Keeping <i>Candida</i> commensal: how lactobacilli antagonize pathogenicity of <i>Candida albicans</i> in an <i>in vitro</i> gut model

Abstract

The intestine is the primary reservoir of <i>Candida albicans</i> that can cause systemic infections in immunocompromised patients. In this reservoir, the fungus exists as a harmless commensal. However, antibiotic treatment can disturb the bacterial microbiota, facilitating fungal overgrowth and favoring pathogenicity. The current <i>in vitro</i> gut models that are used to study the pathogenesis of <i>C. albicans</i> investigate the state in which <i>C. albicans</i> behaves as a pathogen rather than as a commensal. We present a novel <i>in vitro</i> gut model in which the fungal pathogenicity is reduced to a minimum by increasing the biological complexity. In this model, enterocytes represent the epithelial barrier and goblet cells limit <i>C. albicans</i> adhesion and invasion. Significant protection against <i>C. albicans-</i>induced necrotic damage was achieved by the introduction of a microbiota of antagonistic lactobacilli. We demonstrated a time-, dose- and species-dependent protective effect against <i>C. albicans</i>-induced cytotoxicity. This required bacterial growth, which relied on the presence of host cells, but was not dependent on the competition for adhesion sites. <i>Lactobacillus rhamnosus</i> reduced hyphal elongation, a key virulence attribute. Furthermore, bacterial-driven shedding of hyphae from the epithelial surface, associated with apoptotic epithelial cells, was identified as a main and novel mechanism of damage protection. However, host cell apoptosis was not the driving mechanism behind shedding. Collectively, we established an <i>in vitro</i> gut model that can be used to experimentally dissect commensal-like interactions of <i>C. albicans</i> with a bacterial microbiota and the host epithelial barrier. We also discovered fungal shedding as a novel mechanism by which bacteria contribute to the protection of epithelial surfaces.This article has an associated First Person interview with the joint first authors of the paper.