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Invasive pathobionts in intestinal microbiome contributes to cancer initiation by counterbalancing epithelial antimicrobial responses B

ABSTRACT: Microbiota dysbiosis and mucosa-associated bacteria are involved in colorectal cancer progression. We hypothesized that a time-specific interaction between dysbiotic pathobionts and host responses promote tumor growth. This study aimed to elucidate the dysfunctional host-microbe interplay in colon tumorigenesis by using a time-series metagenomics approach. A transient surge in fecal microbial richness was linked to a unique transcriptome profile in the mouse colon during carcinoma transformation. Monitoring gut microbiome may help identifying the window-of-opportunity to induce tumor regression using bacteria-targeted precision medicine.

ORGANISM(S): Mus musculus

PROVIDER: GSE166038 | GEO | 2021/11/24

REPOSITORIES: GEO

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Project description:Background & aimsMicrobiota dysbiosis and mucosa-associated bacteria are involved in colorectal cancer progression. We hypothesize that an interaction between virulent pathobionts and epithelial defense promotes tumorigenesis.MethodsChemical-induced CRC mouse model was treated with antibiotics at various phases. Colonic tissues and fecal samples were collected in a time-serial mode and analyzed by gene microarray and 16S rRNA sequencing. Intraepithelial bacteria were isolated using a gentamicin resistance assay, and challenged in epithelial cultures.ResultsOur study showed that antibiotic treatment at midphase but not early or late phase reduced mouse tumor burden, suggesting a time-specific host-microbe interplay. A unique antimicrobial transcriptome profile showing an inverse relationship between autophagy and oxidative stress genes was correlated with a transient surge in microbial diversity and virulence emergence in mouse stool during cancer initiation. Gavage with fimA/fimH/htrA-expressing invasive Escherichia coli isolated from colonocytes increased tumor burden in recipient mice, whereas inoculation of bacteria deleted of htrA or triple genes did not. The invasive E.coli suppressed epithelial autophagy activity through reduction of microtubule-associated protein 1 light-chain 3 transcripts and caused dual oxidase 2-dependent free radical overproduction and tumor cell hyperproliferation. A novel alternating spheroid culture model was developed for sequential bacterial challenge to address the long-term changes in host-microbe interaction for chronic tumor growth. Epithelial cells with single bacterial encounter showed a reduction in transcript levels of autophagy genes while those sequentially challenged with invasive E.coli showed heightened autophagy gene expression to eliminate intracellular microbes, implicating that bacteria-dependent cell hyperproliferation could be terminated at late phases. Finally, the presence of bacterial htrA and altered antimicrobial gene expression were observed in human colorectal cancer specimens.ConclusionsInvasive pathobionts contribute to cancer initiation during a key time frame by counterbalancing autophagy and oxidative stress in the colonic epithelium. Monitoring gut microbiota and antimicrobial patterns may help identify the window of opportunity for intervention with bacterium-targeted precision medicine.

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Invasive pathobionts in intestinal microbiome contributes to cancer initiation by counterbalancing epithelial antimicrobial responses B

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