The intestinal epithelial monolayer pays a crucial role not only in regulating transcellular and paracellular nutrient absorption, but also by providing an innate barrier against pathogenic and commensal bacteria and microbial and dietary antigens. Breakdown of this protective barrier has been implicated in the pathogenesis of acute illnesses such as bacterial translocation leading to sepsis and multiple organ system failure. It also has been implicated in several chronic diseases having their origins during infancy that manifest in later life. These include atopic disease such eczema, food allergies, celiac enteropathy, type 1 diabetes, asthma, and inflammatory bowel disease. Important inducers of intestinal barrier dysfunctions include proinflammatory cytokines (with IFN-? as a prototypical barrier-damaging cytokine) and infiltrating and translocating neutrophils and their enzymatic products. Chronic and severe neutrophil infiltration, transepithelial migration and enzymatic and oxidative damages of the epithelium and the extracellular matrix, significantly contribute to the impairment of the epithelial barrier. In a number of inflammatory human diseases, including ischemic bowel injury, necrotizing enterocolitis, and idiopathic inflammatory bowel disease, intense neutrophil transepithelial migration is a prevalent feature and correlates with disease pathophysiology. In this proposal, we hypothesize that curcumin improves intestinal barrier through inhibition of IFN-? signaling in the CEC, inhibition of neutrophil recruitment and apical retention, and thorough inhibition of the detrimental effects of neutrophils on the barrier function during transmigration. These effects likely underlie the demonstrated protective effects of curcumin in intestinal inflammation, as demonstrated in animal models of colitis and in the clinical trial with ulcerative colitis patients. We propose to address these newly attributed functions of curcumin in three specific aims tailored to (1) identify the molecular mechanism of the inhibitory effects of curcumin on IFN-? signaling in the colonocytes;(2) identify the molecular mechanisms of inhibitory effects of curcumin on neutrophil chemokinesis and chemotaxis;and (3) to characterize the molecular mechanisms of the protective effects of curcumin on neutrophil-induced epithelial dysfunction. In summary, the proposed project will provide novel information about the mechanisms and molecular targets of curcumin in improving the intestinal barrier function.

Public Health Relevance

This proposal is focused on a clinically relevant aspect of numerous intestinal and extraintestinal disorders initiated or exacerbated by a dysfunction or failure of the intestinal epithelial barrier. Nutritional interventions, such as with the described natural compound, curcumin, hold promise as effective supplemental therapy which may lead to improvement of symptoms, decreased relapse rate in chronic inflammatory conditions, and overall provide easily tolerated and inexpensive means of improving life quality in patients with recurring inflammatory conditions of the bowel.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK067286-08
Application #
8278041
Study Section
Special Emphasis Panel (ZRG1-DKUS-C (04))
Program Officer
Hamilton, Frank A
Project Start
2003-11-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
8
Fiscal Year
2012
Total Cost
$298,778
Indirect Cost
$100,778
Name
University of Arizona
Department
Pediatrics
Type
Schools of Medicine
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Radhakrishnan, Vijayababu M; Kojs, Pawel; Young, Gavin et al. (2014) pTyr421 cortactin is overexpressed in colon cancer and is dephosphorylated by curcumin: involvement of non-receptor type 1 protein tyrosine phosphatase (PTPN1). PLoS One 9:e85796
Midura-Kiela, Monica T; Radhakrishnan, Vijayababu M; Larmonier, Claire B et al. (2012) Curcumin inhibits interferon-? signaling in colonic epithelial cells. Am J Physiol Gastrointest Liver Physiol 302:G85-96
Borbon, Ivan A; Hillman, Zach; Duran Jr, Ernesto et al. (2012) Lack of efficacy of curcumin on neurodegeneration in the mouse model of Niemann-Pick C1. Pharmacol Biochem Behav 101:125-31
Ghishan, Fayez K; Kiela, Pawel R (2012) Small intestinal ion transport. Curr Opin Gastroenterol 28:130-4
Larmonier, C B; Midura-Kiela, M T; Ramalingam, R et al. (2011) Modulation of neutrophil motility by curcumin: implications for inflammatory bowel disease. Inflamm Bowel Dis 17:503-15
Ghishan, Fayez K; Kiela, Pawel R (2011) From probiotics to therapeutics: another step forward? J Clin Invest 121:2149-52
Kiela, Pawel R (2010) Unraveling the pathophysiology of alcohol-induced thiamin deficiency. Am J Physiol Renal Physiol 299:F26-7
Thurston, Robert D; Larmonier, Claire B; Majewski, Pawel M et al. (2010) Tumor necrosis factor and interferon-gamma down-regulate Klotho in mice with colitis. Gastroenterology 138:1384-94, 1394.e1-2
Larmonier, C B; Uno, J K; Lee, Kang-Moon et al. (2008) Limited effects of dietary curcumin on Th-1 driven colitis in IL-10 deficient mice suggest an IL-10-dependent mechanism of protection. Am J Physiol Gastrointest Liver Physiol 295:G1079-91
Billerey-Larmonier, Claire; Uno, Jennifer K; Larmonier, Nicolas et al. (2008) Protective effects of dietary curcumin in mouse model of chemically induced colitis are strain dependent. Inflamm Bowel Dis 14:780-93

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