Invasive Pathobionts Contribute to Colon Cancer Initiation by Counterbalancing Epithelial Antimicrobial ResponsesSummary

Background & Aims: Microbiota dysbiosis and mucosa-associated bacteria are involved in colorectal cancer progression. We hypothesize that an interaction between virulent pathobionts and epithelial defense promotes tumorigenesis. Methods: Chemical-induced CRC mouse model was treated with anti...

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Autores principales:	Linda Chia-Hui Yu, Shu-Chen Wei, Yi-Hsuan Li, Po-Yu Lin, Xin-Yu Chang, Jui-Ping Weng, Yin-Wen Shue, Liang-Chuan Lai, Jin-Town Wang, Yung-Ming Jeng, Yen-Hsuan Ni
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2022
Materias:	Colon Carcinoma Gut Microbiome Intracellular Microbes Xenophagy Reactive Oxygen Species Organoids and Spheroids Diseases of the digestive system. Gastroenterology RC799-869
Acceso en línea:	https://doaj.org/article/36e9e921bad64876b037e38f236fee69
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spelling	oai:doaj.org-article:36e9e921bad64876b037e38f236fee692021-11-12T04:39:35ZInvasive Pathobionts Contribute to Colon Cancer Initiation by Counterbalancing Epithelial Antimicrobial ResponsesSummary2352-345X10.1016/j.jcmgh.2021.08.007https://doaj.org/article/36e9e921bad64876b037e38f236fee692022-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2352345X21001740https://doaj.org/toc/2352-345XBackground & Aims: Microbiota dysbiosis and mucosa-associated bacteria are involved in colorectal cancer progression. We hypothesize that an interaction between virulent pathobionts and epithelial defense promotes tumorigenesis. Methods: Chemical-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. Results: Our 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. Conclusions: 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 identify the window of opportunity for intervention with bacterium-targeted precision medicine.Linda Chia-Hui YuShu-Chen WeiYi-Hsuan LiPo-Yu LinXin-Yu ChangJui-Ping WengYin-Wen ShueLiang-Chuan LaiJin-Town WangYung-Ming JengYen-Hsuan NiElsevierarticleColon CarcinomaGut MicrobiomeIntracellular MicrobesXenophagyReactive Oxygen SpeciesOrganoids and SpheroidsDiseases of the digestive system. GastroenterologyRC799-869ENCellular and Molecular Gastroenterology and Hepatology, Vol 13, Iss 1, Pp 57-79 (2022)
institution	DOAJ
collection	DOAJ
language	EN
topic	Colon Carcinoma Gut Microbiome Intracellular Microbes Xenophagy Reactive Oxygen Species Organoids and Spheroids Diseases of the digestive system. Gastroenterology RC799-869
spellingShingle	Colon Carcinoma Gut Microbiome Intracellular Microbes Xenophagy Reactive Oxygen Species Organoids and Spheroids Diseases of the digestive system. Gastroenterology RC799-869 Linda Chia-Hui Yu Shu-Chen Wei Yi-Hsuan Li Po-Yu Lin Xin-Yu Chang Jui-Ping Weng Yin-Wen Shue Liang-Chuan Lai Jin-Town Wang Yung-Ming Jeng Yen-Hsuan Ni Invasive Pathobionts Contribute to Colon Cancer Initiation by Counterbalancing Epithelial Antimicrobial ResponsesSummary
description	Background & Aims: Microbiota dysbiosis and mucosa-associated bacteria are involved in colorectal cancer progression. We hypothesize that an interaction between virulent pathobionts and epithelial defense promotes tumorigenesis. Methods: Chemical-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. Results: Our 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. Conclusions: 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 identify the window of opportunity for intervention with bacterium-targeted precision medicine.
format	article
author	Linda Chia-Hui Yu Shu-Chen Wei Yi-Hsuan Li Po-Yu Lin Xin-Yu Chang Jui-Ping Weng Yin-Wen Shue Liang-Chuan Lai Jin-Town Wang Yung-Ming Jeng Yen-Hsuan Ni
author_facet	Linda Chia-Hui Yu Shu-Chen Wei Yi-Hsuan Li Po-Yu Lin Xin-Yu Chang Jui-Ping Weng Yin-Wen Shue Liang-Chuan Lai Jin-Town Wang Yung-Ming Jeng Yen-Hsuan Ni
author_sort	Linda Chia-Hui Yu
title	Invasive Pathobionts Contribute to Colon Cancer Initiation by Counterbalancing Epithelial Antimicrobial ResponsesSummary
title_short	Invasive Pathobionts Contribute to Colon Cancer Initiation by Counterbalancing Epithelial Antimicrobial ResponsesSummary
title_full	Invasive Pathobionts Contribute to Colon Cancer Initiation by Counterbalancing Epithelial Antimicrobial ResponsesSummary
title_fullStr	Invasive Pathobionts Contribute to Colon Cancer Initiation by Counterbalancing Epithelial Antimicrobial ResponsesSummary
title_full_unstemmed	Invasive Pathobionts Contribute to Colon Cancer Initiation by Counterbalancing Epithelial Antimicrobial ResponsesSummary
title_sort	invasive pathobionts contribute to colon cancer initiation by counterbalancing epithelial antimicrobial responsessummary
publisher	Elsevier
publishDate	2022
url	https://doaj.org/article/36e9e921bad64876b037e38f236fee69
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Invasive Pathobionts Contribute to Colon Cancer Initiation by Counterbalancing Epithelial Antimicrobial ResponsesSummary

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