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Research Project: Defining Mechanims by which Select Nutrients Determine Cancer Risk

Location: Jean Mayer Human Nutrition Research Center On Aging

Title: Diet- and genetically-induced obesity differentially affect the fecal microbiome and metabolome in Apc1638N mice

Author
item Pfalzer, Anna - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item Nesbeth, Paula-dene - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item Parnell, Laurence
item Iyer, Lakshmana - Tufts University
item Liu, Zhenhua - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item Kane, Anne - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item Chen, Chung-yen - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item Tai, Albert - Tufts University
item Bowman, Thomas - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item Obin, Martin - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item Mason, Joel - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item Greenberg, Andrew - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item Choi, Sang-woon - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item Selhub, Jacob - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item Paul Pottenplackel, Ligi - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item Crott, Jimmy - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: PLoS One
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/24/2015
Publication Date: 8/18/2015
Citation: Pfalzer, A.C., Nesbeth, P.C., Parnell, L.D., Iyer, L.K., Liu, Z., Kane, A.V., Chen, C., Tai, A.K., Bowman, T.A., Obin, M.S., Mason, J.B., Greenberg, A., Choi, S., Selhub, J., Paul Pottenplackel, L., Crott, J.W. 2015. Diet- and genetically-induced obesity differentially affect the fecal microbiome and metabolome in Apc1638N mice. PLoS One. 10(8):e0135758. doi:10.1371/journal.pone.0135758.

Interpretive Summary: Obesity is a major risk factor for colorectal cancer. Alterations in the composition of bacteria in the gut may underlie this increased risk, as well as the composition of chemicals found in the gut. To increase our understanding of the involvement of gut bacteria and chemicals in colorectal cancer we performed a study in which we made mice obese by feeding a high fat diet or by the introduction of a genetic change that causes obesity. The profile of gut bacteria and chemicals from these mice were compared to that of lean low fat fed mice. In addition all mice possessed a mutation that causes intestinal tumors to form. Dozens of differences were observed in each comparison. A specific bacterial species named Parabacteroides distasonis was lower in mice bearing tumors and its decrease was associated with an increase in markers of inflammation in the colon. In addition a specific chemical in the stool called adenosine was lower in obese and in tumor bearing mice its decrease was also associated with an increase in markers of inflammation in the colon. Others have these two entities to be anti-inflammatory in the gut. We speculate that the depletion of these two entities is permissive to the development of inflammation in the gut and may thereby elevate the risk for tumor formation in the gut.

Technical Abstract: Obesity is a risk factor for colorectal cancer (CRC), and alterations in the colonic microbiome and metabolome may be mechanistically involved in this relationship. The relative contribution of diet and obesity per se are unclear. We compared the effect of diet- and genetically-induced obesity on the intestinal microbiome and metabolome in a mouse model of CRC. Apc1638N mice were made obese by either high fat (HF) feeding or the presence of the Leprdb/db (DbDb) mutation. Intestinal tumors were quantified and stool microbiome and metabolome were profiled. Genetic obesity, and to a lesser extent HF feeding, promoted intestinal tumorigenesis. Each induced distinct microbial patterns: taxa enriched in HF were mostly Firmicutes (6of 8) while those enriched in DbDb were split between Firmicutes (7 of 12) and Proteobacteria (5 of 12). Parabecteroides distasonis was lower in tumor-bearing mice and its abundance was inversely associated with colonic Il1b production (p<0.05). HF and genetic obesity altered the abundance of 49 and 40 fecal metabolites respectively, with 5 in common. Of these 5, adenosine was also lower in obese and in tumor-bearing mice (p<0.05) and its concentration was inversely associated with colonic Il1b and Tnf production (p<0.05). HF and genetic obesity differentially alter the intestinal microbiome and metabolome. A depletion of adenosine and P.distasonis in tumorbearing mice could play a mechanistic role in tumor formation. Adenosine and P. distasonis have previously been shown to be anti-inflammatory in the colon and we postulate their reduction could promote tumorigenesis by de-repressing inflammation.