Microbial genomic analysis reveals the essential role of inflammation in bacteria-induced colorectal cancer

Abstract

Enterobacteria, especially Escherichia coli, are abundant in patients with inflammatory bowel disease or colorectal cancer (CRC). However, it is unclear whether cancer is promoted by inflammation-induced expansion of E. coli and/or changes in expression of specific microbial genes. Here we use longitudinal (2, 12 and 20 weeks) 16S rRNA sequencing of luminal microbiota from ex-germ free mice to show that inflamed Il10−/− mice maintain a higher abundance of Enterobacteriaceae than healthy wild-type mice. Experiments with mono-colonized Il10−/− mice reveal that host inflammation is necessary for E. coli cancer-promoting activity. RNA-sequence analysis indicates significant changes in E. coli gene catalogue in Il10−/− mice, with changes mostly driven by adaptation to the intestinal environment. Expression of specific genes present in the tumor-promoting E. coli pks island are modulated by inflammation/CRC development. Thus, progression of inflammation in Il10−/− mice supports Enterobacteriaceae and alters a small subset of microbial genes important for tumor development.

Gut microbiome development along the colorectal adenoma–carcinoma sequence

“…In colitis-associated CRC mouse models, enterotoxigenic B. fragilis induces colitis and colonic tumours through a T helper type 17 (Th17) inflammatory response, and adherent-invasive E. coli also promotes cancer [33][34][35] . B. ovatus and B. vulgatus have been reported to be higher in human cases of Crohn's disease (six discordant and four concordant twin pairs) 36 .…”

Review of the gut microbiome and esophageal cancer: Pathogenesis and potential clinical implications

“…Microbiome research is a rapidly advancing field in human cancers 6, 7, 8, 9, 10. More than 100 trillion bacteria inhabit the human body and form their own flora (ie microbiomes) in individual organs.…”

When our genome is targeted by pathogenic bacteria

“…These data were extended through a longitudinal analysis in mice (germ-free mice transferred to a conventional facility or infected with a single E. coli pks+ strain) to further explore the interplay between an endogenous microbial community, inflammation and host carcinogenesis [29]. E.coli adaptation to the mammalian intestine induces significant changes to the microbial transcriptome [29].…”

“…E.coli adaptation to the mammalian intestine induces significant changes to the microbial transcriptome [29]. Surprisingly, inflammation only alters a small number of microbial genes (< 0.5% of E. coli genes), and even less microbial genes are affected at later stages after colonization.…”

“…Surprisingly, inflammation only alters a small number of microbial genes (< 0.5% of E. coli genes), and even less microbial genes are affected at later stages after colonization. Sixty six genes are influenced by the cancer status (colorectal cancer induced by azoxymethane) and the pks island was among the top five operons (out of 448) upregulated at the dysplasia/pre-cancer stage [29]. Thus, the cancer microenvironment might impact the functional potential of E. coli to promote cancer progression through the modulation of the expression of specific bacterial genes.…”