Microbiota dysbiosis and mucosa-associated bacteria are involved in colorectal cancer (CRC) progression. We hypothesize that an interaction between virulent pathobionts and epithelial defense promotes tumorigenesis.
Our study demonstrated that antibiotic treatment at mid-phase 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 one bacterial encounter showed reduction in transcript levels of autophagy genes while those sequentially challenged with invasive E. coli displayed 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 CRC specimens.
Invasive 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 identifying the window-of-opportunity for intervention with bacterium-targeted precision medicine.
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
Invasive pathobionts contribute to colon cancer initiation by counterbalancing epithelial antimicrobial responses.
