The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor, angiotensin-converting enzyme 2 (ACE2), transmembrane protease serine 2 (TMPRSS2), and furin, which promote entry of the virus into the host cell, have been identified as determinants of SARS-CoV-2 infection. Dorsal tongue and gingiva, saliva, and tongue coating samples were examined to determine the presence of these molecules in the oral cavity. Immunohistochemical analyses showed that ACE2 was expressed in the stratified squamous epithelium of the dorsal tongue and gingiva. TMPRSS2 was strongly expressed in stratified squamous epithelium in the keratinized surface layer and detected in the saliva and tongue coating samples via Western blot. Furin was localized mainly in the lower layer of stratified squamous epithelium and detected in the saliva but not tongue coating. ACE2, TMPRSS2, and furin mRNA expression was observed in taste bud-derived cultured cells, which was similar to the immunofluorescence observations. These data showed that essential molecules for SARS-CoV-2 infection were abundant in the oral cavity. However, the database analysis showed that saliva also contains many protease inhibitors. Therefore, although the oral cavity may be the entry route for SARS-CoV-2, other factors including protease inhibitors in the saliva that inhibit viral entry should be considered.

Chewing is one of the most important orofacial functions. During this process, food is reduced in size, while saliva moistens the food and binds it into a bolus that can be easily swallowed. Characteristics of the oral system, including the number of teeth, bite force, and salivary flow, influence the masticatory process. In addition, salivary glands produce several cell growth factors and play an important role in human health. The nerve growth factor (NGF) family consists of NGF, brain-derived neurotrophic factor (BDNF), and neurotrophins-3 to 7. BDNF is a well-studied neurotrophin involved in the neurogenesis, differentiation, and maintenance of select peripheral and central neuronal cell populations during development and adulthood. However, there has been no detailed description of the expression of neurotrophins other than NGF in the salivary gland. We previously studied the effect of immobilization stress + chewing on BDNF secretion and its receptor, tyrosine receptor kinase B, in rat submandibular glands and found increased BDNF expression in duct cells under these conditions. In this review, we describe recent advances in understanding the role of stress and chewing-related BDNF in the saliva and salivary glands.

Salivary immunoglobulin A (IgA) plays a vital role in preventing upper respiratory tract infections (URTI). In our previous study, we showed that the intake of carbohydrates increases the intestinal levels of short-chain fatty acids (SCFAs), which in turn increase salivary IgA levels. However, the mechanism underlying this phenomenon has not been fully elucidated. In this study, we investigated in rats the effect of polydextrose (PDX) ingestion on salivary IgA level and SCFA concentration in cecal digesta and the portal vein. Five-week-old rats were fed with a fiber-free diet (control) or with 40 g/kg of PDX for 28 days. Compared to the control, ingestion of PDX led to a higher salivary IgA flow rate (p = 0.0013) and a higher concentration of SCFAs in the portal vein (p = 0.004). These two data were positively correlated (r_s = 0.88, p = 0.0002, n = 12). In contrast, the concentration of SCFAs in cecal digesta and cecal digesta viscosity were significantly lower following PDX ingestion, compared to the control (p = 0.008 and 0.05, respectively). These findings suggest that the ingestion of PDX increases the absorption rate of SCFAs in the intestine through PDX-induced fermentation, which is accompanied by an increase in SCFA levels in the blood, and ultimately leads to increased salivary IgA levels.

Consumption of indigestible dietary fiber increases immunoglobulin A (IgA) levels in saliva. The purpose of this study is to clarify the synergistic effect of the intake of a high amount of fats and indigestible dietary fiber on IgA levels in saliva and submandibular glands (SMG). Seven-week-old Wistar rats were fed a low-fat (60 g/kg) fiberless diet, low-fat fructo-oligosaccharide (FOS, 30 g/kg) diet, high-fat (220 g/kg) fiberless diet, or high-fat FOS diet for 70 days. The IgA flow rate of saliva (IgA FR-saliva) was higher in the low-fat FOS group than in the other groups (p < 0.05). Furthermore, the concentration of tyrosine hydroxylase (a marker of sympathetic nerve activation) in the SMG was higher in the low-fat FOS group (p < 0.05) and positively correlated with the IgA FR-saliva (rs = 0.68. p < 0.0001. n = 32) in comparison to that in the other groups. These findings suggest that during low-fat FOS intake, salivary IgA levels may increase through sympathetic nerve activation.

Vascular dementia, caused by cerebrovascular disease, is associated with cognitive impairment and reduced hippocampal metabolite levels. Specifically, cognitive impairment can be induced by decreased hippocampal brain-derived neurotrophic factor (BDNF) expression. The development of low or non-invasive biomarkers to characterize these diseases is an urgent task. Disturbance of metabolic pathways has been frequently observed in cognitive impairment, and salivary molecules also showed the potentials to reflect cognitive impairment. Therefore, we evaluated salivary metabolic profiles associated with altered hippocampal BDNF expression levels in a cerebral ischemia mouse model using metabolomic analyses. The effect of tacrine (a cholinesterase inhibitor) administration was also examined. The arteries of ICR mice were occluded with aneurysm clips to generate the cerebral ischemia model. Learning and memory performance was assessed using the elevated plus maze (EPM) test. Hippocampal and blood BDNF levels were quantified using an enzyme-linked immunosorbent assay. Glutamate decarboxylase 1 (GAD1) mRNA expression, is associated with cognitive impairment, was quantified by a real-time polymerase chain reaction. The EPM test revealed impaired spatial working memory in the cerebral ischemia mouse model; tacrine administration ameliorated this memory impairment. Cerebral ischemia suppressed GAD1 expression by decreasing hippocampal BDNF expression. In total, seven salivary metabolites, such as trimethylamine N-oxide and putrescine, were changed by cognitive impairment and tacrine administration. Our data suggest that salivary metabolite patterns were associated with cognitive function.

SARS-CoV-2 infects a variety of tissues, including the oral cavity. However, there are few reports examining the association of SARS-CoV-2 with tongue mucosal tissues with sticky tongue debris. This study investigated the presence of SARS-CoV-2 and its associated molecules by dissecting tongue tissue from autopsy specimens of 23 patients who died of COVID-19-related illness (pneumonia). Immunohistochemical staining, electron microscopy, and PCR analysis were performed on the tongue tissue specimens. The mucosal epithelium of the tongue formed a very thick keratinized with well-developed filiform papillae in all cases. ACE2 and TMPRSS2 were consistently co-expressed in all samples in the epithelium. The S-protein was strongly expressed in basal cells and the epithelial surface. S-protein-positive viral particles were detected in the tongue’s stratified squamous epithelium via an immunoelectron microscope. Based on PCR amplification of the N1 and N2 regions, the SARS-CoV-2 gene was detected on the tongue epithelium, tongue submucosa, and in tongue debris. This suggests that tongue debris, including the squamous epithelial tissue, could be a source of SARS-CoV-2 in saliva. Furthermore, removing tongue debris may decrease the amount of SARS-CoV-2 in the oral cavity.