# Enterotoxigenic B. fragilis Acquisition in Disease Susceptibility

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $393,750

## Abstract

PROJECT SUMMARY
Inflammatory bowel disease (IBD) and colonic malignancy are heterogeneous disease states that result from a
complex interplay of host genetic and environmental factors. It is becoming increasingly clear that early events
in development of the colonic microbiota influence host immunity, nutrition, and susceptibility to disease.
Bacteroides fragilis comprises up to 2.5% of the human microbiota, and is often acquired within the first month
of life. A subspecies of Bacteroides fragilis termed enterotoxigenic B. fragilis (ETBF) releases B. fragilis toxin
(BFT), a zinc-dependent metalloprotease that causes a pro-inflammatory injury of the intestinal epithelium.
ETBF has been implicated in the pathogenesis of IBD, colon tumorigenesis, acute diarrhea, and undernutrition
in children. ETBF colonizes up to 20% of asymptomatic humans, suggesting that these individuals may incur
an underappreciated long-term health risk from chronic carriage. We have demonstrated that competition for
the B. fragilis niche within the colon is governed by strain-specific determinants including the Type VI bacterial
secretion system. Further, the acquisition of protective strains of NTBF that restrict ETBF acquisition blunt the
toxic effects of ETBF and thereby mitigate disease. The primary goal of this proposal is to examine neonatal
acquisition of ETBF as a determinant of host susceptibility to disease. Through a comprehensive analysis of
the genetic determinants of ETBF colonic niche establishment and the mechanisms by which BFT is
expressed and released to act upon host cells, this study will define fundamental mechanisms that underlie
ETBF-mediated disease. These studies will benefit from the use of a novel model of B. fragilis vertical
transmission in which the temporal and genetic determinants of initial niche colonization by B. fragilis is
examined in neonatal mice. It is anticipated that these studies will shed light on strategic opportunities for
genetically informed probiotic-based approaches to modulate colonic disease through strain-specific niche
competition, precluding the deleterious acquisition of ETBF that renders a host susceptible to disease.

## Key facts

- **NIH application ID:** 9989780
- **Project number:** 5R01AI138565-03
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Juliane Bubeck Wardenburg
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $393,750
- **Award type:** 5
- **Project period:** 2018-09-13 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9989780

## Citation

> US National Institutes of Health, RePORTER application 9989780, Enterotoxigenic B. fragilis Acquisition in Disease Susceptibility (5R01AI138565-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9989780. Licensed CC0.

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