The Impact of Gut-related Carbon Sources on Candida albicans Virulence and Commensalism

Abstract

Candida albicans is a commensal of the human gastrointestinal tract. Under certain conditions, such as a dysbalanced microbiome or immunosuppression, the fungus can become a pathogen and cause life-threatening systemic infections. The intestine is a reservoir for systemic candidiasis, and hence gut-related inputs may play a role in controlling this commensal-to-pathogen transition. Short chain fatty acids (SCFAs) are major products of bacterial anaerobic fermentation in the large intestine, and their concentrations change during intestinal dysbiosis. Therefore, the impact of SCFA mixtures reflecting healthy and dysbiotic profiles upon commensalism- and pathogenicity-related phenotypes in C. albicans was explored. Both SCFA mixes inhibited morphogenesis in clade 1 isolates, but no significant differences were observed between these mixes concerning stress resistance, cell wall phenotypes, adherence to Caco-2 cells, or virulence in the Galleria model. The prebiotic supplement, inulin, has been shown to enhance the abundance of probiotic bacteria in the intestine. However, little is known about the impact of inulin on C. albicans. Yet changes in carbon source are known to influence virulence-related phenotypes of C. albicans, such as morphogenesis, antifungal drug and stress resistance. Hence the potential influence of inulin on commensalism- and pathogenicity-related phenotypes was investigated using a combination of in vitro, ex vivo and in vivo approaches. RNA sequencing suggested that inulin might affect yeast-hypha morphogenesis and adhesion, and these predictions were confirmed experimentally by microscopy and imaging flow cytometry. Transmission electron microscopy revealed that inulin influences the architecture of the C. albicans cell wall, and this correlated with changes in the exposure of the pathogen-associated molecular pattern β-glucan at the cell surface. Therefore, the impact of inulin supplementation upon C. albicans commensalism was explored in vivo in the mouse gut. Inulin supplementation did not robustly impact colonisation levels. However, the dietary inulin influenced the C. albicans transcriptome in vivo and reduced the likelihood of fungal dissemination. Taken together, the data highlight the possibility that dietary interventions might provide a means of reducing the likelihood of C. albicans transitioning from a relatively harmless commensal into a pathogen.