Bacterially-Associated Transcriptional Remodelling in a Distinct Genomic Subtype of Colorectal Cancer Provides a Plausible Molecular Basis for Disease Development

Abstract

The relevance of specific microbial colonisation to colorectal cancer (CRC) disease pathogenesis is increasingly recognised, but our understanding of possible underlying molecular mechanisms that may link colonisation to disease in vivo remains limited. Here, we investigate the relationships between the most commonly studied CRC-associated bacteria (Enterotoxigenic Bacteroides fragilis, pks+ Escherichia coli, Fusobacterium spp., afaC+ E. coli, Enterococcus faecalis & Enteropathogenic E. coli) and altered transcriptomic and methylation profiles of CRC patients, in order to gain insight into the potential contribution of these bacteria in the aetiopathogenesis of CRC. We show that colonisation by E. faecalis and high levels of Fusobacterium is associated with a specific transcriptomic subtype of CRC that is characterised by CpG island methylation, microsatellite instability and a significant increase in inflammatory and DNA damage pathways. Analysis of the significant, bacterially-associated changes in host gene expression, both at the level of individual genes as well as pathways, revealed a transcriptional remodeling that provides a plausible mechanistic link between specific bacterial colonisation and colorectal cancer disease development and progression in this subtype; these included upregulation of REG3A, REG1A and REG1P in the case of high-level colonization by Fusobacterium, and CXCL10 and BMI1 in the case of colonisation by E. faecalis. The enrichment of both E. faecalis and Fusobacterium in this CRC subtype suggests that polymicrobial colonisation of the colonic epithelium may well be an important aspect of colonic tumourigenesis.

Distinct gut microbiome patterns associate with consensus molecular subtypes of colorectal cancer

“…The ability of Fusobacterium species to elicit an immune response, in particular to recruit T-cells, is reflected in the immunological signature seen in the CMS1 tumours. Our targeted qPCR analysis of F. nucleatum that showed an increased abundance associated with CMS1, also reflects the findings of two studies that found that Fusobacterium was associated with a CRC subtype characterised by CpG island methylation, MSI and inflammatory signatures [15], and higher prevalence in right-sided tumours [46], all hallmarks of CMS1 [6].…”

“…Comparison of faecal microbiomes from CRC patients and healthy controls [9][10][11][12] has identified particular bacterial species that are enriched in CRC, and analysis of tumour, adenoma, and matched normal tissue from the same patients found that changes in local communities of potentially interacting bacterial taxa are associated with different disease states [12,13]. Correlations between particular cancer mutations and changes in microbial communities, and transcriptional remodelling associated with specific bacteria have recently been described in CRC [14,15].…”

Impact of the gut microbiome on the genome and epigenome of colon epithelial cells: contributions to colorectal cancer development

“…So, to establish a direct, causal connection between the gut microbiome and CRC development, we must determine whether and how microbes alter mutation rates, gene methylation, chromatin structure, and/or non-coding RNA expression in CECs. Several epidemiological studies have associated specific bacteria in the gut with tumors that are characterized by DNA hypermethylation [36][37][38][39] or by specific mutational patterns [40], strengthening the hypothesis that gut microbes have a role in CRC development through their effects on the genome and epigenome of CECs.…”

Role of Regenerating Islet-Derived Protein 3A in Gastrointestinal Cancer

“…In particular, it had been wellaccepted that specific bacterial species played at least some roles in the initiation and/or progression of colorectal cancer. And up-regulation of Reg3A was found in the tumors with highlevel colonization by Fusobacterium, a kind of colorectal cancerassociated bacteria (33).…”