# C. albicans-intrinsic mechanisms defining gut colonization

> **NIH NIH R01** · BROWN UNIVERSITY · 2024 · $456,224

## Abstract

Project Summary:
 The fungus Candida albicans is a frequent commensal of the gastrointestinal (GI) tract but is also an
important cause of both mucosal and systemic disease. The GI population is particularly relevant to human
health as cells can translocate out of this niche to cause disseminated infections. C. albicans cells in the gut
also play key roles in regulating local and systemic immune responses that can be either beneficial or
detrimental to the host. There is therefore a pressing need to understand how C. albicans colonizes the GI
tract and to define how changes to the commensal environment impact fungal behavior.
 Attention has focused on the ability of C. albicans to transition between yeast and filamentous states,
with yeast-locked cells shown to exhibit higher fitness in the GI tract than wildtype cells. However, these
studies have extensively relied on models that require antibiotic supplementation for stable fungal
colonization. In preliminary studies, we examined C. albicans fitness in colonization models without antibiotic
treatment. Surprisingly, we show that yeast-locked cells are defective for gut colonization in hosts containing
high bacterial loads, including those colonized with defined bacterial consortia. Furthermore, we demonstrate
that Candidalysin, the first toxin identified in a human fungal pathogen, is critical for gut colonization in hosts
carrying high bacteria loads but not in those given antibiotics, indicating that this factor supports fungal
commensalism by enabling competition with the bacterial microbiota.
 To build on these observations, we will examine how C. albicans morphology (and co-regulated genes)
determine GI colonization fitness. Experiments will utilize a variety of murine GI models carrying native or
defined bacterial populations to determine how interkingdom interactions influence fungal gut commensalism
(Aim 1). We are particularly interested in determining how Candidalysin regulates fungal fitness in the GI
niche, and whether this toxin acts intrinsically on fungal cells, to inhibit bacterial cells, or via its impact on host
epithelial cells (Aim 2). Experiments will also perform fitness selection assays to identify novel factors that
determine gut colonization fitness in hosts carrying different gut bacterial populations (Aim 3).
 Together, these experiments will provide novel insights into the fundamental mechanisms used by C.
albicans to colonize the gut, including the role of Candidalysin toxin in increasing the fitness of fungal cells in
the competitive GI niche. Given the importance of gut colonization to fungal-host interactions, these
experiments are critical for understanding how C. albicans operates as a human pathobiont.

## Key facts

- **NIH application ID:** 10803117
- **Project number:** 1R01AI175177-01A1
- **Recipient organization:** BROWN UNIVERSITY
- **Principal Investigator:** Richard John Bennett
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $456,224
- **Award type:** 1
- **Project period:** 2024-07-01 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10803117

## Citation

> US National Institutes of Health, RePORTER application 10803117, C. albicans-intrinsic mechanisms defining gut colonization (1R01AI175177-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10803117. Licensed CC0.

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