# High-resolution genomic interrogation of pathogen-microbiome interactions in Clostridioides difficile infection

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $746,205

## Abstract

ABSTRACT
Clostridioides difficile (Cd) infection (CDI) is a leading cause of healthcare-associated infections in the U.S.,
affecting ~500,000 people and costing ~$5.4B annually. Despite substantial advances in investigating Cd
pathogenesis and transmission over the past 20 years, CDI remains a significant public health burden.
Conventional antimicrobial therapy often fails to clear Cd, can inflict extensive collateral damage to the
commensal gut microbiome (GM), and frequently leads to recurrent CDI, for which treatment options are limited.
A major impediment in mitigating Cd-associated disease is current unclear understanding of the biological basis
for the broad spectrum of disease severity, from asymptomatic Cd colonization to recurrent fatal CDI. In this
context, elucidating mechanisms of Cd colonization and disease necessitates explicit consideration of
confounding GM interactions that increase a patient's CDI risk. Accordingly, we propose a quantitative
investigation of pathogen-GM-host dynamics of clinically prominent Cd lineages and their contribution to CDI,
leveraging a unique cohort of >30,000 Cd-associated patient stools with accompanying well-curated clinical
metadata. We hypothesize that high-resolution genomic analyses of Cd strains and pathogen-GM interactions
will enable sensitive identification of novel genomic elements in virulent lineages associated with variable CDI
outcomes. The rationale for this proposal stems from i) the recognition that most Cd research relies on studying
hypervirulent, previously epidemic lineages that are no longer prevalent in the clinic, ii) the need for stable,
reproducible GM-humanized animal models of CDI to investigate pathogen and human GM variables, and iii)
the observation that taxonomic and functional features of the GM, including bacteriophages, drive Cd's
adaptation as a pathobiont. Our central motivation is to expand the representation of prominent Cd lineages and
leverage our improved understanding of pathogen-GM dynamics, and our innovative technologies, to enable the
design of novel diagnostic, therapeutic, and management avenues to improve patient outcomes. This will be
achieved via three aims: 1) investigate pangenome determinants of CDI risk in clinically representative Cd
strains, 2) model and predict how different patient GM taxonomic and functional architectures, integrated with
clinical metadata, relate to CDI outcomes, and 3) characterize and predict Cd strain-specific dynamics by
employing innovative, defined GM-humanized gnotobiotic mouse models of Cd colonization and CDI. Our
analyses are significant as they pursue new avenues of precisely investigating pathobiont-commensal variables
that influence CDI, a model bacterial-microbiome infectious disease with extensive morbidity and mortality. This
proposal is innovative in improving understanding and prediction of Cd disease spectrum via novel
complementary technologies including GM-humanized gnotobiotic mouse models to identify...

## Key facts

- **NIH application ID:** 10945955
- **Project number:** 1R01AI184858-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** ERIK R DUBBERKE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $746,205
- **Award type:** 1
- **Project period:** 2024-05-22 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10945955

## Citation

> US National Institutes of Health, RePORTER application 10945955, High-resolution genomic interrogation of pathogen-microbiome interactions in Clostridioides difficile infection (1R01AI184858-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10945955. Licensed CC0.

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