Fungal-Bacterial Interactions in Oral Candidiasis and Periodontal Disease: A Narrative Review

Fungal–bacterial adhesion and co-aggregation

Fungal–bacterial adhesion is the first crucial event in polymicrobial oral biofilm development.^[9] Although Streptococcus gordonii and Streptococcus mutans are not primary periodontopathogens, they play a crucial role as early colonisers in biofilm development. These species facilitate initial adhesion and provide binding sites for Candida albicans, thereby contributing to the establishment and maturation of polymicrobial biofilms.^[10] Bacterial counterparts provide complementary surface structures, stabilising such co-aggregation and creating an integrated community.^[11] This improves surface adhesion, structural integrity, and resistance to environmental stress, immune defences, and antimicrobials.^[12] Morphological switching to the hyphal form by C. albicans facilitates bacterial colonisation on mucosal and dental surfaces, acting as a structural scaffold.^[13] High-resolution imaging and omics analyses have identified spatially structured niches within these biofilms, facilitating efficient metabolic exchange.^[14] These interactions are dynamic; bacterial proteases may modulate fungal adhesins, adjusting the interkingdom interface for mature, resistant biofilms.^[15] At the molecular level, fungal adhesins such as ALS3, HWP1, and regulatory genes like EFG1 and CPH1 play a key role in adhesion and hyphal transformation of Candida albicans.^[10,11] Concurrently, bacterial species express complementary adhesins such as antigen I/II family proteins (e.g., SspB in Streptococcus gordonii), glucosyltransferases in Streptococcus mutans, and fimbriae in Porphyromonas gingivalis. These molecules mediate strong interkingdom binding and represent potential therapeutic targets for disrupting polymicrobial biofilms.^[10,11] The key molecular mechanisms underlying fungal-bacterial interactions are summarised in Table 2.

Metabolic cooperation and cross-feeding

In mature biofilms, fungal-bacterial metabolic interactions play a critical role in maintaining community stability, structural integrity, and enhanced virulence.^[16] Streptococcus mutans produces lactic acid, which serves not only as a carbon source but also as a potent inducer of hyphal transformation in Candida albicans, thereby increasing its invasiveness and pathogenic potential.^[17] This interaction is reciprocated, as C. albicans buffers environmental acidity through ammonia release, thereby promoting microbial symbiosis and sustaining a favourable microenvironment. In addition, C. albicans actively alters nutrient availability,^[18] modulating glucose, nitrogen, and iron dynamics in ways that preferentially support the growth and persistence of specific bacterial partners. Furthermore, cooperative enzymatic activities between fungal and bacterial species contribute to the remodelling of the fungal cell wall, leading to masking of pathogen-associated molecular patterns (PAMPs) and facilitating immune evasion.^[19] Cross-feeding occurs through Candida fermentation product metabolism, releasing ethanol, CO₂, and other volatiles, thereby facilitating anaerobes such as Fusobacterium nucleatum and Porphyromonas gingivalis.^[20] Metabolomic profiles indicate upregulated pathways for host substrate degradation, such as mucins and collagen, associating these communities with chronic inflammation and tissue injury.^[21,22] Polymicrobial fungal–bacterial interactions are not limited to oral diseases but are also implicated in systemic conditions such as ventilator-associated pneumonia, cystic fibrosis-associated lung infections, and gastrointestinal dysbiosis.^[6,7] These interactions are supported by both clinical and experimental studies demonstrating enhanced microbial virulence, persistence, and resistance to therapy in mixed-species infections. The presence of fungal species such as Candida albicans can alter the composition of the normal oral microbiota by promoting acidogenic and anaerobic bacterial species such as Streptococcus mutans, Lactobacillus spp., and Fusobacterium nucleatum, while suppressing beneficial commensals like Streptococcus salivarius. This shift contributes to microbial dysbiosis and disease progression.^[9,15]

Quorum sensing and interkingdom communication

Coordinated polymicrobial biofilm behaviour is regulated through quorum sensing (QS).^[23] Candida albicans produces farnesol, which controls its own morphogenesis by inhibiting yeast-to-hyphae transition,^[24] whereas bacterial species such as Streptococcus and Fusobacterium nucleatum generate autoinducer-2 (AI-2), influencing both bacterial and fungal behaviour.^[25] Farnesol also interferes with bacterial QS systems, inhibiting bacterial virulence and biofilm development.^[26] Bacterial signals can enhance or inhibit C. albicans filamentation, depending on the microenvironment.^[26] Tyrosol, another Candida-derived compound, induces germ tube formation, whereas bacterial competence-stimulating peptides affect fungal adhesion.^[27] These signals regulate stress responses, nutrient distribution, and antimicrobial resistance, facilitating chronic infections.^[28] Fungal-bacterial interactions also induce significant changes in the oral epithelium. Hyphal forms of Candida albicans can invade epithelial cells, disrupting tight junctions and adhesion molecules such as E-cadherin. This leads to increased epithelial permeability, activation of inflammatory signalling pathways, and enhanced tissue damage.^[14] Bacterial co-pathogens further amplify epithelial responses by inducing cytokine release and promoting chronic inflammation.

Biofilm structure and resistance

Developed polymicrobial oral biofilms organise a sophisticated 3D architecture based on an extracellular polymeric substance (EPS) matrix composed of eDNA, β-glucans, mannoproteins, lipids, and proteins. C. albicans hyphae act as a structural framework for bacterial attachment, stabilising biofilm structure. Microscopy indicates a stratified structure with oxygen, pH, and nutrient gradients, and a dynamic ecosystem is revealed. The EPS is a barrier to antimicrobials, limiting their penetration and allowing microbial cooperation for drug tolerance. Such conditions favor drug-resistant persister cells and resistance gene transfer, rendering polymicrobial biofilms stronger than mono-species biofilms. In the presence of fungal-bacterial interactions, biofilm architecture becomes more complex, with increased extracellular matrix production, enhanced structural integrity, and altered microenvironmental gradients. These changes significantly improve resistance to antimicrobial agents and host defences. Facultative and obligate anaerobes are highly active in hypoxic niches, adding to chronic infection and risk of relapse.^[29] The structural and functional differences between mono-species and mixed biofilms are summarised in Table 3.

The host immune response plays a pivotal role in controlling polymicrobial infections. Innate immune cells such as neutrophils and macrophages recognise fungal and bacterial components through pattern recognition receptors, including Toll-like receptors.^[8] This interaction leads to the release of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α, along with activation of Th17-mediated immune responses that are critical in antifungal defence.^[6,8] However, polymicrobial biofilms can impair neutrophil phagocytosis, inhibit reactive oxygen species production, and modulate macrophage polarisation, leading to chronic inflammation and immune evasion.^[21,28] Additionally, neutrophil extracellular trap (NET) formation may be altered, further reducing microbial clearance.^[21,28] The modulation of host immune responses in polymicrobial infections is summarised in Table 4.

Clinical implications and therapeutic challenges

Traditional culture-based techniques fail to accurately detect polymicrobial infections, as they cannot replicate in vivo biofilm conditions, often resulting in misdiagnosis and undertreatment. In contrast, advanced molecular technologies such as PCR, next-generation sequencing (NGS), FISH, and MALDI-TOF MS enable more precise biofilm characterisation and support targeted therapeutic strategies.^[8,22] Monotherapies are generally ineffective against mixed-species biofilms; therefore, combination therapies incorporating antifungal agents, antibacterials, and biofilm-disrupting compounds are required. Emerging approaches, including quorum-sensing inhibitors, enzymatic EPS disruptors such as DNase and glucanase, and antimicrobial peptides (AMPs), show promising potential. Additionally, probiotics such as Lactobacillus spp. offer preventive benefits by displacing pathogenic microorganisms and modulating host immune responses. Novel modalities like photodynamic therapy and nanoparticle-based delivery systems are being explored to enhance therapeutic efficacy while minimising damage to healthy tissues. These advances collectively indicate a shift toward targeted, multi-modal therapeutic strategies for managing biofilm-mediated chronic oral infections.^[29] Importantly, these interactions are not limited to experimental models but are also well documented in clinical conditions such as denture stomatitis, oral mucositis, peri-implantitis, periodontal infections, and endodontic infections. Clinical manifestations, including oral candidiasis (oral thrush) affecting the tongue, further highlight the role of Candida albicans in polymicrobial oral diseases. Such lesions frequently harbour mixed microbial biofilms, reinforcing the concept of fungal-bacterial synergy in oral infections. The therapeutic strategies targeting polymicrobial biofilms, along with their mechanisms and examples, have been summarised in Table 5.