Abstract
ABSTRACTThe intestine is the primary reservoir of Candida albicans 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 in vitro gut models that are used to study the pathogenesis of C. albicans investigate the state in which C. albicans behaves as a pathogen rather than as a commensal. We present a novel in vitro 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 C. albicans adhesion and invasion. Significant protection against C. albicans-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 C. albicans-induced cytotoxicity. This required bacterial growth, which relied on the presence of host cells, but was not dependent on the competition for adhesion sites. Lactobacillus rhamnosus 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 in vitro gut model that can be used to experimentally dissect commensal-like interactions of C. albicans 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.
Highlights
The gut epithelium is a barrier between the sterile host environment and gut microbiota
C. albicans-induced epithelial damage is reduced by colonization with Lactobacillus species Our study aimed to establish an in vitro model, which mimics the commensal phase of C. albicans in the gut, in order to dissect commensal-like scenarios
As mucus can dampen virulence attributes of C. albicans (Kavanaugh et al, 2014), the mucus-producing goblet cell line HT29-MTX, which has been extensively validated for compatibility and functional properties with Caco2 brush border expressing 1 (C2BBe1) enterocytes (Ferraretto et al, 2018), was introduced in an existing model for Candida-gut translocation (Allert et al, 2018)
Summary
The gut epithelium is a barrier between the sterile host environment and gut microbiota. Goblet cells within the intestinal epithelium produce a protective mucus layer (Maynard et al, 2012; Yan et al, 2013) This layer serves as an anchor for the attachment of microbes and represents a nutrient source for mutualistic bacteria living within the gut (Cockburn and Koropatkin, 2016) that produce metabolites, nourishing IECs (Maynard et al, 2012). Malignant cells are targeted, and cells of the immune system and intestinal epithelial lining In this immunocompromised state, patients are predisposed to develop opportunistic infections with otherwise harmless commensals of the microbiota. Use of broad-spectrum antibiotics and a compromised immune status are such factors that can lead to C. albicans overgrowth and a switch from commensalism to pathogenicity (Bassetti et al, 2011; Mason et al, 2012), potentially resulting in translocation through the intestinal barrier and disseminated infections (Koh et al, 2008). The main reservoir of C. albicans that causes systemic candidiasis is the gut (Gouba and Drancourt, 2015; Miranda et al, 2009; Nucci and Anaissie, 2001)
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