ABSTRACT
The 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.
Footnotes
Competing interests
The authors declare no competing or financial interests.
Author contributions
Conceptualization: K.G., A.L., B.H.; Methodology: K.G., A.L., R.G., S.A., S.L., M.W.; Software: S.L., M.W., M.S.G.; Validation: A.L.; Formal analysis: K.G., A.L., R.G., S.A., M.G., A.S.M., M.S.G.; Investigation: K.G., A.L., R.G.; Resources: B.H.; Writing - original draft: K.G., A.L.; Writing - review & editing: K.G., S.A., A.S.M., M.S.G., B.H.; Visualization: K.G., A.L.; Supervision: K.G., M.S.G., B.H.; Project administration: K.G., B.H.; Funding acquisition: B.H.
Funding
B.H. and A.S.M. received funding from the European Union Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreements 812969 (FunHoMic) and 812954 (EUROoC). B.H., A.S.M. and A.L. were supported by the Center for Sepsis Control and Care (CSCC)/Bundesministerium für Bildung und Forschung (BMBF) (grant 01EO1002). A.L. is a member of the CSCC Research Training Group. B.H. and A.L. were further supported by the Infect ERA-NET Program (FunComPath; BMBF grant 031L0001A), and M.S.G. was supported by a Humboldt Research Fellowship (Alexander von Humboldt-Stiftung).
Supplementary information
Supplementary information available online at http://dmm.biologists.org/lookup/doi/10.1242/dmm.039719.supplemental
- Received March 20, 2019.
- Accepted August 2, 2019.
- © 2019. Published by The Company of Biologists Ltd
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.