# Dietary and synbiotic strategy to limit gut microbiome dysbiosis and protect against Clostridioides difficile infection

> **NIH NIH U01** · UNIVERSITY OF COLORADO DENVER · 2021 · $776,329

## Abstract

Summary
Clostridioides difficile infection (CDI) is an important cause of morbidity and mortality and rates are on the rise,
indicating that safe and new approaches are urgently needed for treatment and prevention. Emerging evidence
suggests that a high-fat/low-fiber diet may promote CDI. Diets high in saturated fat lead to the production of
primary bile acids that can promote infection by germinating C. difficile spores. Diets deficient in fiber
perpetuate C. difficile colonization in mice, and this effect was linked at least in part with a loss of Short Chain
Fatty Acids (SCFAs). Our preliminary murine studies show that a high-fat/low-fiber diet resulted in increased
microbiome disturbance following broad spectrum antibiotic challenge, increased cecal levels of primary bile
acids that germinate C. difficile spores, markedly decreased levels of secondary bile acids that can kill C.
difficile, and increased morbidity and mortality upon C. difficile exposure. These results suggest that dietary
intervention has promise for preventing CDI in individuals at high risk. Aim 1A will determine the effects of
dietary levels of fat and fiber in preventing antibiotic induced gut microbiome disturbance and CDI,
using conventional mice fed varied diets. Aim 1B will directly evaluate the role of increased intestinal
levels of primary bile acids in the increased C. difficile pathogenicity by chemically inhibiting the ileal
apical sodium-dependent bile salt transporter. Oncology patients have high incidence of CDI, driven by risk
factors that include frequent hospitalization, antibiotic use, and use of chemotherapeutic drugs. Aim 2 will test
a higher-fiber/lower-fat dietary intervention for prevention of C. difficile recurrence and maintenance of
gut microbiome diversity in oncology patients. Production of SCFAs may be one mechanism contributing
to the protective effects of fiber in CDI. Metabolism of the SCFA butyrate by intestinal epithelial cells plays a
key role in the establishment of intestinal hypoxia, which is important because reversion to hypoxia is a key
process in promoting the reestablishment of an anaerobe dominated complex gut microbiome following
disturbance. SCFA production from fiber is limited in individuals with a low complexity facultative anaerobe-
dominated microbiome, which is common in individuals with recurrent CDI. In our earlier work, we have
identified butyrate-producers, including Clostridium symbiosum and Anaerostipes caccae that specialize to
infant and disturbed guts and that can produce butyrate using a simple substrate, gluconic acid, as a sole
source of carbon. Thus, in Aim 3 we will test the hypothesis that synbiotic treatment with disturbance
adapted butyrate-producers and gluconic acid will increase butyrate production, increase intestinal
hypoxia and facilitate the activity of anaerobic secondary bile acid producers that prevent CDI, using
mice humanized with a disturbed/ low-complexity microbiota.

## Key facts

- **NIH application ID:** 10085098
- **Project number:** 1U01AI150589-01A1
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Catherine Lozupone
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $776,329
- **Award type:** 1
- **Project period:** 2021-04-23 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10085098

## Citation

> US National Institutes of Health, RePORTER application 10085098, Dietary and synbiotic strategy to limit gut microbiome dysbiosis and protect against Clostridioides difficile infection (1U01AI150589-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10085098. Licensed CC0.

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