Dentists and physicians’ practices meet once again: Potential unfavorable clinical effects of frequent mouthwash use

Nitric oxide (NO) plays an important role in hypertension (HTN) as well as metabolic diseases such as diabetes mellitus (DM). A significant portion of the NO is from oral intake; however, the bioavailability of NO may be diminished due to the disruption of oral microbiome due to mouthwash use. The goal of this editorial is to raise awareness of the potential risk of metabolic disease and endothelial damage due to mouthwash overuse.

The classical notion that NO was simply an insignificantly small noxious environmental pollutant molecule found in cigarette smoking, smog, and exhaust from combustion vehicles was radically transformed with the discovery that NO release accounted for the biological activity of endothelium-derived relaxing factor. [1] This paradigm shift continued to evolve over the years as NO accounted for other biological processes, not simply limited to vascular endothelium but also regulating organ perfusion, systemic and pulmonary circulation, and atherosclerosis. [1,2]

Albeit all the well-known physiological reactions being ascribed to NO, its protective role regarding the vascular endothelium is particularly important given the global epidemic of metabolic syndrome. The major source of NO is synthesized from the endothelial NO synthase (eNOS) pathway; [2] it is therefore reasonable to assume that NO abnormalities would be intricately related to both HTN and DM. These associations are clinically relevant as both clinical entities are common precursors of cardiovascular disease (CVD) by targeting the endothelium damage resulting in progressive inflammation and atherosclerosis.

Obesity, another major metabolic syndrome component, is also involved in NO abnormalities. Specifically, among obese individuals, the expression of eNOS is blunted through various pathways leading to a decreased serum NO concentration [1]. Poor vascular regulation can cause endothelial dysfunction leading to a further decrease in NO concentration, and high levels of fatty acids and asymmetric dimethylarginine (ADMA) can further inhibit the expression of NOS[1]. This unfortunately causes a feedback loop causing worsening metabolic disease.

Dietary inorganic nitrates and nitrites can act like storage pools complementing the NOS pathway, which has been shown to possess therapeutic effects in diseases such as myocardial infarction, stroke, systemic and pulmonary hypertension, and gastric ulceration. [2] However, the bioavailability of NO may be diminished due to the disruption of nitrate-nitrite-nitric oxide pathway[3]. The American Dental Association advocates for mouthwashes as an adjunct to daily brushing in efforts to prevent plaque and gingivitis. [4] Currently, 60% of the US population use mouthwash one or more times weekly and a third use it daily[5]. However, the nondiscriminatory antibiotic activity of mouthwashes can destroy nitrite-reducing bacteria, which is essential in the bioactivation of NO since humans lack the necessary enzymes to reduce nitrites. Consequently, a decreased in serum plasma nitrate/nitrite levels leads to both HTN and DM.

Seminal work by Joshipura et al. was the first publication reporting an association between frequent regular use of over-the-counter mouthwash and pre-diabetes/diabetes. [5] This was a longitudinal study in which 945 patients were followed over the course of 3 years and data were collected in Puerto Rico. [5] Study participants were overweight/obese between the ages of 40–65 without diagnosis of diabetes prior to baseline exam, and no significant CVD or other health conditions. The primary outcome was a progression from no diabetes to prediabetes/diabetes and/or prediabetes to diabetes. The study used a Poisson regression model adjusting for age, gender, smoking, physical activity, waist circumference, alcohol, and diagnosis and treatment of HTN in a 3-year follow-up. The results suggested a 49–55% increased risk of developing diabetes or prediabetes; IRR = 1.55 (95% confidence interval [CI], 1.2 to 1.97) for participants using mouthwash more than twice a day vs less frequent use; IRR = 1.49 (95% CI, 1.13 to 1.95) for participants using mouthwash more than twice a day vs no use.

In a second publication using the same study population, Joshipura et al. studied whether the frequency of mouthwash use was associated with the devolvement of HTN. [6] For this analysis, data from 540 patients without a prior HTN diagnosis were used. [6] In this study, the investigators demonstrated 85–117% significant increased risk of developing HTN; IRR = 1.85 (95% CI, 1.17 to 2.94) for patients using mouthwash more than twice a day vs less frequent use; IRR = 2.17 (95% CI, 1.27 to 3.71) for patients using mouthwash more than twice a day vs no use [5]. The authors concluded that while causation is not established, the use of mouthwashes may likely lead to DM II and HTN by reducing the bioavailability of NO [5,6].

These two studies were the first to investigate the systemic impact of over-the-counter mouthwash. These results are particularly relevant as the population studied were both older and obese, since these individuals are expected to be more susceptible to changes in decreased NO bioavailability via disruption of the effects of dietary nitrite intake. [1] Furthermore, the analysis was also adjusted for dietary factors. This is very important, particularly as BH4 and L-glargine are essential cofactors for endogenous NO synthesis via NOS pathway. [1] Perhaps one way the author could have strengthened their argument was to collect data on serum NO levels, angiotensin levels, change in hemoglobin a1c (degree of insulin resistance), and ADMA levels as they have all been implicated in the synthesis of NO[1].

While the authors were rightfully cautious about causal interpretation, there is growing evidence for a causal effect. However, there are growing evidence that link oral microbiome to cardiovascular health[7]. Furthermore, in a recent study by Goh and associates, analysis of microbial DNA extracted from subgingival dental plaques and 16S rRNA gene sequencing, these investigators showed that a higher relative abundance of oral nitrate-reducing bacteria was associated with lower insulin resistance and mean systolic blood pressure with normotension[8].

It is our belief that these results need to be readily available to general practitioners, internists, pediatricians, endocrinologists, and cardiologists who might not come across this literature or may need help to understand the relevance. Certainly, this is an aspect of our patients’ daily practices that for the most part, is never investigated and largely ignored unless we encounter specific patients having obvious dental issues or simply poor oral hygiene. Based on the available data, the routine use of mouthwash preparations ought to be included in our assessments when determining the overall health of our patients.

Importantly, this represents an important call to action to further advance our understanding and continue investigating how more targeted mouthwash formulation and use may be developed and promoted to optimize oral and cardiovascular health. In a similar fashion, the American Dental Association should revisit guidelines and recommendations for mouthwash use given its potential implications regarding DM II and HTN.

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The contents of the paper and the opinions expressed within are those of the authors, and it was the decision of the authors to submit the manuscript for publication.

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