Candida albicans Induces Oral Microbial Dysbiosis and Promotes Oral Diseases.

Biofilms are organized societies of various microbes, embedded within self-made extracellular polysaccharides. Biological macromolecules such as proteins, carbohydrates, and nucleic acids comprise the matrix scaffold. Such biofilms are observed practically everywhere on humid surfaces, including the oral cavity [ 14 ]. The development of oral biofilm is a dynamic process where (i) a planktonic microbe attaches to a surface randomly or via chemical attraction, (ii) the microorganisms join to form microcolonies in the complex biofilm, and (iii) the virulent microbial colonies disperse and colonize distant favorable areas [ 15 ]. C. albicans biofilms contain yeast, pseudo-hyphal, and hyphal-form cells. After initial adhesion, the biofilm matures with increased cell proliferation and morphological change from yeast to hyphae [ 16 ]. With further development, a biofilm matrix forms that supports the cells in unfavorable environmental conditions. The biofilm matrix of C. albicans contains protein, carbohydrates (mainly mannans and glucans), lipids, and nucleic acids (representing approximately 55%, 25%, 15%, and 5% of the biofilm matrix). Fungal hyphae are fundamental components that support and provide a scaffold for the attachment of additional yeast cells as well as bacteria, developing multispecies biofilms [ 17 ]. In the final phase, a mature biofilm is formed, and the diffusion of nonadherent cells occurs, resulting in the dissemination of fungal cells in the tissue. Most of the dispersal occurs from the uppermost layers of the biofilm [ 18 ] ( Figure 1 ). The adhesion of oral microbes to host tissue is required for tissue invasion and infection. C. albicans adhesins play a major role in biofilm formation. The three important adhesion families are (a) the agglutinin-like sequence (Als) family, (b) the hyphal wall protein (Hwp) family, (c) and the individual protein file family F/hyphally regulated (Iff/Hyr) family [ 19 ]. Among these families, during biofilm formation, the Als family is important in mediating the initial attachment of C. albicans yeast cells. These yeast cells enable adhesion via an amyloid-forming region, critical for yeast cell–cell aggregation and cell-substrate adhesion [ 20 ]. Extracellular deoxyribonucleic acid (eDNA) released by C. albicans contributes to biofilms’ development, maintenance, and stability. eDNA can modulate the host immune response by activating bone marrow-derived myeloid dendritic cells [ 21 ]. Similarly, neuregulin 1 (Nrg1), pescadillo (Pes1), and unscheduled meiotic gene expression (Ume6) are known C. albicans transcription regulators of dispersal. The results of an in vitro study showed the overexpression of Nrg1, which promotes the dispersal of yeast cells from the biofilm. In addition, Nrg1 is a negative regulator of the morphological switch from yeast to hyphae [ 22 ]. The overexpression of Pes1 also indicates increased dispersal; in comparison, the overexpression of Ume6 reduces the dispersal of fungal cells. Moreover, dispersed cells showed enhanced pathogenicity in an in vivo study [ 18 ]. Other transcriptional factors contributing to C. albicans biofilm formation, development, and dispersion are presented in Table 1 [ 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ].

Over the past few decades, it has been established that C. albicans can become pathogenic under certain conditions. Changes in the properties and morphological variations of C. albicans are indicative of its virulence. Complex regulatory networks, signaling pathways, and environmental changes are responsible for the transition of yeast-like cells to hyphae [ 39 ]. Active penetration into host cells by the invasive and pathogenic C. albicans hyphae is regulated by the cAMP-dependent protein kinase A pathway [ 40 ]. The scaffold formed by C. albicans allows several bacteria to form multispecies consortia, which are heterogeneous, multicellular, and multilayered three-dimensional structures bounded by an extracellular matrix (ECM) [ 41 ]. The members of the adhesins family of C. albicans interact with specific host ligands, such as laminin, fibronectin, collagen, fibrinogen, vitronectin, or complement proteins [ 42 ]. Other virulent factors include enzymes (proteases, phospholipases, and lipases), toxins (hypha-specific α-helical amphipathic peptide—candidalysin), and molecules involved in quorum sensing (farnesol, farnesoic acid, phenylethyl alcohol, tryptophol, and tyrosol). All of these substances facilitate penetration into the host tissue, triggering cellular stress and host inflammatory responses [ 43 ]. The human oral cavity is guarded by the oral mucosal barrier complex, the oral mucosal immune system, and salivary defense mechanisms. All play a key role in the oral balance between health and disease [ 44 ]. C. albicans expresse pathogen-associated molecular patterns (PAMPs) on their surface that are recognized by the pathogen-recognition receptors (PRRs) of oral epithelial cells [ 45 ]. This process orchestrates host cytokines through signaling molecules and activates the innate and adaptive immune systems. In addition, salivary secretory IgA, in the first instance, suppresses harmful fungal effectors and conversely, interacts with bacteria to maintain balance in the commensal microbe’s composition [ 46 ]. Oral mucosal epithelial cells exhibit toll-like receptors (TLRs) at the cell surface for the recognition of fungal mannoproteins and the detection of fungal DNA. This recognition leads to the release of pro-inflammatory cytokines and chemokines that promote macrophages and neutrophils to the infected area [ 47 ]. Oral epithelial cells are sensitive to the fungal toxin, candidalysin, as it can activate the epithelial growth factor receptor (EGFR), leading to several responses [ 48 ]. However, phagocytes play a crucial role in mucosal homeostasis against fungal dysbiosis [ 49 ].

The oral cavity comprises unique anatomical features of soft (mucosal) and mineralized hard (tooth) tissues for Candida colonization. C. albicans primarily affects the soft oral mucosa rather than teeth. However, the niches around the tooth surface are the preferred site for dental biofilm (plaque) formation intermixed with C. albicans and bacterial species [ 50 ]. Cell–cell adhesion is the main factor that mediates C. albicans and oral bacterial species interaction. The C. albicans cell wall contains polysaccharides, including glucans, mannans, chitin, and several adhesion proteins and receptors that help it interact with oral microorganisms, forming a polymicrobial biofilm. In this polymicrobial biofilm, C. albicans grows along with Gram-positive and Gram-negative bacteria [ 51 ]. The interaction between C. albicans and mitis group streptococci, (such as Streptococcus gordonii , Streptococcus sanguinis , and Streptococcus oralis ), Porphyromonas gingivalis , and Staphylococcus aureus forms a well-organized structure [ 52 ]. S. oralis and S. gordonii have been observed forming near the C. albicans hyphae within a few hours of nutrient supply [ 53 ]. S. gordonii , an oral commensal non-pathogenic bacterium, plays an integral role in dental plaque formation. It was shown in an in vitro study of early polymicrobial biofilm formation that S. gordonii binds to C. albicans via cell wall proteins and enhances hyphal development [ 54 ]. In addition, the O-mannosylation of the C. albicans cell wall contributes to the development of an inter-kingdom biofilm [ 55 ]. Streptococcus mutans , the main cariogenic bacteria work in coordination with C. albicans and other mitis group streptococci in a sucrose-dependent partnership. Rather than cell–cell adhesion, S. mutans produce extracellular polysaccharides (water-insoluble glucans) to establish interaction with C. albicans [ 56 ]. In the biofilm containing C. albicans/S. mutans , S. mutans form microcolonies around fungal cells entangled in an extra polysaccharide-rich extracellular matrix [ 52 ]. The results of a recent study have confirmed that in the absence of a sucrose environment, C. albicans binds twice as strongly to S. gordonii , and in the presence of a sucrose environment, the binding of S. mutans and C. albicans increases dramatically (up to ∼6 fold) [ 57 ]. Furthermore, extracellular signaling, quorum sensing molecules, and other factors can facilitate C. albicans interaction with oral bacteria ( Table 2 ) [ 20 , 54 , 58 , 59 , 60 , 61 ]. It is recognized that the quorum-sensing molecule, farnesol, in C. albicans promotes yeast-to-hyphae transition. Recently, in a C. albicans/S. mutans biofilm, low levels of farnesol were shown to stimulate glucosyltransferase-I (GtfB) expression/activity and increase bacterial growth. In contrast, high levels of farnesol were found to inhibit S. mutans growth [ 61 ]. Cross-feeding in biofilm maintains the specific environment for the growth of microorganisms. For example, S. mutans breaks sucrose into glucose and fructose, where glucose is used as a carbon source by C. albicans and enables persistence in acidic conditions. S. mutans and C. albicans biofilms produce lactate, formate, and fumarate as carbohydrate metabolism products, which facilitate their growth and make them acid tolerant [ 62 ]. C. albicans ensures strictly anaerobic conditions by consuming oxygen from the local environment and increases the abundance of anaerobic bacteria of the Veillonella , Prevotella , Leptotrichia , and Fusobacterium genera [ 63 ]. As an example, C. albicans can provide a hypoxic microenvironment to support the growth of Bacteroides fragilis , B. vulgatus , and Clostridium perfringens [ 64 ]. Hence, the commensal C. albicans growth in the oral cavity that enhances polymicrobial interactions, cross-feeding, and environmental change facilitates the growth of several pathogenic oral microbiomes and causes oral microbial dysbiosis.

Candida spp. are found in mucous membranes, such as the gastrointestinal tract, mouth, nose, reproductive organs, skin, etc. C. albicans is a member of the resident human microbiota and is responsible for several types of oral diseases [ 65 ]. The dispersion of candidal cells is ‘preconditioned’ for maximum virulence where it upregulates the expression of genes whose products are involved in the acquisition of micronutrients, drug resistance, and the hydrolysis of host substrates [ 66 ] ( Figure 2 ). Table 3 presents several studies confirming the overpopulation of C. albicans in the saliva of patients with oral diseases where C. albicans increases the risk of disease progression [ 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 ]. In dental caries, C. albicans (yeast cell wall) adhesins interact with the salivary pellicle and adhere to the tooth enamel. S. mutants are the main causative organism of dental caries; they selectively bind to salivary lectins in the pellicle. After binding, S. mutants and other microbes proliferate to form a three-dimensional community to distribute nutrients, oxygen, and signaling molecules [ 83 ]. It has been shown that children with oral C. albicans are at increased risk of dental caries (>5 times) compared to children without C. albicans [ 84 ]. In the oral cavity, C. albicans can produce acid by metabolizing carbohydrates (i.e., glucose) to cause a reduction in pH from 7 to 4 [ 85 ]. In an in vivo study, it was shown that C. albicans has a roughly 20 times stronger ability to dissolve hydroxyapatite than S. mutans . C. albicans adheres to hydroxyapatite through electrostatic interaction [ 86 ]. C. albicans colonization occurs through the mycelial network with bacteria or by forming a spatial arrangement with Streptococcus [ 87 ]. The total loads of C. albicans and S. mutans were increased in supragingival dental plaque obtained from active carious lesions in children with early childhood caries [ 88 ]. C. albicans was isolated with Peptostreptococcus micros from root canal samples in patients with persistent endodontic infections. These findings implicate Candida in root canal infections with pulp necrosis [ 89 ]. C. albicans raises the glucose intake of S. mutans , which was confirmed when S. mutans were co-cultured with C. albicans . The co-culture showed a higher glucose metabolic rate than the pure-culture group. Furthermore, the transcription of S. mutans genes associated with the transportation and metabolization of carbohydrates is affected by C. albicans [ 62 , 71 , 90 ]. During coexistence, S. mutans genes are upregulated and participate in carbohydrate metabolism, galactose metabolism, and glycolysis/gluconeogenesis. Similarly, C. albicans genes responsible for carbohydrate metabolism (sugar transport, aerobic respiration, pyruvate breakdown, and the glyoxylate cycle) are enhanced by co-culturing [ 62 ]. Of late, findings on S. mutans cells secreting membrane vesicles have been presented. Membrane vesicles have been shown to contain the glucosyltransferase-I (Gtf) enzyme that, in the extracellular matrix of C. albicans biofilm, can contribute to sucrose metabolism [ 60 ]. The results of a recent study showed that the protein kinase A (PKA) pathway plays a central role in C. albicans activity. Mutanocylin (unacylated tetramic acid) secretion has been shown to have an impact on the transcriptional profile of C. albicans , which mainly regulates cell wall biogenesis and remodeling through the PKA signaling pathway [ 91 ]. The presence of C. albicans and S. mutans in dental caries produces synergistic and antagonistic effects. The synergistic effects during biofilm formation, through quorum sensing molecules, and in metabolic activity are discussed above. The results of salivary studies have also shown the prevalence of C. albicans in dental caries ( Table 3 ). Periodontitis is a polymicrobial disease that affects the supporting structures of the teeth, causing attachment loss and bone loss. It is caused by a synergistic and dysbiotic dental plaque microbial community that results in disruption of tissue homeostasis. The main pathogens involved are Porphyromonas gingivalis [ 92 ]. Tannerella forsythia , and Treponema denticola also colonize with P. gingivalis . P. gingivalis is known to induce inflammation by remodeling the microbiota from a normal state to dysbiosis [ 93 ]. Periodontal microbial progression is mediated by a change in pH or redox potential, or a decrease in oxygen level. This change facilitates the existence of the subsequent colonizer. Lastly, the close intercellular interaction engages the microbial surface adhesins on the periodontium [ 94 ]. C. albicans and early colonizers such as mitis group streptococci form a scaffold for other microbes to attach. Fusobacterium nucleatum is a bridging colonizer between fungal biofilm and periodontal pathogens in the oral cavity. The results of an extensive in vitro study on F. nucleatum showed that it is able to inhibit C. albicans growth and filament formation without affecting its cell viability [ 95 ]. It is hypothesized that if the fungal morphological changes are blocked by bacteria, this weakens the host immune response. As a result, it is beneficial for them to remain unnoticed, escape the host immune system, and spread to other organs [ 95 ]. Other bridging colonizers include P. nigrescens (genus Prevotella ) and Campylobacter . P. nigrescens can modulate fungal biofilm formation and fungal cell viability. The viability of C. albicans decreases with the increase in P. nigrescens cell abundance [ 96 ]. A similar effect was observed in a study involving Campylobacter where secretion of bacteriocin-like substances inhibited the growth of C. albicans [ 97 ]. P. gingivalis , T. forsythia , and T. denticola belong to the red complex as they are the major etiologic agents of periodontal disease. P. gingivalis induces germ-tube formation of C. albicans in both oral isolates and the strain. P. gingivalis results in the generation of a more invasive fungal phenotype [ 98 ]. P. gingivalis effortlessly adheres to the blastospore or pseudohyphae form of C. albicans and this adhesion is mediated by the bacterial internalin protein family (InlJ) and gingipain, Arg-x-specific proteinase, and adhesins (RgpA) [ 99 ]. In a study, chronic periodontitis patients showed higher levels of Candida colonization compared to healthy controls; however, the relationship between Candida colonization and the severity of chronic periodontitis could not be established [ 79 ]. Nonetheless, it is recognized that C. albicans play a role in the formation of periodontal microbial plaque and the adherence of bacterial species to the periodontal tissues. Oral microbiome dysbiosis in periodontal diseases can be assessed using saliva and salivary metabolomics ( Table 3 ). Upregulation in the salivary levels of valine, isoleucine, phenylalanine, tyrosine, proline, succinate, butyrate, and cadaverine was presented in our previous publication [ 44 ]. The synthesis of polyamine biosynthetic enzymes, such as ornithine decarboxylase and spermidine synthase, also depends on the presence of Candida yeasts in polymicrobial biofilm [ 100 ]. In addition, changes in the salivary levels of lactate, pyruvate, N-acetyl groups, and methanol are indicators of oral health or disease. Changes in lactate and pyruvate levels can influence the cell wall of C. albicans and its proteome and secretome, depending on access to carbon sources [ 101 ]. Interest in the study of C. albicans has increased because of its association with precancerous lesions of the oral mucosa. In 2007, the World Health Organization (WHO) proposed the term oral potentially malignant disorders (OPMD) for precancerous lesions and conditions [ 102 ]. Candidal leukoplakia is a precancerous lesion, with a high rate of malignant change [ 103 ]. For decades, however, it has been debatable as to whether Candida species are secondarily acting on a pre-existing leukoplakia or leukoplakia’s high malignancy rate supports the role of fungus. The results of prior animal studies have shown epithelial hyperplasia and cellular atypia induced by Candida species [ 104 ]. Candida is known to produce nitrosamines, namely, N-nitrosobenzylmethylamine, a carcinogenic compound. Candida strains obtained from advanced precancerous lesions showed dispersion of candidal infections from the superficial mucosal surface to the deeper epithelial cell layers, thereby transporting and depositing carcinogenic compounds into deeper layers and causing dysplasia [ 105 ]. It was postulated that these compounds may directly, or with other chemical carcinogens, activate specific proto-oncogenes to initiate the development of a malignant lesion [ 106 ]. A positive association between fungal infection and different grades of epithelial dysplasia, squamous cell carcinoma, and hyperkeratosis was observed; despite this, no causal relation between Candida species and other lesions was established. However, the presence of Candida and other microorganisms in the lesions was confirmed [ 107 ]. Hence, the relationship between C. albicans and oral precancer, and its malignant transformation, remains controversial. However, it is reasonable to postulate that C. albicans is a co-causative factor in oral precancers. Recent statistics show that over 389,485 new cases of oral cancer and 188,230 deaths are reported annually [ 108 ]. Roughly, 90% of oral cancer cases are oral squamous cell carcinoma (OSCC). Various aggravating factors contribute to OSCC development, such as oral dysbiosis, genetic, and environmental factors, and exposure to chemicals, which can induce genetic and epigenetic alterations [ 109 ]. Current investigations are inclined toward the oral microbiota’s role in carcinogenesis primarily through chronic inflammation, the synthesis of carcinogens, and epithelial integrity change. The incidence rate of Candida infection reported in OSCC varies from 25% to 74.7% [ 110 ]. The formation of C. albicans hyphae results in the production of interleukin (IL1β) and activates proinflammatory cytokines. C. albicans colonization in OSCC shows genotypic diversity that affects the carcinogenic process [ 111 ]. Several molecular mechanisms are proposed with regard to dysplasia and malignancy induced by C. albicans . These mechanisms are as follows. (1) Candida upregulate proinflammatory cytokines, interleukins (IL), tumor necrosis factor (TNF)-α, interferon (IFN-γ), and the granulocyte monocyte colony-forming unit (GM-CSF). The cytokines influence the metabolic pathways and induce endothelial dysfunction. Hence, they promote cancer development by altering the host immune system [ 112 , 113 ]. (2) p53, a cell proliferative marker, was significantly more abundant in lesions exhibiting epithelial dysplasia with candidal infection [ 114 ]. p53 and Ki-67 overexpression is widely recognized in malignant lesions. Prostaglandin endoperoxide synthase 2 (COX-2) releases prostaglandins and increases inflammation in cancer. Thus, it influences cell proliferation, cell death, and tumor invasion [ 115 ]. (3) The release (via hyphal invasion) of nitrosamines, such as N-nitrosobenzyl methylamine, into the dysbiotic oral cavity, causes tumor development [ 105 ]. (4) The virulence factor of C. albicans is also by the production of acid aspartyl proteinase, which maintains an acidic pH and degrades the extracellular matrix (laminin 332 and E-cadherin). Therefore, dysplastic alterations in the oral epithelium and the dissemination of C. albicans into the systemic circulation occur [ 116 ]. (5) In oral cancers, C. albicans can produce large quantities of acetaldehyde and acetyl-CoA synthetase. Acetaldehydes are produced by metabolizing ethanol and glucose. Due to mutagenic qualities in DNA, acetaldehyde acts as a carcinogen [ 117 , 118 ]. (6) C. albican hyphae produce the toxin ‘candidalysin’ which work in conjugation with the cytolytic activity of C. albicans . Candidalysin can induce NF-κB and MAPK pathways and excite GM-CSF, an essential component in carcinogenesis. In a study, it was shown to induce mucosal epithelial damage and elicit host inflammatory processes by triggering NLR family pyrin domain-containing protein 3 (NLRP3) [ 119 , 120 ].

The human oral cavity comprises host–bacteria complex oral microbiota, with interactive polymicrobial communities involved in oral biofilm formation [ 1 ]. The oral cavity exhibits broad diversity, with more than 700 microbial species having been detected, and it is the second primary site for microbial colonization after the colon. Most microorganisms in the oral cavity are bacteria; however, fungi, archaea, protozoa, and bacteriophages are also present. Oral health is balanced by symbiotic, competitive, and antagonistic microbiota activity [ 2 ]. Oral dysbiosis occurs due to disturbed interaction between inter-bacterial communities and host–bacteria, resulting in oral diseases such as dental caries, periodontitis, oral premalignancy, and oral cancer [ 3 ]. Cross-kingdom interactions between commensal fungi and oral bacteria require attention. The extensive interaction between fungi, mainly Candida albicans , and oral bacteria is crucial for their persistence and possibly contributes to infection [ 4 ]. It has been shown that in such interactions, fungi provide mechanical support for adhesion and colonization and provide an ideal substratum for bacterial attachment [ 5 ]. In diseases such as dental caries and periodontitis, C. albicans has been co-isolated alongside other oral microbial communities [ 6 , 7 ]. Interactions between bacterial species and C. albicans form biofilms through physical interactions, quorum sensing, and secretory proteases [ 8 ]. The microbial species in the oral biofilm release their cellular components and breach host barriers to reach distant sites and cause tissue destruction. Proteomic analyses of biofilms have shown virulence-related proteins among other pathologic secreted proteins [ 9 ]. The oral cavity is a complex organ with different niches colonized by millions of microorganisms. Several factors, such as a weak immune system, nutritional deficiencies, metabolic diseases, different types of diet (high sugar consumption), and poor oral hygiene and habits, can contribute to microbiome diversity, which facilitates the incorporation of Candida species into different oral niches [ 10 ]. The results of a recent study show that salivary change in smokers causes yeast overgrowth. The further spread of microorganisms via the bloodstream to different parts of the body occurs when infections are left untreated. The consequences of systemic infection have been reported in the literature, with mortality rates of 30–80% being noted [ 11 ]. The notable contributing Candida species include C. albicans , C. tropicalis , C. glabrata , C. krusei , C. parapsilosis , and the recently identified C. auris . Most Candida infections are endogenous, apart from C. krusei , which has an exogenous source [ 12 ]. It has been shown that C. albicans and its biofilms can induce cytokine production in host cells. The biofilm of C. albicans provides a suitable location for bacteria, and during such mutual co-existence, microbial cells avoid host recognition or elimination through antimicrobial action [ 13 ]. Hence, C. albicans can change the oral microbial environment, become pathologic, and induce cell–cell interaction with bacteria. This narrative review focuses on C. albicans mutualistic interactions with oral commensal bacteria and its change in different oral diseases. In addition, the cross-kingdom interaction between Candida and bacteria and its impact on polymicrobial biofilm and the host are presented. We also highlight the relevance of saliva and salivary metabolites to biofilm-related oral diseases caused by C. albicans .

C. albicans causes disease by altering the host’s immune condition and the pathogen. The change in the oral microbial population and preeminent growth and colonization of C. albicans on the oral mucosa cause it to develop into a disseminated form [ 121 ]. Factors that contribute to such an onset include prosthesis, salivary gland dysfunction, certain medications (i.e., broad-spectrum antibiotics and steroids), and a high-carbohydrate diet. Smoking cigarettes, diabetes, cancer, and immunosuppression are important contributing factors for C. albicans to aggravate oral diseases [ 122 ]. Mono-species colonization seldom causes infections of the oral cavity. As discussed, C. albicans is co-isolated alongside oral microbial communities in oral diseases. A high incidence of mixed colonization of C. albicans (66.7%) and S. aureus (49.5%) was shown in individuals with denture stomatitis. The cocolonization or coinfection of fungal–bacterial interaction (polymicrobial interaction) is associated with a multitude of other conditions including infections of endotracheal tubes, biliary stents, silicone voice, orthopedic prostheses, and acrylic dentures [ 123 , 124 ]. Concern arises when the mutual coexistence of pathogens within the biofilm and the local transformation of their environment occurs. In a study, an in vitro study model of a mixed biofilm formed by P. gingivalis and C. albicans showed inhibition of host cell migration. The combined effect of organisms appeared stronger than the separate effects [ 125 ]. Inter-genus interaction also occurs within mixed C. albicans bacteria biofilms. Although C. albicans is studied extensively, other candidal species such as C. dubliniensis , C. glabrata , C. krusei , C. tropicalis , and C. auris are also sources of increased concern in the clinical setting. In a study, dental acrylic resin strips showed mixed species biofilms in the oral cavity, predominantly, C. albicans and fewer non- C. albicans species [ 126 ]. In addition, in other studies, C. albicans and C. dubliniensis organisms were found in the oral cavity of immunocompromised patients, and patients with denture-associated stomatitis presented with C. albicans and C. glabrata [ 127 , 128 ]. Such mixed microbial species biofilms pose a major threat in the clinical setting due to issues relating to drug resistance. Another important concern is the metabolic interactions in polymicrobial environments for microbial adaptation. Direct or indirect metabolic interactions between microbes are involved in the production of metabolites. The metabolites produced by one species are subsequently consumed by another or enable other species to persist [ 129 ]. Saliva is a complex biological fluid where salivary components serve as a defense against C. albicans . Levels of salivary metabolites such as histidine, tyrosine, choline, phosphoenolpyruvate, octanoate, uridine monophosphate, 6-phosphogluconate, ornithine, butyrate, aminovalerate, and aminolevulinate have been shown to increase or decrease in patients with Candida infection. The release of such metabolites affects C. albican growth, oral biofilm formation, pyrimidine synthesis, and nucleic acid synthesis [ 130 ]. The comprehensive analysis of salivary metabolites sheds light on their role in C. albicans pleomorphism. Hence, the metabolites observed in the saliva confirm oral dysbiosis and its association with oral inflammatory diseases and oral cancer. It is a challenge to eradicate Candida–bacterial polymicrobial biofilm-induced oral diseases. Polysaccharides secreted by microorganisms in biofilm play an important role in preventing drug penetration and, hence, lead to antibiotic resistance [ 131 ]. The biofilm formed by C. albicans , and S. aureus cells can induce bursts of reactive oxygen species that activate the expression of the outflow pump in S. aureus cells and enhance drug tolerance [ 43 ]. Difficulties arise because antifungal therapy targeting only C. albicans is nonspecific. Therefore, a new approach to identifying effective therapeutic techniques for Candida–bacterial polymicrobial biofilm emphasizes inhibiting potential pathogens and the environmental factors that promote the selection and enrichment of the microbiota.

In conclusion, a strong association can be observed between C. albicans in oral biofilms, Candida–bacteria interactions, and oral diseases. It appears that C. albicans plays an important role in causing oral microbial dysbiosis, which could serve as the basis for various oral diseases. The salivary metabolic signature provides information on biomarkers specific to C. albicans , contributing to early detection and the establishment of new treatment methods. Most C. albicans biofilm research focuses on biofilm development, antifungal resistance, and polymicrobial interactions. However, how to effectively utilize this knowledge to develop efficient strategies to treat C. albicans biofilms and biofilm-related infections remains uncertain.