title: A food-based approach that targets interleukin-6, a key regulator of chronic intestinal inflammation and colon carcinogenesis.
abstract: Studies have shown a causal link between high-calorie diet (HCD) and colon cancer. However, molecular mechanisms are not fully elucidated. To understand etiology of HCD-induced colon carcinogenesis, we screened 10 pathways linked to elevated colonic cell proliferation and chronic inflammation in an HCD-consuming human-relevant pig model. We observed elevated colonic mucosal interleukin-6 (IL-6) expression in HCD-consuming pigs compared to standard diet controls (SD, P=.04), and IL-6 strongly correlated with Ki-67 proliferative index and zone, early biomarkers of colon cancer risk (r=0.604 and 0.743 and P=.017 and .002, respectively). Liquid chromatography-tandem mass spectrometry-based proteomic analysis and Ingenuity Pathway Analysis showed that HCD consumption altered IL-6 signaling pathway proteins (PI3KR4, IL-1α, Mapk10, Akt3, PIK3CG, PIK3R5, Map2k2). Furthermore, these proteins also correlated with Ki-67 proliferative index/zone. Anti-IL-6 therapeutics are available for treating colon cancer; however, they are expensive and induce negative side effects. Thus, whole foods could be a better way to combat low-grade chronic colonic inflammation and colon cancer. Whole plant foods have been shown to decrease chronic diseases due to the potential of anti-inflammatory dietary compounds acting synergistically. We observed that supplementation of HCD with anthocyanin-containing purple-fleshed potatoes (10% w/w), even after baking, suppressed HCD-induced IL-6 expression (P=.03) and the IL-6-related proteins IL-1α and Map2k1 (P≤.1). Our results highlight the importance of IL-6 signaling in diet-linked induction/prevention of colonic inflammation/cancer and demonstrate the potential of a food-based approach to target IL-6 signaling.
authors.affiliation: Department of Food Science, The Pennsylvania State University, University Park, PA, USA.
authors.forename: Abigail
authors.initials: A
authors.lastname: Sido
authors.affiliation: Department of Food Science, The Pennsylvania State University, University Park, PA, USA.
authors.forename: Sridhar
authors.initials: S
authors.lastname: Radhakrishnan
authors.affiliation: Department of Animal Science, North Carolina State University, Raleigh, North Carolina, USA.
authors.forename: Sung Woo
authors.initials: SW
authors.lastname: Kim
authors.affiliation: Department of Biotechnology, Lund University, Lund, Sweden.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Eriksson
authors.affiliation: Department of Statistics, The Pennsylvania State University, University Park, PA, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Shen
authors.affiliation: Agilent Technologies, Wilmington, DE, USA.
authors.forename: Qunhua
authors.initials: Q
authors.lastname: Li
authors.affiliation: Agilent Technologies, Wilmington, DE, USA.
authors.forename: Vadiraja
authors.initials: V
authors.lastname: Bhat
authors.affiliation: Department of Plant Science, The Pennsylvania State University, University Park, PA, USA.
authors.forename: Lavanya
authors.initials: L
authors.lastname: Reddivari
authors.affiliation: Department of Food Science, The Pennsylvania State University, University Park, PA, USA; The Pennsylvania State University Milton S. Hershey College of Medicine, Hershey, PA, USA; Center for Molecular Immunology and Infectious Diseases, The Pennsylvania State University, University Park, PA, USA. Electronic address: juv4@psu.edu.
authors.forename: Jairam K P
authors.initials: JKP
authors.lastname: Vanamala
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D049109:Cell Proliferation; D003092:Colitis / Q000178:diet therapy* / Q000209:etiology* / Q000473:pathology; D003106:Colon / Q000473:pathology; D004032:Diet / Q000009:adverse effects; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000378:metabolism; D008297:Male; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D011198:Solanum tuberosum; D013552:Swine
chemical_list: D015415:Biomarkers; D015850:Interleukin-6; D051057:Proto-Oncogene Proteins c-akt; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2
keywords: Colon cancer; Colonic inflammation; High-calorie diet; Interleukin-6; Pig model; Purple-fleshed potatoes