Colibactin-Producing Escherichia coli Induce the Formation of Invasive Carcinomas in a Chronic Inflammation-Associated Mouse Model

Abstract

Background: Escherichia coli producing the genotoxin colibactin (CoPEC or colibactin-producing E. coli) abnormally colonize the colonic mucosa of colorectal cancer (CRC) patients. We previously showed that deficiency of autophagy in intestinal epithelial cells (IECs) enhances CoPEC-induced colorectal carcinogenesis in ApcMin/+ mice. Here, we tested if CoPEC trigger tumorigenesis in a mouse model lacking genetic susceptibility or the use of carcinogen. Methods: Mice with autophagy deficiency in IECs (Atg16l1∆IEC) or wild-type mice (Atg16l1flox/flox) were infected with the CoPEC 11G5 strain or the mutant 11G5∆clbQ incapable of producing colibactin and subjected to 12 cycles of DSS treatment to induce chronic colitis. Mouse colons were used for histological assessment, immunohistochemical and immunoblot analyses for DNA damage marker. Results: 11G5 or 11G5∆clbQ infection increased clinical and histological inflammation scores, and these were further enhanced by IEC-specific autophagy deficiency. 11G5 infection, but not 11G5∆clbQ infection, triggered the formation of invasive carcinomas, and this was further increased by autophagy deficiency. The increase in invasive carcinomas was correlated with enhanced DNA damage and independent of inflammation. Conclusions: CoPEC induce colorectal carcinogenesis in a CRC mouse model lacking genetic susceptibility and carcinogen. This work highlights the role of (i) CoPEC as a driver of CRC development, and (ii) autophagy in inhibiting the carcinogenic properties of CoPEC.

Biosynthesis and bioactivities of microbial genotoxin colibactins

“…Based on its molecular weight of 788, they proposed that this compound is a hydroxylated derivative of colibactin-770 ( 19), but larger-scale fermentation of E. coli-50 and subsequent purication failed to yield the pure target compound. Instead, they obtained two degenerated compounds, colibactin-420 ( 22) and colibactin-430 (23). These results suggest spontaneous hydrolysis in 20, consistent with the 1,2-diketone cleavage reaction proposed by Herzon and coworkers.…”

“…24 Furthermore, infection with pks+ E. coli triggers the formation of invasive colonic tumours in a DSS-induced chronic inammation mouse model. 23 Overall, the high abundance of pks+ E. coli in CRC patients and the mutant ngerprint suggest the carcinogenic role of colibactin in CRC development. However, the colibactin mutational signature is also found in healthy human colon crypts, 25,26 suggesting that colibactin may initiate cancer only under specic conditions or certain mutant accumulations.…”

Mucosa-Associated Escherichia coli in Colorectal Cancer Patients and Control Subjects: Variations in the Prevalence and Attributing Features

“…Indeed, bacterial infection has long been known as key factor in the etiology of CRC [ 8 ]. More recently, accumulating evidence supports that mucosa-associated E. coli can affect the development of CRC [ 8 , 29 , 30 ]. However, there are relatively few data available about the prevalence and characterization of mucosa-associated E. coli from CRC specimens.…”

Inflammatory Bowel Disease and Risk of Colorectal Cancer: An Overview From Pathophysiology to Pharmacological Prevention

“…Among the Enterobacteriaceae family, Escherichia coli utilizes virulence factors, such as colibactin, a genotoxic compound, that promotes tumor growth in a xenograft mouse model and in mice with functioning autophagy, who lack for this reason genetic susceptibility for carcinogenesis, after treatment with AOM/DSS to induce CRC (Dalmasso et al, 2014;Salesse et al, 2021). Indeed, colibactin alkylates DNA and induces double-stranded breaks, playing thus a pro-tumorigenic role (Yang et al, 2020).…”