Improved detection of colibactin-induced mutations by genotoxic E. coli in organoids and colorectal cancer.

Co-culture of intestinal organoids with a colibactin-producing pks ⁺ E. coli strain (EcC) revealed mutational signatures also found in colorectal cancer (CRC). E. coli Nissle 1917 (EcN) remains a commonly used probiotic, despite harboring the pks operon and inducing double strand DNA breaks. We determine the mutagenicity of EcN and three CRC-derived pks ⁺ E. coli strains with an analytical framework based on sequence characteristic of colibactin-induced mutations. All strains, including EcN, display varying levels of mutagenic activity. Furthermore, a machine learning approach attributing individual mutations to colibactin reveals that patients with colibactin-induced mutations are diagnosed at a younger age and that colibactin can induce a specific APC mutation. These approaches allow the sensitive detection of colibactin-induced mutations in ∼12% of CRC genomes and even in whole exome sequencing data, representing a crucial step toward pinpointing the mutagenic activity of distinct pks ⁺ E. coli strains.
Competing Interests: Declaration of interests H.C. is a full-time member of the executive board of F. Hoffmann-La Roche Ltd. as head of Pharma, Research and Early Development (pRED) in Basel, Switzerland. Additionally, H.C. is inventor on multiple organoid patents, licensed by the KNAW to the Foundation HUB in Utrecht.
(Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)