particular physiological states.2 This area of research has captured the imagination of scientists and policymakers, and it has the potential to place the dental health care profession in the enviable position of helping physicians and patients identify systemic disease early. Although this supplement does not dwell on the diagnostic aspects of saliva, they are important to note because they are a function of saliva that can put the dentist into the role of primary care provider.
This supplement focuses on how saliva can be used in caries prevention. The fundamental approach to preventing caries by using saliva is to ensure there is an adequate flow rate of saliva, which has critical components such as proteins, buffers and antimicrobial agents.
In one sidebar to this introduction, Curro (page 6S) describes the use of chewing gum as an adjunct to medications and suggests areas of future research regarding the use of gum chewing as an adjunctive therapy. Curro also provides postulates for a broader role of saliva in health and wellness, which is based on known potential neurophysiological changes initiated by the act of gum chewing. In a second sidebar, Zero (page 9S) describes the cariogenic potential of various sugar substitutes, including sugar alcohols, that can be delivered by foods, chewing gum and liquids.
In the first article in this supplement, Stookey3 provides an overview of the benefits of saliva stimulation and its effects on the prevention of dental caries. He describes the results of seven significant clinical trials that attest to the merits of stimulating salivary flow by using chewing gum for caries prevention. Dawes4 reviews the role of saliva in some of the diseases that affect the hard and soft oral tissues. His article focuses on the sources of saliva, the importance of salivary flow, the components of saliva, salivary clearance and saliva’s role in protecting against hard- and soft-tissue damage. García-Godoy and Hicks5 describe the multifactorial and complex disease process that occurs at the interface between the dental biofilm and the enamel surface. They also describe the factors in saliva that are absorbed preferentially by dental biofilm to protect the enamel surface. They note that the demineralization and remineralization equilibrium is affected by the ion concentration in saliva. In addition, the authors describe protective factors present in saliva and others derived from external sources that can reduce the risk of developing caries.
Navazesh and Kumar6 describe the methodology used for collecting saliva to assess qualitative and quantitative changes associated with local or systemic diseases. Their article is designed to help clinicians understand and use salivary collection methods to assess patients’ risk of disease, including diseases related to salivary hypofunction such as Sjögren syndrome, rheumatoid arthritis and systemic lupus erythematosus.
This supplement is designed to help dental health care professionals better understand the role of saliva in oral health protection. The articles in the supplement provide a collective basis for the clinician and public health community to use vehicles such as chewing gum in at-risk patients to stimulate salivary flow and reduce the risk of caries. The precious nature of saliva will become even more evident as it is used more effectively to prevent oral disease and as its role expands to assist in the early diagnoses of systemic diseases and disorders.
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FOOTNOTES
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Dr. DePaola is president emeritus, The Forsyth Institute, Boston, and a professor and special programs director, Nova Southeastern University College of Dental Medicine, Fort Lauderdale, Fla. He also is the guest editor of this supplement. Address reprint requests to Dr. DePaola at 144 Coventry Place, Palm Beach Gardens, Fla. 33418, e-mail "DDePaola{at}forsyth.org".
Disclosure: Dr. DePaola did not report any disclosures.
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REFERENCES
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- Whelton H. Introduction: the anatomy and physiology of salivary glands. In: Edgar M, Dawes C, O’Mullane D, eds. Saliva and Oral Health. 3rd ed. London: British Dental Association; 2004:1–3.
- Wong DT. Salivary diagnostics. Amer Sci 2008;96:37–43.
- Stookey GK. The effect of saliva on dental caries. JADA 2008;139 (5 suppl):11S–17S.
- Dawes C. Salivary flow patterns and the health of hard and soft oral tissues. JADA 2008;139(5 suppl):18S–24S.
- García-Godoy F, Hicks MJ. Maintaining the integrity of the enamel surface: The role of dental biofilm, saliva and preventive agents in enamel demineralization and remineralization. JADA 2008;139(5 suppl):25S–34S.
- Navazesh M, Kumar KS. Measuring salivary flow: challenges and opportunities. JADA 2008;139(5 suppl):35S–40S.
Gum chewing as an adjunct to use of medications
Frederick A. Curro, DMD, PhD
Abbreviations: 5-HT: 5-hydroxytryptamine.
Gum chewing is a gross voluntary physiological motor activity that uses numerous functional neuroanatomical pathways. In this sidebar, I postulate how gum chewing can stimulate various neuronal pathways that may affect a number of clinical outcomes. These clinical outcomes have yet to be demonstrated. The act of gum chewing fulfills many of the hypotheses related to recognizing stimuli of areas of the body not well-represented in the brain, such as neuronal convergence and summation. It also has been associated with many physiological attributes, including increased blood flow in the cerebral and orofacial region, which may account for increased alertness and improved memory. There are two areas—headache and possible inhibition of the satiety center—in which gum chewing works synergistically. For headache, it is a matter of increased blood flow, which prevents the vasoconstriction that initiates a headache. For inhibition of the satiety center, the physical motor activity of chewing sends input to the brain that a person is chewing, and as people normally do not eat food with gum in their mouths, this reduces food intake.
Gum chewing also may be considered a teleological function, and neural circuits may be able to produce self-sustaining patterns of behavior in what are termed "central pattern generators." The literature suggests that the pattern elaborated by the central pattern generator includes selective modifications of sensory transmission.1 The cranial nerves involved in the function of chewing—which include the hypoglossal, spinal accessory, glossopharyngeal and vagus nerves—can affect many other areas of the brain owing to their anatomical location, their neurotransmitter release and, especially, their location in the region of the pons in which the solitary nucleus and nucleus ambiguous can affect systemic functions.2
The neurotransmitter serotonin, or 5-hydroxytryptamine (5-HT), has been implicated in modulating nociceptive transmission. The 5-HT descending inhibitory pathway is essential in mediating the nonopioid systems for antinociception. Prolonged chewing exercise can suppress the nociceptive responses, and the blood 5-HT levels can increase significantly in response to chewing.3 Furthermore, since voluntary rhythmic movements enhance the activity of 5-HT neurons, other prolonged repetitive movements such as locomotion or breathing are considered to produce the same effect.4 Difficulty in chewing may be diagnostic in conditions such as referred otalgia.5
Chewing sugar-free gum at least three times a day significantly reduces caries irrespective of the type of sugar alcohol it contains.6 This is the most obvious use of chewing gum as an adjunct to fluoride for the treatment of caries.
Altering central neurotransmission either directly with drugs or possibly indirectly with the act of chewing would be the goal of a clinical study demonstrating the efficacy of how chewing affects drug action.
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POSTULATED CLINICAL IMPLICATIONS
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Stimulation or inhibition of central neurotransmitters can affect many clinical endpoints. Altering central neurotransmission either directly with drugs (for example, antidepressant, antiobesity or antihypertensive agents) or possibly indirectly with the act of chewing would be the goal of a clinical study demonstrating the efficacy of how chewing affects drug action. To some extent, drugs affecting central neurotransmission most likely will affect the autonomic nervous system. Xerostomia is a condition in which gum chewing can have a direct adjunctive affect on many of the medications prescribed for its treatment. Gum chewing stimulates salivary flow and helps keep the salivary ducts patent. Gum chewing also can be adjunctive to the treatment of temporomandibular disorder and in maintaining the patency of the auditory canals.
If gum chewing can be viewed as a physical activity that affects people’s lifestyles, it may be possible to view gum chewing in the broader context of health and wellness. For example, as noted previously, people usually do not eat food at the same time they chew gum. With the prevalence of obesity on the rise, the metabolic syndrome encompasses a constellation of metabolic abnormalities and is thought to place patients at a higher risk of developing diabetes and cardiovascular disease.7 The physical activity of gum chewing may be a cost-effective way of limiting food and caloric intake.
There is a growing interest in the role of the endocannabinoid system in energy metabolism and how blocking cannabinoid receptors may optimize fat distribution, insulin sensitivity and blood lipids to improve cardiovascular risk profile. Abdominal obesity can affect the status and properties of a number of key adipokines, including adiponectin, angiotensinogen, C-reactive protein, interleukin-6, leptin, plasminogen-activating inhibitor-1, resistin and tumor necrosis factor-alpha.8 Many of these cytokines can affect many systemic outcomes, including periodontal disease.
Gum chewing can be adjunctive to use of medications directed at obesity, such as insulin sensitizers and biguanides, orlistat, sibutramine, phentermine and rimonabant.7 The mechanism of rimonabant treats obesity by blocking the endocannabinoid-1 receptor. This receptor is located in the central and peripheral nervous systems, adipose tissue, gastrointestinal tract, liver and muscle. It prevents weight gain by blocking the overactivation of the endocannabinoid system centrally and peripherally and by regulating energy balance and body composition.
The results of a study demonstrated that gum chewing or mastication can be used as a model to evaluate the increase in neuronal activities in various regions of the human brain.9 Some regional increases in neuronal activity in the brain are age-dependent.10 The results of another study showed that chewing moderately hard chewing gum produced a stronger effect on the blood oxygenation level–dependent signals in the sensorimotor cortex, the thalamus and other brain regions.11 In humans, gum chewing not only results in transient increases in energy expenditure and heart rate response,12 but it also increases cerebral blood flow owing to changes in internal carotid arterial blood flow.13 Positron emission tomography of cerebral blood flow during gum chewing shows increased blood flow in the bilateral lower frontal and parietal lobes.9 These data would suggest that gum chewing is an effective adjunctive treatment for headache. Gum chewing at peak times of the headache onset14 may be worth further clinical study. The difficulty in demonstrating clinical efficacy of the physical act of gum chewing is underscored by the results of a recent multi-center randomized trial of using chewing gum to prevent oral mucositis in children undergoing chemotherapy.15 Investigators found that there was no overall reduction in severe oral mucositis when children chewed five pieces of gum per day.
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CONCLUSION
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Gum chewing usually is not considered to be part of adjunctive medication treatment. Gum chewing may not have a direct effect on a systemic clinical outcome parameter as we know it, but given the data that have been published, gum chewing probably can have an indirect effect on a number of medications and their clinical outcome parameters. The basis for this effect resides in the complexity of the neuroanatomical pathways subserving chewing and mastication, which affects a number of central and peripheral neurotransmitters. Increased blood flow suggests increased neuronal activity that affects neurotransmitters, which can control and communicate information to many parts of the brain, thus affecting systemic clinical outcome parameters. The subtle clinical effects resulting from gum chewing have yet to be determined. The difficulty is in designing studies to capture the subtle additive effects of gum chewing. That said, increased cerebral blood flow caused by gum chewing could be an interesting outcome in age-related studies of dementia and Alzheimer disease, as well as their treatments.
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FOOTNOTES
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Frederick A. Curro, DMD, PhD, is a clinical professor, Department of Oral and Maxillofacial Pathology, Radiology and Medicine; and the director of pharmacotherapeutic research, Bluestone Center for Clinical Research, New York University College of Dentistry, 421 First Ave., 2nd Floor, New York, N.Y. 10010-4086, e-mail "fac3{at}nyu.edu". Address reprint requests to Dr. Curro.
Disclosure: Dr. Curro did not report any disclosures.
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REFERENCES
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- Olsson KA, Sasamoto K, Lund JP. Modulation of transmission in rostral trigeminal sensory nuclei during chewing. J Neurophysiol 1986;55(1):56–75.[Abstract/Free Full Text]
- Andresen MC, Kunze DL. Nucleus tractus solitarius: gateway to neural circulatory control. Annu Rev Physiol 1994;56:93–116.[Medline]
- Mohri Y, Fumoto M, Sato-Suzuki I, Umino M, Arita H. Prolonged rhythmic gum chewing suppresses nociceptive response via serotonergic descending inhibitory pathway in humans. Pain 2005;118(1–2): 35–42.[Medline]
- Jacobs BL, Fornal CA. 5-HT and motor control: a hypothesis. Trends Neurosci 1993;16(9):346–352.[Medline]
- Charlett SD, Coatesworth AP. Referred otalgia: a structured approach to diagnosis and treatment. Int J Clin Pract 2007;61(6): 1015–1021.[Medline]
- Van Loveren C. Sugar alcohols: what is the evidence for caries-preventive and caries-therapeutic effects? Caries Res 2004;38(3): 286–293.[Medline]
- Batsis JA, Nieto-Martinez RE, Lopez-Jimenez F. Metabolic syndrome: from global epidemiology to individualized medicine. Clin Pharmacol Ther 2007;82(5):509–524.[Medline]
- Saavedra LE. Endocannabinoid system and cardiometabolic risk. Clin Pharmacol Ther 2007;82(5):591–594.[Medline]
- Watanabe RP, Ishiyama N, Senda M. Cerebral blood flow during mastication measures with positron emission tomography. Geriatric Dent 1992;6:148–150.
- Onozuka M, Fujita M, Watanabe K, et al. Age-related changes in brain regional activity during chewing: a functional magnetic resonance imaging study. J Dent Res 2003;82(8):657–660.[Abstract/Free Full Text]
- Onozuka M, Fujita M, Watanabe K, et al. Mapping brain region activity during chewing: a functional magnetic resonance imaging study. J Dent Res 2002;81(11):743–746.[Abstract/Free Full Text]
- Suzuki M, Shibata M, Sato Y. Energy metabolism and endocrine responses to gum-chewing. J Mastica Health Sci 1992;2:55–62.
- Nakata M. Masticatory function and its effects on general health (published correction appears in Int Dent J 1999;49[1]:pre-ceding 3). Int Dent J 1998;48(6):540–548.[Medline]
- Gobel H, Cordes P. Circadian variation of pain sensitivity in pericranial musculature. Headache 1990;30(7):418–422.[Medline]
- Gandemer V, Le Deley MC, Dollfus C, et al. Multicenter randomized trial of chewing gum for preventing oral mucositis in children receiving chemotherapy. J Pediatr Hematol Oncol 2007;29(2): 86–94.[Medline]
Are sugar substitutes also anticariogenic?
Domenick T. Zero, DDS, MS
Abbreviations: FDA: U.S. Food and Drug Administration.
The irrefutable importance of sugar as the principal dietary substrate that drives the caries process has led to a growing interest in sugar substitutes. These can be broadly classified as high-intensity sweeteners, which are noncaloric, and bulk sweeteners, which are caloric. Five high-intensity sweeteners—acesulfame potassium, aspartame, saccharin, sucralose and neo-tame—are classified as generally recognized as safe by the U.S. Food and Drug Administration (FDA). They are used mainly as a table sugar replacement and in diet beverages, and increasingly they are used in many reduced-calorie foods. Bulk sweeteners include a variety of dietary polyols that are used in baked goods and confectionery products such as chewing gum, candies, chocolates and mints; in oral care products such as dentifrices and mouthrinses; and in cough syrups and throat lozenges. The polyols used in the United States include sorbitol, xylitol, erythritol, isomalt (glucomannitol and glucosorbitol), lactitol, maltitol and mannitol.
Most of the perspective on whether sugar substitutes can be considered anticariogenic is shaped by the limitations of the classical methods of measuring caries by using the decayed, missing and filled teeth index with frank caries as the outcome measure, as well as the limited knowledge of the natural history of caries as a disease process. Traditional caries indexes are relatively insensitive to the dynamic nature of caries, as well as to the prospect that the disease process can be arrested and possibly reversed during its early enamel caries stages and even at later stages.
The oral environment is influenced by the presence of saliva, which favors tooth preservation. Demineralization leading to caries occurs when the duration and frequency of ingested fermentable carbohydrates (sugars) that interact with a biofilm-covered tooth surface result in acid formation, which overcomes the protective influences of saliva. In the postfluoride era, the threshold for caries progression has been raised, so a more highly cariogenic diet can be tolerated before caries occurs in many people.1 Any measure that shifts the caries process from demineralization toward remineralization will help support tooth preservation. The replacement of dietary sugar with sweeteners that cannot be metabolized or that are metabolized slowly by plaque microorganisms will prevent enamel demineralization and encourage remineralization in the presence of saliva and fluoride. If the frequency of sugar substitution is high enough, it can shift the caries process toward the maintenance of tooth structure and possibly remineralization, and it can help prevent caries—but not in the therapeutic sense of an agent such as fluoride. The additional mechanical and gustatory salivary stimulation across the extended period of product use is an added benefit of sugar substitutes when used in chewing gum and, to a lesser extent, in candies and mints.
High-intensity sweeteners are nonacidogenic; they cannot be metabolized by oral microorganisms to produce acids. Along with bulk sweeteners, high-intensity sweeteners can be considered noncariogenic when used in foods and beverages that do not contain sugars. No anticariogenic attributes have been ascribed to high-intensity sweeteners yet. Bulk sugar substitutes (polyols) that are hypoacidogenic (isomalt, sorbitol, mannitol, maltitol and lactitol) are considered to be of low or noncariogenic potential, and nonacidogenic sweeteners (xylitol and erythritol) have been characterized as non-cariogenic. Sugar-free foods and confectioneries containing polyols have FDA approval to be labeled with a "does not promote tooth decay" health claim.
Of the bulk sweeteners, xylitol has been the most studied and reviewed, and it is the most controversial.2–5 The controversy revolves around whether xylitol has an anticaries benefit and, therefore, is superior to the other polyols. The results of studies have shown that when sorbitol- and xylitol-containing chewing gum and candies were used three to five times per day, they had a caries-preventive effect in subjects compared with results in subjects who did not use chewing gum or candy, and xylitol generally had a larger caries-preventive benefit.4,5 Questions have been raised about whether the caries-preventive benefit of xylitol-containing chewing gum is due to salivary stimulation or to an antimicrobial effect. Unlike sorbitol, which can be metabolized slowly by some oral bacteria, xylitol has a bacteriostatic effect on mutans streptococci. It also has been reported to reduce mutans streptococci levels in plaque and saliva,6 block mother-to-child transmission of mutans streptococci7 and alter the acidogenic potential of plaque to subsequent sugar challenges.8 The results of direct head-to-head comparisons of sorbitol and xylitol have been mixed, and concerns have been raised about the independence and quality of the research.4
In summary, sugar substitutes can play an important role in shifting the caries process in favor of maintaining dental health, and they should be recommended as part of an overall preventive treatment plan for patients at high risk of developing caries. Although xylitol has anticariogenic properties, there is not sufficient evidence to recommend xylitol as a first-line anticaries strategy in light of the large body of evidence on the effectiveness of topical fluoride and dental sealants. However, xylitol-containing chewing gum and mints can be recommended as an adjunct to other preventive intervention strategies if cost considerations do not outweigh effectiveness.
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FOOTNOTES
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Domenick T. Zero, DDS, MS, is the associate dean for research; a professor and the chair, Department of Preventive and Community Dentistry; and the director, Oral Health Research Institute, Indiana University School of Dentistry. Address reprint requests to Dr. Zero at Indiana University School of Dentistry, Oral Health Research Institute, 415 Lansing St., Indianapolis, Ind. 46202-2876, e-mail "dzero{at}iupui.edu".
Disclosure: Dr. Zero has conducted studies of chewing gum products containing sugar substitutes that were sponsored by Cadbury Adams USA, Parsippany, N.J., and the Wm. Wrigley Jr. Company, Chicago. He also has served as a consultant for these companies. He currently is consulting for the Hershey Company, Hershey, Pa.
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REFERENCES
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- Zero DT. Sugars: the arch criminal? Caries Res 2004;38(3): 277–285.[Medline]
- Scheie AA, Fejerskov OB. Xylitol in caries prevention: what is the evidence for clinical efficacy? Oral Dis 1998;4(4):268–278.[Medline]
- Maguire A, Rugg-Gunn AJ. Xylitol and caries prevention: is it a magic bullet? Brit Dent J 2003;194(8):429–436.[Medline]
- Van Loveren C. Sugar alcohols: what is the evidence for caries-preventive and caries-therapeutic effects? Caries Res 2004;38(3): 286–293.[Medline]
- Burt BA. The use of sorbitol- and xylitol-sweetened chewing gum in caries control (published correction appears in JADA 2006;137[4]: 447). JADA 2006;137(2):190–196.
- Milgrom P, Ly KA, Roberts MC, Rothen M, Mueller G, Yamaguchi DK. Mutans streptococci dose response to xylitol chewing gum. J Dent Res 2006;85(2):177–181.[Abstract/Free Full Text]
- Söderling E, Isokangas P, Pienihäkkinen K, Tenovuo J. Influence of maternal xylitol consumption on acquisition of mutans streptococci by infants. J Dent Res 2000;79(3):882–887.[Abstract/Free Full Text]
- Aguirre-Zero O, Zero DT, Proskin HM. Effect of chewing xylitol chewing gum on salivary flow rate and the acidogenic potential of dental plaque. Caries Res 1993;27(1):55–59.[Medline]
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FOOTNOTES 
