J Cancer 2016; 7(13):1780-1790. doi:10.7150/jca.15792 This issue

Research Paper

Diet- and Genetically-induced Obesity Produces Alterations in the Microbiome, Inflammation and Wnt Pathway in the Intestine of Apc+/1638N Mice: Comparisons and Contrasts

Wei Liu1,2, Jimmy W. Crott3, Lin Lyu1, Anna C. Pfalzer3, Jinchao Li1, Sang-Woon Choi1, 4, Yingke Yang5, Joel B. Mason3,6, Zhenhua Liu1,3✉

1. Nutrition and Cancer Prevention Laboratory, School of Public Health and Health Sciences, University of Massachusetts, Amherst, USA.
2. Institute of Food Science and Technology, Shandong Academy of Agricultural Sciences, Jinan, China.
3. Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, USA.
4. CHA Cancer Research Center, CHA University, Seoul, Korea.
5. Department of Molecular Medicine, Hunan University, Changsha, China.
6. Tufts Medical Center Cancer Center, Tufts University, Boston, USA.

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Liu W, Crott JW, Lyu L, Pfalzer AC, Li J, Choi SW, Yang Y, Mason JB, Liu Z. Diet- and Genetically-induced Obesity Produces Alterations in the Microbiome, Inflammation and Wnt Pathway in the Intestine of Apc+/1638N Mice: Comparisons and Contrasts. J Cancer 2016; 7(13):1780-1790. doi:10.7150/jca.15792. Available from https://www.jcancer.org/v07p1780.htm

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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+/1638NLepr+/+ fed a low fat diet (10% fat), Apc+/1638NLepr+/+ fed a high fat diet (60% fat, diet-induced obesity), and Apc+/1638NLeprdb/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 (IFNγ and TNF-α 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.

Keywords: Obesity, Microbiome, Inflammation, Wnt pathway, Intestinal cancer.