# Investigation of gut microbiota metabolite-mediated transkingdom interactions with fungi

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $828,994

## Abstract

Project Summary
 The human intestinal tract supports a complex microbial environment consisting of bacterial (or
microbiota) and fungal (or mycobiota) constituents. Although the role of each of these communities has been a
subject of multiple studies, the role of transkingdom interactions between fungi and bacteria in shaping host
immunity and physiology has been much less explored. The chemical basis for such interactions, critical for the
rational design of mechanistic studies with regards to host immunity and disease development, remain
completely uncharted territory in the literature. We have established a genetic manipulation pipeline to identify
gene transfer methodology and build a genetic tool for nonmodel human gut bacteria on a large scale. Via a
multifactorial optimization of their conjugation/transformation conditions and targeting bacterial conserved 16s
rRNA genes, this pipeline efficiently identified the gene transfer methods for multiple nonmodel gut bacterial
commensals and set up CRISPR-based or gene insertion tools in multiple of them. This library of genetically
targetable microbes comes from 5 different phyla. This genetic manipulation pipeline and this library of tractable
commensals will facilitate our investigation of trans-kingdom microbiota-mycobiota interactions at the molecular
level. A high throughput screening of bacterial metabolite libraries from gut bacteria identified metabolites with
direct effect on intestinal mycobiota. We identified bacterial species and corresponding gene clusters responsible
for the production of these metabolites. Our preliminary data suggest strong ties and specific molecular
interactions between fungi and bacteria in the gut that have previously unappreciated role in microbial dynamics,
metabolite production and immunity. We will utilize such bacterial strains and isogenic mutants in key
biosynthetic pathways to target metabolites with mycobiota modulatory properties. We will use several mouse
models and synthetic microbial communities to define the role of trans kingdom interaction between bacteria and
fungi in modulating host immunity and colonization resistance in the gut. We hypothesize that metabolites from
the human bacterial microbiota modulate the fungal communities in the gut to affect microbial composition, the
microbiome function and immunity. In addition to revealing novel mechanisms of fungal-bacterial interaction at
an unprecedented small molecule level, the results of this proposed investigation will illuminate potential new
strategies for targeting of fungal pathogens

## Key facts

- **NIH application ID:** 10883988
- **Project number:** 1R01AI178683-01A1
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Chun-Jun Guo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $828,994
- **Award type:** 1
- **Project period:** 2024-03-01 → 2029-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10883988

## Citation

> US National Institutes of Health, RePORTER application 10883988, Investigation of gut microbiota metabolite-mediated transkingdom interactions with fungi (1R01AI178683-01A1). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10883988. Licensed CC0.

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