# Identifying sources of variation in microbiome-pathogen dynamics during Clostridioides difficile colonization

> **NIH NIH K99** · WASHINGTON UNIVERSITY · 2024 · $126,333

## Abstract

PROJECT SUMMARY
Clostridioides difficile infection (CDI) is a major cause of healthcare-related mortality and a significant public
health burden in the US. C. difficile (Cd) remains a persistent cause of morbidity and mortality in healthcare
settings, in part because many patients are asymptomatic for CDI yet colonized with Cd. These patients
outnumber CDI patients, can transmit Cd and progress to CDI (especially in the context of antibiotic exposure).
Importantly, the clinical outcomes in Cd-colonized patients exists on a spectrum influenced both by the
microbial community and the virulence of the Cd strain. Critically, conventional animal models of CDI do not
recapitulate microbiome and pathogen variation seen in asymptomatically-colonized patients, thus requiring
the development of novel animal models to study this patient population. The long-term goal of this research is
to identify opportunities for novel therapeutic intervention or pathogen surveillance by better understanding and
predicting Cd-associated clinical outcomes. The objective of this proposal is to use clinically-relevant animal
models to 1) investigate the extent to which commensal microbiota protect the host from diverse Cd strains, 2)
predict microbiome vulnerabilities to antibiotic-induced CDI, and 3) identify microbiome features that synergize
with prebiotic administration. The central hypothesis of this work is that the composition of the commensal
microbiota plays a central role in determining host disease severity. The specific aims of this proposal are to: 1)
investigate the in vivo role of commensal Eubacteriaceae in microbiome-based protection against Cd infection
and 2) identify microbiome correlates of antibiotic-induced CDI and prebiotic synergy. The proposal will use
microbiome-humanized models of Cd colonization/infection that integrate both clinically-represented Cd strains
and patient-derived bacterial communities to understand the microbiota's impact on host inflammation,
community metabolism, and Cd proliferation. This research will spur the development of innovative treatment
and diagnostic approaches to mitigating CDI. Dr. Dantas will oversee the project, provide direct mentoring on
statistical modeling of multi-omics data, and help Dr. Fishbein's transition to independence through support of
networking strategies. Dr. Fishbein has prepared a Scholarly Advisory Committee along with other Significant
Contributors with expertise in host-pathogen interactions, gut microbiome-pathogen dynamics, and intestinal
inflammation. The training plan combines primary mentorship, committee interactions, formal coursework (at
the University and externally), and seminar/conference presentations to expand Dr. Fishbein's technical and
conceptual foundations in the microbiome field. This award will facilitate Dr. Fishbein's acquisition of
independent funding, enabling her transition to an independent research program at a research-intensive
academic institution.

## Key facts

- **NIH application ID:** 10808480
- **Project number:** 1K99AI175674-01A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Skye Rebecca Fishbein
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $126,333
- **Award type:** 1
- **Project period:** 2024-06-06 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10808480

## Citation

> US National Institutes of Health, RePORTER application 10808480, Identifying sources of variation in microbiome-pathogen dynamics during Clostridioides difficile colonization (1K99AI175674-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10808480. Licensed CC0.

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