**1. Introduction**

Salivary glands, an essential component to maintaining oral health, are susceptible to a variety of pathologies, including candidiasis. The salivary glands are commonly classified as either major or minor salivary glands based on their sizes, distributions, and functional characteristics [1]. The major salivary glands consist of the parotid, submandibular, and sublingual glands [2], which produce and secrete saliva, moisturize intraoral mucosa and teeth, maintain oral hygiene, and facilitate taste, swallowing, speech, and mastication [3]. The minor salivary glands are distributed throughout oral mucosa surfaces, producing mucous saliva with organic substances, even at night, and protect oral mucosa from injury [4–6]. Notably, salivary glands produce high concentrations of the secretory immunoglobulin (Ig) A, which prevents other Igs from being broken down by proteolytic enzymes from microbes [7,8]. These critical functions of saliva are repressed when the salivary glands are damaged by *Candida* infections.

*Candida* is a genus of yeast and major human fungal pathogens [9]. *Candida* species are opportunistic pathogens that could repeatedly and chronically cause oral mucosa infections [10,11]. The most prevalent species found in oral *Candida* infection is *Candida albicans*, due to its cell adherence properties and great pathogenic potential [12]. *C. albicans* is isolated from more than 80% of oral *Candida* lesions [13]. Other

clinically relevant species include *Candida glabrata*, *Candida* tropicalis*, Candida* parapsilosis*, Candida kefyr, Candida* dubliniensis*, Candida* lusitaniae*, Candida* krusei, and Candida guilliermondii [14]. It has been reported that 30–45% of healthy adults carry oral *Candida* organisms, and 25–80% of adults develop oral candidiasis under the condition of using antibiotics, steroids, or immunosuppressants; impaired salivary gland function; improperly fitted dentures; poor oral hygiene; and a high carbohydrate diet. Additionally, 49–54% of healthy infants carry oral *Candida* organisms, and 5–7% of infants develop oral candidiasis [15,16]. In general, the most commonly affected populations are middle-aged to elderly people. Prevalence rates as high as 70% have been reported in nursing-home residents [17]. Denture-associated oral candidiasis is frequent and occurs globally. Additionally, females are affected slightly more frequently than males [17]. Oral candidiasis also occurs in immunocompromised patients, with an estimated prevalence of 9–31% of acquired immunodeficiency syndrome (AIDS) patients and 20% of cancer patients [18].

Host inflammatory reaction to *Candida* infection may negatively affect salivary gland tissue and function. During *Candida* infection, epithelial leukocyte penetration and subepithelial inflammation are observed in histological examinations [19]. The inflammatory mediators, such as chemokines and cytokines (TNF-α, IL-6, and IL1β), are secreted from oral epithelial cells and phagocytic cells, including neutrophils, macrophages, and dendritic cells [19]. The inflammatory reaction could damage salivary glands in the form of sialectasis, ductal ectasia, and progressive acinar destruction. The sublingual and minor salivary glands are located in the superficial layer of the oral mucosa and may be more vulnerable to inflammatory-mediated damage.

Based on clinical observation and pathological evidence from the literature, this review article discusses the anatomy and function of the salivary gland, the association between *Candida* and saliva, the effects of oral *Candida* infection on salivary glands, and treatment strategies to combat *Candida* infection.

#### **2. Anatomy and Function of the Salivary Glands**

To understand the implications of *Candida* infection and how it affects salivary glands, the anatomy and function of normal salivary gland are described. As shown in Figure 1, there are three major salivary glands: parotid, submandibular, and sublingual glands in the oral cavity. The paired parotid glands are the largest of the major salivary gland; they are encapsulated and located lateral to the ramus of the mandible [20]. The parotid gland consists mainly of serous acini, secreting α-amylase-rich saliva. Saliva α-amylase is known to play a secondary role in preventing bacterial attachment to the oral surface and removing bacteria from the oral cavity [21]. The paired submandibular glands are the second largest salivary gland, located in the submandibular triangle, consisting of anterior and posterior digastric muscles, and lower border of the mandible, making up the posterior part of the floor of the mouth, above the mylohyoid muscle. The submandibular glands are composed of mixed acini populations with mucous and serous function [20]. The sublingual glands are the smallest major salivary gland and are located right under the mucous membrane at the floor of the mouth [22]. Unlike the parotid and submandibular glands, the sublingual glands are not encapsulated and spread throughout the sublingual space. The sublingual space is just below the floor of mouth and above the mylohyoid muscles. The sublingual glands secrete mucous saliva, a viscous solution rich in mucins. While the parotid and submandibular glands have long branched ducts containing all the ductal segments (excretory, intercalated, and striated), the sublingual glands lack striated ducts. The three main salivary glands account for more than 90% of secreted saliva by volume.

**Figure 1.** Drawing shows the location of the major salivary glands and its ducts. Note: Sublingual gland is located below the oral epithelium of the floor of the mouth. Adapted with permission of Radiological Society of North America, from "Imaging the Floor of the Mouth and the Sublingual Space", 31, 5, 2011 [23]; permission conveyed through Copyright Clearance Center, Inc.

Minor salivary glands are located in the submucosa, where they are surrounded by connective tissue, or embedded between muscle fibers (Figure 2). Between 600 and 1000 minor salivary glands are scattered throughout the oral mucosa except for the gingiva, the anterior dorsal aspect of the tongue, the midline and anterior part of the hard palate. Minor salivary glands consist of small secretory cell clusters with short excretory ducts that convey saliva products to the mucosal surface [4]. Minor salivary glands have a diameter of 1–5 mm and no actual capsule like the sublingual gland. Most of the minor salivary glands secrete mucus saliva; however, Von Ebner glands secrete serous or mixed saliva. The Von Ebner glands are adjacent to the foliate and circumvallate papillae in the dorsum and posterior tongue [4]. Although minor salivary glands produce about 10% of the total saliva volume [24], the minor salivary glands are widely distributed throughout the oral submucosa and secrete an abundance of salivary mucins, which acts as a lubricant. Mucin is important component of saliva, to avoid the subjective sensation of oral dryness [6]. By secretion of salivary mucins from the minor salivary glands, the formation of a lubricating film on the oral surfaces contributes to mucosal wetting and protection [5]. Meanwhile, researchers demonstrated that the flow rate of the minor salivary glands is a critical factor for dry-mouth assessment [25,26]. Since subjective feelings from dry mouth are associated with decreased flow rates of the minor salivary gland, the minor salivary gland flow rate could be used a xerostomia-assessment tool [25,26]. Furthermore, minor salivary glands produce saliva during sleep. It appears that a reduced minor salivary gland flow rate could account for dry mouth at night [27]. By secretion of salivary mucins from the minor salivary glands, the formation of a lubricating film on the oral surfaces contributes to mucosal wetting and protection [5]. Minor salivary glands also secrete high concentrations of antibacterial components, such as IgA, to protect the oral mucosa [28]. More than a third of secretory IgA is secreted from the minor salivary glands in whole saliva [29]. Secretory IgA enhances the antibacterial activity of mucin, lactoferrin, peroxidase, and aglutinin [30].

**Figure 2.** (**a**) Minor salivary gland distribution in the oral cavity (shown as purple shade). Adapted with permission of Wolters Kluwer Medknow Publications from Review of the Major and Minor Salivary Glands, Part 1: Anatomy, Infectious, and Inflammatory Processes, 8, 1, 2018 [31]. (**b**) Minor salivary gland are located just below the oral epithelium (Adapted with permission of Elsevier Science and Technology Books from *Comparative Anatomy and Histology: A Mouse, Rat, and Human Atlas*, 2017 [32]). (**a**,**b**) Permission conveyed through Copyright Clearance Center, Inc.

Whole saliva secreted by both major and minor salivary glands is an essential fluid for oral maintenance and function. Saliva initiates the digestive process with digestive enzymes, while simultaneously lubricating the solid diet, to assist with passage through the esophagus. Saliva plays an important role in pronunciation and taste by moisturizing the tongue and other tissues in the mouth. Saliva maintains the acid–base balance of the oral cavity, to protect teeth and soft tissues from prolonged acid exposure due to diet and gastroesophageal reflux [33,34]. Additionally, whole saliva contains several signaling molecules essential for the regeneration of oral and esophageal mucosa, including epidermal growth factor, fibroblast growth factor, nerve growth factor, and transforming growth factor alpha. Furthermore, lactoferrin, saliva's Ig, and lysozyme inhibit the progression of oral bacterial or fungal infections [33]. Due to their location directly below the mucosa, the sublingual gland and the minor salivary glands are susceptible to mucosal infection. Therefore, saliva from the major and minor salivary glands prevents oral mucosal diseases, maintains oral hygiene, and lubricates the oral cavity.
