Poor oral health has been linked with cardiovascular disease, diabetes, neurodegenerative diseases, and various cancers. This connection is rooted in the body’s complex microbial ecosystem: alongside trillions of human cells, we harbor a diverse population of microorganisms in the mouth, composed of hundreds of bacterial, fungal, viral, and protozoal species. These oral microbes exist in dynamic balance, shaped by diet, environment, and lifestyle, and are continually swallowed—interacting with the gastrointestinal tract and influencing metabolism, immune responses, and inflammation. Oral dysbiosis is also implicated in chronic pain and central sensitization, and emerging evidence suggests that reducing whole-body inflammation may benefit patients with a variety of chronically painful conditions.
Research further indicates that physical activity may modulate the composition and function of the oral microbiome, highlighting exercise as a potential contributor to microbial balance. The connection between the oral microbiome and regular physical activity is bidirectional—each influences the other, partly through the signaling molecule nitric oxide (NO).
What Is Nitric Oxide?
Nitric oxide is a free radical gas that functions as a critical signaling molecule throughout the body. It serves important cardiac, vascular, and metabolic functions and can act as a neurotransmitter [1]. As a potent vasodilator, NO regulates blood pressure, improves circulation, and supports heart and brain health. It also affects muscle strength and exercise performance, as excess nitrite stored in skeletal muscles is metabolized into NO during physical activity [1]. NO’s half-life is extremely short—less than one second—meaning the body must continuously produce it [2].
NO is generated through two primary mechanisms: dietary ingestion of nitrate, which oral bacteria convert to nitrite and is further reduced to NO in the stomach or peripheral tissues; and the enzymatic conversion of L-arginine by nitric oxide synthase (NOS) in endothelial cells [1, 2, 3]. As patients age and the intrinsic NOS pathway slows, oxidative stress and inflammation increase, making the complementary salivary pathway increasingly important [3].
The salivary pathway depends on a two-way interaction between oral microbiota and dietary nitrate. Certain bacterial species are known nitrate-reducers, and nitrate-rich diets encourage their growth [1, 2, 3]. Dietary nitrate comes primarily from green leafy vegetables and root vegetables such as beetroot. Salivary glands extract nitrate from plasma and concentrate it in the oral cavity, where nitrate-reducing bacteria produce nitrite-enriched saliva. This saliva is swallowed and further reduced to NO by stomach acid [3]. Notably, NO production may be impaired by antacids, proton-pump inhibitors, and antiseptic mouthwash, which disturb the oral microbiome and reduce nitrite availability [3].
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Exercise and Alterations in Oral Flora
Exercise may directly influence both pathways of NO production. It enhances endogenous NO synthesis by upregulating the NOS pathway [1], while increased intake of nitrate-rich foods or supplements such as beetroot juice has been associated with improved exercise performance and muscle efficiency [2, 4]. Emerging evidence also suggests exercise modulates the oral microbiome. A pilot study comparing in-season and off-season collegiate athletes found reduced pathogenic bacteria and increased microbial diversity during competition, while a randomized controlled trial in older adults observed reductions in pathogenic taxa following exercise interventions [5, 6]. Exercise may also elevate salivary lactate levels, providing an additional substrate for nitrate reduction and promoting short-chain fatty acid (SCFA) production with anti-inflammatory and pain-modulating effects [1, 7].
A 2025 interventional study evaluated 8 weeks of high-intensity interval training on the tongue microbiome in 11 previously sedentary men [7]. The program produced measurable shifts in nitrate-reducing bacterial species, accompanied by changes in salivary nitrite concentrations and altered nitrate levels in plasma and muscle tissue. Some microbiome changes persisted even after detraining, suggesting a potentially lasting effect of physical activity on the oral-systemic nitric oxide axis.
Exercise, NO, the Oral Microbiome, and Chronic Pain
In chronic pain, NO plays a dual role—anti-inflammatory at normal concentrations, but pro-inflammatory when overproduced. Overproduction can generate reactive cytotoxic compounds that amplify pain signaling and contribute to central sensitization [8]. Both oral and gut dysbiosis have been increasingly associated with chronic pain conditions, including temporomandibular joint disorder (TMD) [9, 10]. Dysbiosis can increase pain sensitivity, reduce SCFA production, and promote neuroinflammation, while chronic pain states may further disrupt microbial homeostasis, perpetuating a cycle of dysregulation [10]. Specific oral microorganisms have also been linked to systemic pain conditions such as rheumatoid arthritis, fibromyalgia, and migraines [9].
Aerobic exercise and strength training have been shown to improve clinical outcomes in patients with orofacial pain and migraine, reducing pain intensity, frequency, and disability [11, 12]. These benefits extend beyond traditional mechanisms like endorphin release and improved circulation. Exercise simultaneously enhances NO bioavailability, modulates microbial composition, and promotes SCFA production—collectively reducing systemic inflammation, improving endothelial function, and modulating pain processing pathways, including central sensitization.
Conclusion
In summary, the oral microbiome serves as a critical interface linking lifestyle factors, systemic inflammation, and chronic pain. These insights underscore the potential of integrative strategies—combining oral health optimization with regular physical activity—to prevent and manage chronic pain conditions, particularly within the orofacial region.
Are you interested in a variety of issues focused on orofacial pain, medicine and sleep disorders? Consider enrolling in the Herman Ostrow School of Dentistry of USC’s online, competency-based certificate or master’s program in Orofacial Pain and Oral Medicine.
References
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