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403 Epithelial hypoxia maintains colonization resistance against Candida albicans

Published online by Cambridge University Press:  03 April 2024

Derek J. Bays
Affiliation:
Department of Internal Medicine, Division of Infectious Diseases, School of Medicine, University of California Davis, Sacramento, CA 95817, USA
Hannah P. Savage
Affiliation:
Department of Medical Microbiology and Immunology, School of Medicine, University of California Davis, Davis, CA 95616, USA Current address: Department of Pathology Microbiology and Immunology, School of Veterinary Medicine, University of California Davis, Davis, CA 95616, USA
Connor Tiffany
Affiliation:
Department of Medical Microbiology and Immunology, School of Medicine, University of California Davis, Davis, CA 95616, USA
Mariela A. F. Gonzalez
Affiliation:
Department of Medical Microbiology and Immunology, School of Medicine, University of California Davis, Davis, CA 95616, USA
Eli. J. Bejarano
Affiliation:
Department of Medical Microbiology and Immunology, School of Medicine, University of California Davis, Davis, CA 95616, USA
Henry Nguyen
Affiliation:
Department of Medical Microbiology and Immunology, School of Medicine, University of California Davis, Davis, CA 95616, USA
Hugo L. P. Masson
Affiliation:
Department of Medical Microbiology and Immunology, School of Medicine, University of California Davis, Davis, CA 95616, USA
Thaynara P. Carvalho
Affiliation:
Department of Medical Microbiology and Immunology, School of Medicine, University of California Davis, Davis, CA 95616, USA Departamento de Clinica e Cirurgia Veterinária, Escola de Veterinária da Universidade Federal de Minas Gerais, Universidade Federal de Minas Gerais, Av. Antonio Carlos, 6627, Belo Horizonte, MG, Brazil
Renato L. Santos
Affiliation:
Department of Medical Microbiology and Immunology, School of Medicine, University of California Davis, Davis, CA 95616, USA Departamento de Clinica e Cirurgia Veterinária, Escola de Veterinária da Universidade Federal de Minas Gerais, Universidade Federal de Minas Gerais, Av. Antonio Carlos, 6627, Belo Horizonte, MG, Brazil
Andrew Tritt
Affiliation:
Computer Science, Lawrence Berkeley National Laboratory, Berkeley, CA 94143, USA
Suzanne M. Noble
Affiliation:
Department of Microbiology
George R. Thompson
Affiliation:
Department of Internal Medicine, Division of Infectious Diseases, School of Medicine, University of California Davis, Sacramento, CA 95817, USA
Andreas J. Bäumler
Affiliation:
Department of Medical Microbiology and Immunology, School of Medicine, University of California Davis, Davis, CA 95616, USA
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Abstract

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OBJECTIVES/GOALS: Antibiotic treatment sets the stage for intestinal domination by Candida albicanswhich is necessary for development of invasive disease, but the resources driving this bloom remain poorly defined. We sought to determine these factors in order to design novel prophylaxis strategies for reducing gastrointestinal (GI) colonization. METHODS/STUDY POPULATION: We initially developed a generalizable framework, termed metabolic footprinting to determine the metabolites C. albicanspreferentially uses in the mouse GI tract. After identifying the metabolites C. albicansutilizes, we usedin vitro growth assays in the presence and absence of oxygen to validate out metabolomics findings. We next determined if a probiotic E. coli that utilizes oxygen would reduce C. albicanscolonization compared to a mutant E. coli that could not respire oxygen. Finding that oxygen was a necessary resource, we utilized germ-free mice to determine if Clostridiaspp. known to reduce GI oxygen would prevent C. albicanscolonization. Lastly, we sought to see if 5-aminosalicylic acid (5-ASA) could prevent C. albicanscolonization. RESULTS/ANTICIPATED RESULTS: We found that C. albicans preferentially utilizes simple carbohydrates including fructo-oligosaccharides (e.g., 1-kestose), disaccharides (e.g., β-gentiobiose), and alcoholic sugars (e.g., sorbitol) and is able to grow in vitro on minimal media supplemented with either of these nutrients. However, in the hypoxic environment that is found in the “healthy” colon, C. albicans cannot utilize these nutrients. We next found that pre-colonization in a mouse model with a probiotic E. coli significantly reduced C. albicanscolonization, but the mutant E. coli had no effect on colonization. We next showed that Clostridia supplementation restored GI hypoxia and reduced C. albicanscolonization. Remarkably, we found that 5-ASA significantly reduced GI colonization of C. albicans. DISCUSSION/SIGNIFICANCE: We have shown that C. albicans requires oxygen to colonize the GI tract. Importantly, we found that 5-ASA can prevent an antibiotic mediated bloom of C. albicans by restoring GI hypoxia, which warrants additional studies to determine if 5-ASA can be used as an adjunctive prophylactic treatment in high risk patients.

Type
Precision Medicine/Health
Creative Commons
Creative Common License - CCCreative Common License - BYCreative Common License - NCCreative Common License - ND
This is an Open Access article, distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives licence (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is unaltered and is properly cited. The written permission of Cambridge University Press must be obtained for commercial re-use or in order to create a derivative work.
Copyright
© The Author(s), 2024. The Association for Clinical and Translational Science