期刊
JOURNAL OF CANCER
卷 7, 期 13, 页码 1780-1790出版社
IVYSPRING INT PUBL
DOI: 10.7150/jca.15792
关键词
Obesity; Microbiome; Inflammation; Wnt pathway; Intestinal cancer
类别
资金
- USDA grants [2014-67017-21762, MAS00454]
- SPHHS Deans Incentive Grant
- Agricultural Research Service of United States Department of Agriculture [58-1950-0-014, 58-1950-4-003]
Obesity is an established risk factor for colorectal cancer (CRC). Our previous study indicated that obesity increases activity of the pro-tumorigenic Wnt-signaling. Presently, we sought to further advance our understanding of the mechanisms by which obesity promotes CRC by examining associations between microbiome, inflammation and Wnt-signaling in Apc(+/1638N) mice whose obesity was induced by one of two modalities, diet-or genetically-induced obesity. Three groups were employed: Apc(+/1638N)Lepr(+/+) fed a low fat diet (10% fat), Apc(+/1638N)Lepr(+/+) fed a high fat diet (60% fat, diet-induced obesity), and Apc(+/1638N)Lepr(db/db) fed a low fat diet (genetically-induced obesity). All animals received diets for 16 weeks from 8 to 24 weeks of age. The abundance of 19 bowel cancer-associated bacterial taxa were examined by real-time PCR. The abundance of Turicibacter and Desulfovibrio decreased, but F. prausnitizii increased, in diet-induced obese mice (p < 0.05). In contrast, in genetically-induced obese mice, Bifidobacterium, A. muciniphila and E. rectale decreased, but Peptostrptococcus, and E. coli increased (p < 0.05). Both diet-and genetically-induced obesity altered the expression of genes involved in bacterial recognition (MyD88) and increased inflammation as indicated by elevated levels of cytokines (IFN gamma and TNF-alpha for genetically-induced obesity, and IL-6 for diet-induced obesity). The elevated inflammation was associated with altered expression of genes that are integral components of the Wnt-signaling cascade in a fashion indicating its activation. These findings demonstrate that the composition of the small intestinal microbiome is affected differently in diet-and genetically-induced obesity, but both are associated with elevated intestinal inflammation and alterations of the Wnt pathway towards enhancing tumorigenesis.
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