Abstract
BackgroundMucosa-associated Escherichia coli are frequently found in the colonic mucosa of patients with colorectal adenocarcinoma, but rarely in healthy controls. Chronic mucosal E. coli infection has therefore been linked to colonic tumourigenesis. E. coli strains carrying eae (encoding the bacterial adhesion protein intimin) attach intimately to the intestinal mucosa and are classed as attaching and effacing E. coli (AEEC). Enteropathogenic Escherichia coli (EPEC) are the most common form of AEEC identified in man. EPEC utilise a type III secretion system to translocate effector proteins into host cells and infection induces wide-ranging effects on the host cell proteome. We hypothesised that EPEC infection could influence molecular pathways involved in colorectal tumourigenesis.Methodology/Principal FindingsWhen co-cultured with human colorectal cell lines, EPEC dramatically downregulated the expression of key DNA mismatch repair proteins MSH2 and MLH1 in an attachment specific manner. Cytochrome c staining and TUNEL analysis confirmed that this effect was not a consequence of apoptosis/necrosis. Ex vivo human colonic mucosa was co-cultured with EPEC and probed by immunofluorescence to locate adherent bacteria. EPEC entered 10% of colonic crypts and adhered to crypt epithelial cells, often in the proliferative compartment. Adenocarcinoma and normal colonic mucosa from colorectal cancer patients (n = 20) was probed by immunofluorescence and PCR for AEEC. Mucosa-associated E. coli were found on 10/20 (50%) adenocarcinomas and 3/20 (15%) normal mucosa samples (P<0.05). AEEC were detected on 5/20 (25%) adenocarcinomas, but not normal mucosa samples (P<0.05).Significance/ConclusionsThe ability of EPEC to downregulate DNA mismatch repair proteins represents a novel gene-environment interaction that could increase the susceptibility of colonic epithelial cells to mutations and therefore promote colonic tumourigenesis. The potential role of AEEC in colorectal tumourigenesis warrants further investigation.
Highlights
Colorectal cancer is responsible for nearly half a million deaths annually, and over 940,000 new cases are diagnosed worldwide each year [1]
Previous studies have established that mucosally adherent E. coli are often present on colonic tissue from colorectal cancer patients [4,5]
This study demonstrates for the first time an association of AEEC strains with human colorectal adenocarcinomas
Summary
Colorectal cancer is responsible for nearly half a million deaths annually, and over 940,000 new cases are diagnosed worldwide each year [1]. Studies on cancer patients in the UK and Germany reveal that mucosa-associated bacteria are more frequently identified in colon tissue from patients with adenocarcinomas than in controls [4,5]. Martin et al found that 70% of colorectal cancer patients had mucosa-associated bacteria, and that a significant proportion of the bacterial isolates were E. coli strains that adhered to HT29 cells in vitro [4]. These studies clearly demonstrate a link between mucosally adherent E. coli and colon cancer. We hypothesised that EPEC infection could influence molecular pathways involved in colorectal tumourigenesis
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