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Physiol Genomics. 2016 Aug 1;48(8):545-53. doi: 10.1152/physiolgenomics.00034.2016. Epub 2016 Jun 17.

Interactions between the colonic transcriptome, metabolome, and microbiome in mouse models of obesity-induced intestinal cancer.

Author information

1
Cancer Cluster, USDA Jean Mayer Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts; Vitamins and Carcinogenesis Laboratory, USDA Jean Mayer Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts; Friedman School of Nutrition Science and Policy, Tufts University, Boston, Massachusetts;
2
Nutrition and Genomics Laboratory, USDA Jean Mayer Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts;
3
Cancer Cluster, USDA Jean Mayer Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts; Agricultural Research Service, USDA, Jean Mayer Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts;
4
Genomics Core, Tufts University School of Medicine, Boston, Massachusetts; and.
5
Cancer Cluster, USDA Jean Mayer Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts; School of Public Health and Health Sciences, University of Massachusetts, Amherst, Massachusetts.
6
Cancer Cluster, USDA Jean Mayer Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts; Vitamins and Carcinogenesis Laboratory, USDA Jean Mayer Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts; Friedman School of Nutrition Science and Policy, Tufts University, Boston, Massachusetts; Jimmy.crott@tufts.edu.

Abstract

Obesity is a significant risk factor for colorectal cancer (CRC); however, the relative contribution of high-fat (HF) consumption and excess adiposity remains unclear. It is becoming apparent that obesity perturbs both the intestinal microbiome and metabolome, and each has the potential to induce protumorigenic changes in the epithelial transcriptome. The physiological consequences and the degree to which these different biologic systems interact remain poorly defined. To understand the mechanisms by which obesity drives colonic tumorigenesis, we profiled the colonic epithelial transcriptome of HF-fed and genetically obese (DbDb) mice with a genetic predisposition to intestinal tumorigenesis (Apc(1638N)); 266 and 584 genes were differentially expressed in the colonic mucosa of HF and DbDb mice, respectively. These genes mapped to pathways involved in immune function, and cellular proliferation and cancer. Furthermore, Akt was central within the networks of interacting genes identified in both gene sets. Regression analyses of coexpressed genes with the abundance of bacterial taxa identified three taxa, previously correlated with tumor burden, to be significantly correlated with a gene module enriched for Akt-related genes. Similarly, regression of coexpressed genes with metabolites found that adenosine, which was negatively associated with inflammatory markers and tumor burden, was also correlated with a gene module enriched with Akt regulators. Our findings provide evidence that HF consumption and excess adiposity result in changes in the colonic transcriptome that, although distinct, both appear to converge on Akt signaling. Such changes could be mediated by alterations in the colonic microbiome and metabolome.

KEYWORDS:

Akt; metabolome; microbiome; obesity; transcriptome

[Indexed for MEDLINE]

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