# Understanding the Mechanism of a Gut Microbial Genotoxin Involved in Colorectal Carcinogenesis

> **NIH NIH R01** · HARVARD UNIVERSITY · 2020 · $383,288

## Abstract

Project Summary / Abstract
Colorectal cancer (CRC) is the third most prevalent form of cancer in the US and the second leading cause of
cancer deaths, with an estimated 50,000 Americans succumbing to CRC in 2015. Studies over the last several
decades have revealed that the gut microbiota influences multiple types of cancer, including CRC, and recent
work has implicated bacterial genotoxins as key effectors in cancer development and progression. One of the
bacterial genotoxins most strongly connected to cancer is colibactin, a metabolite produced by human gut
commensal E. coli strains that possess a biosynthetic gene cluster dubbed the pks island. The increased
abundance of pks+ E. coli found in CRC and inflammatory bowel disease (IBD) patients and the ability of pks+
strains to potentiate tumorigenesis in mouse models of CRC suggests that colibactin may promote cancer
progression. However, achieving a mechanistic understanding of colibactin-mediated DNA damage and
genotoxicity has been impeded by an inability to isolate this metabolite or otherwise assign its chemical
structure. The overall objective of this proposal is to uncover the molecular mechanism underlying colibactin's
genotoxic activity in order to understand and prevent colibactin-mediated carcinogenesis. Preliminary results
have revealed that the colibactin biosynthetic pathway assembles structural features found in other DNA-
damaging natural products, leading to the hypothesis that colibactin's genotoxicity arises from a direct
interaction with DNA. To test this idea and obtain critical knowledge needed to ascertain colibactin's impact on
CRC, our three complementary specific aims are to: 1) elucidate the chemical structure of colibactin by
integrating multiple isolation strategies; 2) decipher the mechanism by which colibactin exposure leads to DNA
damage; and 3) identify small molecules that inhibit colibactin biosynthesis. These advances will be enabled by
our multidisciplinary approach, which merges knowledge and techniques from organic chemistry, chemical
biology, biosynthesis and enzymology, microbiology, toxicology, and human cell biology. Overall, this effort will
generate the tools and knowledge needed to elucidate the role of colibactin-producing bacteria in CRC
initiation and progression in humans. By successfully demonstrating that studying and manipulating individual
disease-associated microbial metabolic pathways can provide key mechanistic insights, this work will support
and validate our future efforts to understand how other gut microbial metabolic activities influence CRC
initiation and development.

## Key facts

- **NIH application ID:** 9961539
- **Project number:** 5R01CA208834-05
- **Recipient organization:** HARVARD UNIVERSITY
- **Principal Investigator:** Emily Patricia Balskus
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $383,288
- **Award type:** 5
- **Project period:** 2016-07-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9961539

## Citation

> US National Institutes of Health, RePORTER application 9961539, Understanding the Mechanism of a Gut Microbial Genotoxin Involved in Colorectal Carcinogenesis (5R01CA208834-05). Retrieved via AI Analytics 2026-07-21 from https://api.ai-analytics.org/grant/nih/9961539. Licensed CC0.

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