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

Authors: PFALZER, ANNA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; KAMANU, FREDERICK - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; Parnell, Laurence; TAI, ALBERT - Tufts University; LIU, ZHENHAU - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; MASON, JOEL - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; CROTT, JIMMY - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Physiological Genomics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/15/2016
Publication Date: 8/1/2016
Citation: Pfalzer, A., Kamanu, F.K., Parnell, L.D., Tai, A., Liu, Z., Mason, J.B., Crott, J.W. 2016. Interactions between the colonic transcriptome, metabolome and microbiome in mouse models of obesity-induced intestinal cancer. Physiological Genomics. 48(8):545-553.

Interpretive Summary: This clinical study was performed to help understand whether obesity increases the risk of developing colon cancer, in part, by producing inflammation in the lining of the colon. Concentrations of four proteins known to incite inflammation were measured in the blood and colonic lining of 16 lean and 26 obese individuals undergoing routine colonoscopy screenings. Also, differences in the degree to which the entire array of all genes were expressed in the colons of the two groups were defined. The results indicated that two inflammatory proteins, IL-6 and TNF-alpha, were two-fold elevated in the colons of obese individuals. Accompanying this rise in inflammatory molecules was the activation of two pro-cancerous biochemical pathways. These observations suggest that obesity produces inflammation on a biochemical level in the colon and is accompanied by changes in gene expression that are pro-cancerous.

Technical Abstract: Obesity is a significant risk factor for colorectal cancer (CRC); however, the relative contribution of high-fat consumption and excess adiposity remains unclear. It is becoming apparent that obesity perturbs both the intestinal microbiome and gut metabolome, and each has the potential to induce pro-tumorigenic changes in the epithelial transcriptome. The physiologic consequences and the degree to which these different biologic systems interact remain poorly defined. To better understand the mechanisms by which obesity drives colonic tumorigenesis, we profiled the colonic epithelial transcriptome of high fat (HF) diet-induced and genetically-induced (DbDb) obese mice with a genetic predisposition to intestinal tumorigenesis (Apc1638N). 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. Co-expression analysis comparing associations between the colonic transcriptome and microbiome revealed that three bacterial taxa previously correlated with tumor burden were significantly correlated with a gene module enriched for Akt-related genes. Similarly, co-expression analysis of the colonic transcriptome and metabolome 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 high-fat 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.