Evolutionary biologic changes of gut microbiota in an ‘adenoma-carcinoma sequence’ mouse colorectal cancer model induced by 1, 2-Dimethylhydrazine

Nov 24, 2016Oncotarget

Changes in Gut Bacteria During Colon Cancer Development in a Mouse Model Caused by 1,2-Dimethylhydrazine

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Abstract

The inflammatory group exhibited an enrichment of Bacteroidetes and Porphyromonadaceae (P < 0.01).

A modified mouse model was used to explore changes in the gut microbiota and related molecules during the transition from normal colon tissue to premalignant adenoma.
OTUs affiliated with Firmicutes were found to be enriched in the hyperproliferative group (P < 0.01).
Rikenellaceae and Ruminococcaceae showed an increasing trend throughout the colorectal cancer (CRC) process, while Prevotellaceae and Enterobacteriaceae displayed a decreasing pattern.
The presence of Alistipes finegoldii significantly increased as CRC developed, while the expression of the APC gene decreased over time.
The study suggests that a shift in gut microbiota, with a decrease in beneficial bacteria and an increase in those associated with DNA damage, is linked to tumor development.

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The molecular biological mechanisms underlying the evolutionary biologic changes leading to carcinogenesis remain unclear. The main objective of our study was to explore the evolution of the microbiota community and molecules related with CRC in the dynamic transition from normal colon epithelium to premalignant adenoma with the aid of an 'adenoma-carcinoma sequence' mouse CRC model induced by DMH. We generated a modified mouse CRC model induced by DMH for DNA sequences, and characterized the molecular networks. Data from 454 pyrosequencing of the V3- V5 region of the 16S rDNA gene and immunohistochemical detection of APC, P53, K-RAS and BRAF genes were assessed with Principal coordinates, UniFrac, and Kruskal-Wallis rank sum test. The inflammatory group showed enrichment of Bacteroidetes and Porphyromonadaceae (P < 0.01). OTUs affiliated with Firmicutes were enriched in the hyperproliferative group (P < 0.01). Rikenellaceae and Ruminococcaceae showed an increasing trend during the CRC process while the opposite pattern was observed for Prevotellaceaeand Enterobacteriaceae. OTUs related to Alistipes finegoldii were significantly increased during CRC development, P53, K-RAS and BRAF, were gradually increased (P < 0.05). Conversely, expression of APC was decreased during the course of development of CRC. Our results demonstrate that the biological evolutionary shift of gut microbiota, characterized by a gradual decrease in 'driver' bacteria and an increase in DNA damage-causing bacteria, is accompanied by tumor development in the CRC model. The synergistic actions of microbiota dysbiosis and effects of bacterial metabolites on related molecular events are proposed to contribute to the progression of CRC tumorigenesis.

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Evolutionary biologic changes of gut microbiota in an ‘adenoma-carcinoma sequence’ mouse colorectal cancer model induced by 1, 2-Dimethylhydrazine

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