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Title: Incremental elevations of TNF-alpha and IL-6 in the human colon and procancerous changes in the mucosal transcriptome accompany adiposity

Author
item PFALZER, ANNA - Vanderbilt University
item LEUNG, KEITH - 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
item KIM, SUSIE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item TAI, ALBERT - Tufts University
item Parnell, Laurence
item KAMANU, FREDERICK - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item LIU, ZHENHUA - University Of Massachusetts
item ROGERS, GAIL - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item SHEA, KYLA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item GARCIA, PALOMA - University Of Michigan
item MASON, JOEL - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Cancer Epidemiology Biomarkers and Prevention
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/16/2018
Publication Date: 10/5/2018
Citation: Pfalzer, A.C., Leung, K., Crott, J.W., Kim, S.J., Tai, A.K., Parnell, L.D., Kamanu, F.K., Liu, Z., Rogers, G., Shea, K., Garcia, P.E., Mason, J.B. 2018. Incremental elevations of TNF-alpha and IL-6 in the human colon and procancerous changes in the mucosal transcriptome accompany adiposity. Cancer Epidemiology Biomarkers and Prevention. https://doi.org/10.1158/1055-9965.EPI-18-0121.
DOI: https://doi.org/10.1158/1055-9965.EPI-18-0121

Interpretive Summary: Those who are overweight or obese are at substantially higher risk of developing colorectal cancer. It is postulated that some of the bodily chemicals that mediate inflammation (i.e. cytokines,) which are known to be elevated in the blood in obese individuals, might also be increased in the colon and be responsible in part for the increase in cancer risk. This study examined the concentrations of several cytokines in the blood and colonic lining of 16 lean and 26 obese individuals undergoing routine colonoscopy screenings. In addition, differences between the two groups in the expression of genes in the colon were determined. Blood levels of two cytokines, IL-6 and TNF-alpha, were 1.4- to 3-fold elevated in moderately-to-severe obese subjects compared to the lean controls, and colonic concentrations of IL-6 and TNF-alpha were two-fold greater than in lean subjects. Colonic IL-6 and TNF-alpha concentrations increased incrementally over the entire range of body mass indices (BMIs) examined, and regular use of aspirin-type drugs was associated with a reduction in colonic IL-6. Gene expression profiling identified 182 differentially expressed genes. The changes in gene expression in the obese subjects were indicative of activation of two cell signaling networks that were pro-cancerous in nature. Conclusions: The concentrations of two major pro-inflammatory cytokines rise incrementally in the colon with increasing BMI, and in the obese state are accompanied by several changes in the colonic gene expression profile that are pro-cancerous in nature.

Technical Abstract: Background: Excess adiposity increases the risk of colorectal cancer. Objective: Elevations in proinflammatory mediators in the colon might accompany obesity and act mechanistically but objective evidence in humans is lacking. We sought to obtain such evidence. Design: Using a cross-sectional design, concentrations of TNF-alpha, IL-1beta, IL-6 and IFNgamma in blood and colonic mucosa of 16 lean and 26 obese individuals undergoing routine screening colonoscopy were examined and, utilizing RNA-sequencing, differences in the mucosal transcriptome between the two groups were defined. Results: Plasma IL-6 and TNF-alpha were 1.4- to 3-fold elevated in obese subjects (body mass index [BMI] >/=34 kg/m2) compared to the lean controls (p<0.01). Among individuals with BMI >/=34 kg/m2 colonic concentrations of IL-6 and TNF-alpha were two-fold greater than in lean subjects (p<0.03). In a general linear model, adjusted for non-steroidal anti- inflammatory drug (NSAID) use, colonic IL-6 (partial r=0.41; p<0.01) and TNF-alpha (partial r=0.41; p=0.01) concentrations increased incrementally over the entire range of BMIs examined (18.1-45.7), and regular use of NSAIDs was associated with a reduction in colonic IL-6 by a constant amount over this range of BMIs (beta= -0.65, p<0.02). RNA-sequencing (users of NSAIDs excluded) identified 182 differentially expressed genes. The two biologic networks most strongly linked to the observed changes in expression included several differentially expressed genes known to regulate the pro-carcinogenic signaling pathways, NFkappaB and ERK, and the altered patterns of expression were consistent with the upregulation of each in the obese subjects. Conclusions: The concentrations of two major pro-inflammatory cytokines rise incrementally in the colon with increasing BMI, and in the obese state are accompanied by several changes in the colonic gene expression profile that are pro-cancerous in nature.