Cytolytic proteins and peptide toxins are classical virulence factors of several bacterial pathogens which disrupt epithelial barrier function, damage cells and activate or modulate host immune responses. Such toxins have not been identified previously in human pathogenic fungi. Here we identify the first, to our knowledge, fungal cytolytic peptide toxin in the opportunistic pathogen Candida albicans. This secreted toxin directly damages epithelial membranes, triggers a danger response signalling pathway and activates epithelial immunity. Membrane permeabilization is enhanced by a positive charge at the carboxy terminus of the peptide, which triggers an inward current concomitant with calcium influx. C. albicans strains lacking this toxin do not activate or damage epithelial cells and are avirulent in animal models of mucosal infection. We propose the name ‘Candidalysin’ for this cytolytic peptide toxin; a newly identified, critical molecular determinant of epithelial damage and host recognition of the clinically important fungus, C. albicans.

Candidalysin is a Fungal Peptide Toxin Critical for Mucosal Infection and Immune Activation

Candida albicans has been detected in root carious lesions. The current study aimed to explore the action of this fungal species on the microbial ecology and the pathogenesis of root caries. Here, by analyzing C. albicans in supragingival dental plaque collected from root carious lesions and sound root surfaces of root-caries subjects as well as caries-free individuals, we observed significantly increased colonization of C. albicans in root carious lesions. Further in vitro and animal studies showed that C. albicans colonization increased the cariogenicity of oral biofilm by altering its microbial ecology, leading to a polymicrobial biofilm with enhanced acidogenicity, and consequently exacerbated tooth demineralization and carious lesion severity. More importantly, we demonstrated that the cariogenicity-promoting activity of C. albicans was dependent on PHR2. Deletion of PHR2 restored microbial equilibrium and led to a less cariogenic biofilm as demonstrated by in vitro artificial caries model or in vivo root-caries rat model. Our data indicate the critical role of C. albicans infection in the occurrence of root caries. PHR2 is the major factor that determines the ecological impact and caries-promoting activity of C. albicans in a mixed microbial consortium.

Candida albicans promotes tooth decay by inducing oral microbial dysbiosis.

Advanced combinatorial treatments of surgery, chemotherapy, and radiotherapy do not have any effect on the enhancement of a 5-year survival rate of oral squamous cell carcinoma (OSCC). The discovery of early diagnostic non-invasive biomarkers is required to improve the survival rate of OSCC patients. Recently, it has been reported that oral microbiome has a significant contribution to the development of OSCC. Oral microbiome induces inflammatory response through the production of cytokines and chemokines that enhances tumor cell proliferation and survival. The study aims to develop saliva-based oral microbiome and cytokine biomarker panel that screen OSCC patients based on the level of the microbiome and cytokine differences. We compared the oral microbiome signatures and cytokine level in the saliva of OSCC patients and healthy individuals by 16S rRNA gene sequencing targeting the V3/V4 region using the MiSeq platform and cytokine assay, respectively. The higher abundance of Prevotella melaninogenica, Fusobacterium sp., Veillonella parvula, Porphyromonas endodontalis, Prevotella pallens, Dialister, Streptococcus anginosus, Prevotella nigrescens, Campylobacter ureolyticus, Prevotella nanceiensis, Peptostreptococcus anaerobius and significant elevation of IL-8, IL-6, TNF-α, GM-CSF, and IFN-γ in the saliva of patients having OSCC. Oncobacteria such as S. anginosus, V. parvula, P. endodontalis, and P. anaerobius may contribute to the development of OSCC by increasing inflammation via increased expression of inflammatory cytokines such as IL-6, IL-8, TNF-α, IFN-γ, and GM-CSF. These oncobacteria and cytokines panels could potentially be used as a non-invasive biomarker in clinical practice for more efficient screening and early detection of OSCC patients.

Dysbiosis of salivary microbiome and cytokines influence oral squamous cell carcinoma through inflammation.

Candida albicans infections range from superficial to systemic and are one of the leading causes of fungus-associated nosocomial infections. The innate immune responses during these various infection types differ, suggesting that the host environment plays a key role in modulating the host–pathogen interaction. In addition, C. albicans is able to remodel its cell wall in response to environmental conditions to evade host clearance mechanisms and establish infection in niches, such as the oral and vaginal mucosa. Phagocytes play a key role in clearing C. albicans, which is primarily mediated by Pathogen Associated Molecular Pattern (PAMP)–Pattern Recognition Receptor (PRR) interactions. PRRs such as Dectin-1, DC-SIGN, and TLR2 and TLR4 interact with PAMPs such as β-glucans, N-mannan and O-mannan, respectively, to trigger the activation of innate immune cells. Innate immune cells exhibit distinct yet overlapping repertoires of PAMPs, resulting in the preferential recognition of particular Candida morphotypes by them. The role of phagocytes in the context of individual infection types also differs, with neutrophils playing a prominent role in kidney infections, and dendritic cells playing a prominent role in skin infections. In this review, we provide an overview of the key receptors involved in the detection of C. albicans and discuss the differential innate immune responses to C. albicans seen in different infection types such as vulvovaginal candidiasis (VVC) and oral candidiasis.

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Immune Sensing of Candida albicans

To understand the effects of saccharides on our metabolism and health, we need a clear understanding of what they are, how they differ, and why some types are deemed "less healthy" and others "better for health." There are various ways to look at this topic. Firstly, saccharides can be classified according to their degree of polymerization (DP). This classification is useful when qualitative or quantitative analysis and calculation of intakes are required or for food-labeling definitions. However, it does not account for the fact that saccharides with a similar DP can differ in molecular composition, which will influence digestion, absorption, and metabolism. Secondly, another approach widely used in the biomedical and nutritional sciences is therefore a physiological classification, which addresses the rate and degree of digestibility and absorption, the glycemic response, and the metabolic fate. The individual health status also plays a role in this respect. An active, lean person will have a metabolic response that differs from an inactive person with overweight and insulin resistance. However, this approach will not give a complete answer either because the characteristics of the matrix/meal in which these carbohydrates (CHOs) are present will also influence the responses of our body. Thirdly, one can also rank CHOs by comparing their functional/technological properties, such as relative sweetness, viscosity, and solubility. Understanding CHO characteristics and related physiological responses will help understand health and disease implications. Therefore, a brief outline of different carbohydrate classifications is presented. This outline will be placed in the context of potential overall effects after consumption. The answer to the question whether we should we eat less of certain sugars depends on the angle from which you look at this matter; for example, do you address this question from a single molecular characteristic point of view or from a meal quality perspective? Looking at one particular CHO characteristic will almost always lead to a different conclusion (e.g., the labeling of fructose as toxic) than evaluating from a "total perspective" (fructose has adverse effects in certain conditions). Examples are given to help understand this matter for the benefit of justified dietary/food-based recommendations.

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Saccharide Characteristics and Their Potential Health Effects in Perspective.

Sucrose has long been regarded as the most cariogenic carbohydrate. However, why sucrose causes severer dental caries than other sugars is largely unknown. Considering that caries is a polymicrobial infection resulting from dysbiosis of oral biofilms, we hypothesized that sucrose can introduce a microbiota imbalance favoring caries to a greater degree than other sugars. To test this hypothesis, an in vitro saliva-derived multispecies biofilm model was established, and by comparing caries lesions on enamel blocks cocultured with biofilms treated with sucrose, glucose and lactose, we confirmed that this model can reproduce the in vivo finding that sucrose has the strongest cariogenic potential. In parallel, compared to a control treatment, sucrose treatment led to significant changes within the microbial structure and assembly of oral microflora, while no significant difference was detected between the lactose/glucose treatment group and the control. Specifically, sucrose supplementation disrupted the homeostasis between acid-producing and alkali-producing bacteria. Consistent with microbial dysbiosis, we observed the most significant disequilibrium between acid and alkali metabolism in sucrose-treated biofilms. Taken together, our data indicate that the cariogenicity of sugars is closely related to their ability to regulate the oral microecology. These findings advance our understanding of caries etiology from an ecological perspective.

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Sucrose promotes caries progression by disrupting the microecological balance in oral biofilms: an in vitro study.

Objectives Oestrogen deficiency is an aetiological factor of postmenopausal osteoporosis (PMO), which not only decreases bone density in vertebrae and long bone but also aggravates inflammatory alveolar bone loss. Recent evidence has suggested the critical role of gut microbiota in osteoimmunology and its influence on bone metabolisms. The present study aimed to evaluate the therapeutic effects of probiotics on alveolar bone loss under oestrogen-deficient condition. Materials and methods Inflammatory alveolar bone loss was established in ovariectomized (OVX) rats, and rats were daily intragastrically administered with probiotics until sacrifice. Gut microbiota composition, intestinal permeability, systemic immune status and alveolar bone loss were assessed to reveal the underlying correlation between gut microbiota and bone metabolisms. Results We found administration of probiotics significantly prevented inflammatory alveolar bone resorption in OVX rats. By enriching butyrate-producing genera and enhancing gut butyrate production, probiotics improved intestinal barrier and decreased gut permeability in the OVX rats. Furthermore, the oestrogen deprivation-induced inflammatory responses were suppressed in probiotics-treated OVX rats, as reflected by reduced serum levels of inflammatory cytokines and a balanced distribution of CD4+ IL-17A+ Th17 cells and CD4+ CD25+ Foxp3+ Treg cells in the bone marrow. Conclusions This study demonstrated that probiotics can effectively attenuate alveolar bone loss by modulating gut microbiota and further regulating osteoimmune response and thus represent a promising adjuvant in the treatment of alveolar bone loss under oestrogen deficiency.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1111/cpr.13075

Probiotics ameliorate alveolar bone loss by regulating gut microbiota.

Candida albicans is a symbiotic fungus that commonly colonizes on oral mucosal surfaces and mainly affects immuno-compromised individuals. Polymicrobial interactions between C. albicans and oral microbes influence the cellular and biochemical composition of the biofilm, contributing to change clinically relevant outcomes of biofilm-related oral diseases, such as pathogenesis, virulence, and drug-resistance. Notably, the symbiotic relationships between C. albicans and oral bacteria have been well-documented in dental caries, oral mucositis, endodontic and periodontal diseases, implant-related infections, and oral cancer. C. albicans interacts with co-existing oral bacteria through physical attachment, extracellular signals, and metabolic cross-feeding. This review discusses the bacterial–fungal interactions between C. albicans and different oral bacteria, with a particular focus on the underlying mechanism and its relevance to the development and clinical management of oral diseases.

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Qian Du

Papers

Candida albicans promotes tooth decay by inducing oral microbial dysbiosis.

Sucrose promotes caries progression by disrupting the microecological balance in oral biofilms: an in vitro study.

Probiotics ameliorate alveolar bone loss by regulating gut microbiota.

Cross-kingdom interaction between Candida albicans and oral bacteria