# Candida Albicans Gastrointestinal Colonization and Dissemination

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $405,000

## Abstract

Candida albicans (CA) colonization is required for invasive disease. Adult mice are resistant to CA
gastrointestinal (GI) colonization. We have identified two genetically distinct anaerobic commensal bacteria
that can individually maintain CA colonization resistance in germ-free mice. These anaerobic commensals
induce host immune effectors (transcription factor, HIF1-α, and antimicrobial peptide, CRAMP/LL-37) that
significantly decrease CA GI colonization. By pharmacologically inducing both HIF1-α and CRAMP, we were
able to significantly reduce CA colonization and reduce mortality from CA dissemination by 50%. Interestingly,
the anaerobic bacteria that can expel CA from the gut share the ability to produce short-chain fatty acids
(SCFAs). SCFAS have been shown to have numerous immunomodulatory properties. Therefore, my central
hypothesis is that SCFAs produced by gut commensal anaerobic bacteria are necessary to maintain CA
colonization resistance. This work will involve two specific aims. First, I will determine whether SCFAs are
necessary for CA colonization resistance. I will evaluate whether commensal anaerobe Bacteroides
thetaiotamicron mutants unable to produce SCFAs or SCFAs alone can reduce CA colonization. I predict that
SCFAs are necessary for maintaining CA colonization resistance. Second, I will determine if HIF-1α and/or
CRAMP are necessary for SCFA-induced GI colonization reduction. I will evaluate whether SCFAs can
promote CA clearance in cultured human and mouse gut epithelial cells and CA colonization reduction in Hif1a
and Cramp knockout mice. I predict that HIF1-α and CRAMP are necessary for maintaining CA colonization
resistance. Given the high morbidity and mortality associated with invasive fungal infections, the limited arsenal
of antifungal antibiotics, and the continuing emergence of antibiotic resistant strains, new approaches to
treating and preventing invasive fungal infections in patients are desperately needed. Using natural occurring
anaerobic bacterial metabolites (SCFAs) to boost GI mucosal immune effectors to reduce fungal colonization
and ultimately decrease dissemination could represent paradigm shift in the way we prevent/treat fungal
infections in patients. These studies will lay the groundwork for the following innovations: 1) a novel
mechanism by which SCFAs activate gut immune defenses to maintain CA colonization resistance; 2) a novel
approach (SCFAs) to inhibit CA dissemination; and 3) a novel approach to preventing fungal infections in
patients. Together, these studies should lead to fundamental insights into bacterial/fungal interactions within
the intestinal tract and will provide new perspectives in combating invasive fungal disease in the human host.

## Key facts

- **NIH application ID:** 9989015
- **Project number:** 5R01AI123163-05
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Andrew Young Koh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $405,000
- **Award type:** 5
- **Project period:** 2016-09-28 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9989015

## Citation

> US National Institutes of Health, RePORTER application 9989015, Candida Albicans Gastrointestinal Colonization and Dissemination (5R01AI123163-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9989015. Licensed CC0.

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