Arginine and the Healthy Oral Microbiome

Caries: Defining the Disease and Its Continued Impact—Pitts and Wolff

Nigel Pitts, BDS, PhD, FRSE opens this special edition with a detailed examination of the current theories surrounding the etiology and natural history of dental caries¹. He begins with a succinct definition of the disease, which, as quoted, provides the conceptual framework for each of the papers included in this collection:

Dental caries is a biofilm-mediated, diet modulated, multifactorial, non-communicable, dynamic disease resulting in net mineral loss of dental hard tissues [Fejerskov 1997; Pitts et al., 2017]. It is determined by biological, behavioural, psychosocial, and environmental factors. [Because of this] process, a caries lesion develops. 

This quote defines caries as a dynamic process—one in which an almost continual process of demineralization and remineralization is occurring within our patients’ mouths—the balance of which can be influenced by a range of factors, each of which is described in this elegant definition. Pitts goes on to link this definition to the management of this balance described as “caries care, management and control,” in which actions are taken to favor the remineralization side of the caries process, be they by professional, chemical, patient, or environmental interventions. Both Dr. Nigel Pitts et al.¹ and Dr. Mark S. Wolff et al.², in the second paper in the monograph, remind us of the ongoing importance of dental disease and its global impact.

We are reminded that caries is a lifelong disease—not one restricted to children—where risk extends into adulthood, placing untreated dental caries in the permanent dentition as the most prevalent disease at 35% of the population. For our actions to disrupt the demineralization process and to have a meaningful impact on this burden of disease, we need to identify carious lesions early in their natural history, affording the best opportunity to prevent progression from surface intact lesions to those requiring restorative treatment. In the absence of early intervention and treatment, caries sufferers experience pain, discomfort, and lack of function.

Wolff discusses the current methods and therapeutics that are used to shift the biological balance towards remineralization or at least arrest the carious process.² His review covers fluoride, both in its familiar forms (gels, varnishes, and dentifrices) and as silver diamine fluoride (SDF). It is interesting to note that the silver element of the SDF complex is thought to exert an antimicrobial effect, inhibiting Streptococcus mutans[A1] [A2] and Lactobacillus acidophilus. The move to consider the microbiome in the caries process is the subject of the next paper.

Oral Microbiome and Arginine: Mechanisms of Action and Laboratory Studies—Burne and Shi

Dr. Robert A. Burne et al.³ provides us with a tour-de-force review of the role of the microbiome in dental disease, with an important statement that helps us understand how new therapeutics may fit within the framework of disease management described by Pitts and Wolff:

Present therapeutic and treatment strategies for caries largely ignore the critical role that intermicrobial interactions and microbial ecology play in the development and progression of the disease. Vaccination has fallen by the wayside, while biofilm removal and excavation of damaged tissue have remained the standard of care, although major strides have been made in the nonsurgical management of caries. Recently, though, basic and clinical research has highlighted that incorporation of arginine into oral health care formulations is a promising novel approach to caries prevention and management.

What is arginine? Arginine is an amino acid that was first isolated in 1886 from lupin seedlings and is classified as a conditionally (or semi-) essential amino acid and one that is sold in numerous food supplements. Its ability to impact the oral microbiome (and hence caries) was recognized as early as 1970, but it is only recently that its mechanism of action has become fully understood. Burne states that the primary actions of arginine are dependent on the biochemical and physiological activities of the oral microbiome3 and goes on to describe how arginine provides selective bioenergetic advantages to health-associated microbiota, pushing the microbiome in essence towards favoring remineralization. He describes in vitro and in vivo studies of arginine that suggest it can be a “highly effective anti-caries agent on its own, or in combination with fluoride”.³ Arginine improves the stability of plaque pH, inhibits the actions of cariogenic pathogens, and favors the microbiome towards a health-promoting profile.

This leads us to the paper by Dr. Wenyuan Shi et al.⁴ that further explores the mechanisms by which arginine exerts its anticaries effects, examining and describing studies that show how oral bacteria metabolize arginine and, in turn, how this improves pH homeostasis, modulates the microbial profile, and inhibits caries pathogens. Shi describes arginine as a prebiotic—a substrate that is selectively used by microorganisms to promote or confer a health benefit. Shi concludes that the evidence to support the use of arginine has largely been developed from in vitro and in vivo studies; hence, there is a need to supplement these findings within clinical studies.

Clinical Studies of Arginine—Ryan

Shi’s conclusion leads us to the final paper in this special monograph, where Dr. Maria Ryan⁵ describes the current clinical studies that have examined the use of arginine as a caries therapeutic. She describes promising results from studies where arginine has been used with fluoride and alone, with the potential for arginine-only toothpastes to benefit those areas of the world where fluorosis remains an issue, or where, for various cultural reasons, there is a low uptake of fluoride-containing dentifrices, leaving consumers with the choice of a toothpaste with no active anticaries ingredient.

As an example of the studies described, a 2-year double-blind randomized control trial found that a dentifrice with 1.5% arginine was at least as effective as a 1100 ppm fluoride toothpaste in reducing the formation of caries.⁶ Ryan describes a developing portfolio of clinical evidence that supports the efficacy of arginine as a novel caries preventive agent.

Conclusion
The clinical studies described by Ryan⁵ lend further weight to the developing evidence that has been so well articulated by the contributors to this special monograph—that arginine is a promising anticaries agent with a sound biological mechanism of action that may offer, for the first time in decades, a new caries therapeutic.

There are currently further large-scale clinical studies being undertaken both in China and the United States and, as a caries researcher, it is exciting to see that this area of study has been invigorated by the potential for a new dentifrice formulation. I invite you to read each of the scholarly articles in this special monograph; they are a superb resource not only on a novel therapeutic but for the underlying basis of the oral disease caries known to be prevalent throughout the world that, as dentists, we spend a great amount of our time treating and trying to prevent.

Conflict of Interest Statement

Pretty receives funding from the Colgate-Palmolive Company via an educational grant to the University of Manchester for support of the Manchester Dental Health Unit.

References

1. Pitts N. Caries overview 2021: Epidemiology, etiology, and evidence-into-action considerations. JADA+ Monograph. July 2023: 7-13.
2. Lee C, Wolff M. Caries – an ongoing public health crisis. JADA+ Monograph. July 2023: 14-18.
3. Burne RA. Anti-caries mechanisms of action of arginine. JADA+ Monograph. July 2023: 19-23.
4. Tian J, Tingxi W, He X, Shi W. The role and impact of arginine on dental caries therapeutics. July 2023: 24-29.
5. Ryan M. Clinical perspective: Arginine as an anticaries agent. July 2023: 30-35.
6. Acevedo AM, Machado C, Rivera LE, Wolff M, Kleinberg I. The inhibitory effect of an arginine bicarbonate/calcium carbonate CaviStat-containing dentifrice on the development of dental caries in Venezuelan school children. J Clin Dent. 2005;16(3):
   63-70.
   

Dr. Iain A. Pretty Biography

Iain A. Pretty, ain A. Pretty, BDS, MSc, PhD, MPH, FDSRCS(Ed), FFPH, FFCI, FFSoc
Dental Health Unit
The University of Manchester