Abstract
Disrupted interactions between host and intestinal bacteria are implicated in colorectal cancer (CRC) development. However, activities derived from these bacteria and their interplay with the host are unclear. Here, we examine this interplay by performing mouse and microbiota RNA sequencing on colon tissues and 16S and small RNA sequencing on stools from germfree (GF) and gnotobiotic ApcMin Δ 850/+ ;Il10-/- mice associated with microbes from biofilm-positive human CRC tumor (BF+T) and biofilm-negative healthy (BF-bx) tissues. The bacteria in BF+T mice differentially expressed (DE) >2,900 genes, including genes related to bacterial secretion, virulence, and biofilms but affected only 62 host genes. Small RNA sequencing of stools from these cohorts revealed eight significant DE host microRNAs (miRNAs) based on biofilm status and several miRNAs that correlated with bacterial taxon abundances. Additionally, computational predictions suggest that some miRNAs preferentially target bacterial genes while others primarily target mouse genes. 16S rRNA sequencing of mice that were reassociated with mucosa-associated communities from the initial association revealed a set of 13 bacterial genera associated with cancer that were maintained regardless of whether the reassociation inoculums were initially obtained from murine proximal or distal colon tissues. Our findings suggest that complex interactions within bacterial communities affect host-derived miRNA, bacterial composition, and CRC development.IMPORTANCE Bacteria and bacterial biofilms have been implicated in colorectal cancer (CRC), but it is still unclear what genes these microbial communities express and how they influence the host. MicroRNAs regulate host gene expression and have been explored as potential biomarkers for CRC. An emerging area of research is the ability of microRNAs to impact growth and gene expression of members of the intestinal microbiota. This study examined the bacteria and bacterial transcriptome associated with microbes derived from biofilm-positive human cancers that promoted tumorigenesis in a murine model of CRC. The murine response to different microbial communities (derived from CRC patients or healthy people) was evaluated through RNA and microRNA sequencing. We identified a complex interplay between biofilm-associated bacteria and the host during CRC in mice. These findings may lead to the development of new biomarkers and therapeutics for identifying and treating biofilm-associated CRCs.
Highlights
Disrupted interactions between host and intestinal bacteria are implicated in colorectal cancer (CRC) development
To examine the bacterial activities associated with biofilm-positive microbes from CRC patients, we examined mouse and bacterial gene expression from colon tissues and mouse small RNA sequencing from stools collected from biofilm-positive associated ApcMinΔ850/ϩ;Il10Ϫ/Ϫ mice
In order to elucidate microbial activities associated with biofilm-forming bacteria derived from human CRC patients that promote tumorigenesis in ApcMinΔ850/ϩ;Il10Ϫ/Ϫ mice [13], we characterized mouse and microbial gene expression from colon tissue snips using RNA sequencing
Summary
Disrupted interactions between host and intestinal bacteria are implicated in colorectal cancer (CRC) development. We identified a complex interplay between biofilmassociated bacteria and the host during CRC in mice These findings may lead to the development of new biomarkers and therapeutics for identifying and treating biofilm-associated CRCs. Numerous 16S rRNA and shotgun metagenomic studies have demonstrated that colorectal cancer (CRC) patients have an altered intestinal microbiota compared to healthy controls [1, 2]. Colibactin-producing Escherichia coli, enterotoxigenic Bacteroides fragilis, and Fusobacterium nucleatum among others, are implicated in CRC pathogenesis due to their abilities to produce genotoxins and adhesins which promote proliferation and modulate immune responses in preclinical models [3, 4] How these bacteria interact with the rest of the complex microbiota to influence CRC initiation and/or progression is still unclear. It is uncertain how human CRC-associated microbial communities as a whole impact fecal miRNA expression and whether host miRNAs affect bacterial composition/gene expression during CRC
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