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International audience; The etiology of inflammatory bowel diseases remains largely unknown. We previously demonstrated that the expression of the peroxisome proliferator activated receptor-gamma (PPARγ) is downregulated in colonic epithelial cells of patients with ulcerative colitis (UC). PPARγ is a nuclear receptor that modulates inflammation. We hypothesized that its deficiency may play a role in the loss of intestinal homeostasis through the control of immunomodulatory factors. We found that thymic stromal lymphopoietin (TSLP), an epithelial cytokine with pleiotropic functions, is regulated by PPARγ. While this cytokine possesses two isoforms, only the short form (sfTSLP) was regulated by PPARγ. sfTSLP mRNA expression was decreased both in PPARγ knock-down Caco2 cells and cells treated with PPARγ antagonist, whereas PPARγ agonists induced the expression of sfTSLP in Caco2 and T-84 cells. The response element activated by PPARγ was identified in the promoter of the sfTSLP gene by chromatin immunoprecipitation and gene reporter assays. The expression of sfTSLP was significantly decreased in the colonic mucosa of UC patients compared to controls and was correlated with PPARγ expression. Our results identified sfTSLP as a new PPARγ-target gene and support the hypothesis that, in UC, PPARγ deficiency in colonic mucosa could play a role in the loss of intestinal tolerance through an impaired sfTSLP expression.

Lactase (LCT) deficiency affects approximately 75% of the world's adult population and may lead to lactose malabsorption and intolerance. Currently, the regulation of LCT gene expression remains poorly known. Peroxisome proliferator activator receptor gamma (PPAR gamma) is a key player in carbohydrate metabolism. While the intestine is essential for carbohydrate digestion and absorption, the role of PPAR gamma in enterocyte metabolic functions has been poorly investigated. This study aims at characterizing PPAR gamma target genes involved in intestinal metabolic functions. In microarray analysis, the LCT gene was the most upregulated by PPAR gamma agonists in Caco-2 cells. We confirmed that PPAR gamma agonists were able to increase the expression and activity of LCT both in vitro and in vivo in the proximal small bowel of rodents. The functional response element activated by PPAR gamma was identified in the promoter of the human LCT gene. PPAR gamma modulation was able to improve symptoms induced by lactose-enriched diet in weaned rats. Our results demonstrate that PPAR gamma regulates LCT expression, and suggest that modulating intestinal PPAR gamma activity might constitute a new therapeutic strategy for lactose malabsorption.

S. Speca, M. Body-Malapel, C. Fradin, M. Djouina, E. Boulanger, AM. Schmidt, P. Desreumaux and C. Vignal Background: Our aim was to determine the role of RAGE in intestinal fibrogenesis. Methods: Fibrosis was induced in WT and RAGE-/- mice by administration of dextran sulfate sodium. The colon was scored for macroscopic lesions and subject to Hematoxylin/Eosin staining, to assess the degree of inflammation, and Picrosirius red for collagen deposition. mRNA expression of the profibrotic mediator, Tgf-β1, and ECM components, collagen types I-III (Col1A1 gene) and fibronectin (FN-1 gene), were evaluated by RT-qPCR. Results: Compared to WT mice, DSS-treated RAGE-/- mice showed a significant decrease in colon weight/length ratio, and macroscopic and microscopic scores. Tgf-β1, Col1A1 and FN-1 mRNA expressions were significantly increased by the DSS administration in WT mice colon, whereas it was unchanged in RAGE-/- mice. Conclusion: This study represents a first insight into the involvement of RAGE in intestinal fibrosis in mice. The potential profibrotic role of RAGE could shed light into the complex and dynamic fibrogenic processes and pave the way for new anti-fibrotic agents., Journal of International Society of Antioxidants in Nutrition & Health, Vol 3, No 2 (2016): Journal of ISANH Volume 3: Special Issue for Maillard Reaction & Glycation

Intestinal fibrosis is a progressive process characterized by de novo synthesis and uncontrolled deposition of extracellular matrix components (ECM) following a tissue chronic inflammation mainly regulated by Transforming Growth Factor (TGF)β/ Smads pathway. Frequently associated to Inflammatory Bowel Disease (IBD), intestinal fibrosis may lead to stenosis and obstructions that require surgery up to 75% of patients as drugs currently used in IBD are unable to improve fibrostenosis lesions (1). Peroxisome proliferator-activated receptor (PPAR)-γ is able to antagonize (TGF) β/Smads and could be an crucial target to develop novel antifibrotic therapeutic strategies (2). Aim of this study is to evaluate the antifibrotic action of a novel PPARγ agonist, GED 0507-34 levo, in colonic fibrosis in mice. Immunohistochemistry and immunoblotting evaluations, TGFβ1, CTGF, Collagen types I-III, Smad3, α-SMA, were performed in in three groups of C57BL/6 mice: Dextran Sulphate Sodium (DSS) colitis group, DSS+GED group and controls. Evident macroscopic and microscopic lesions in the most of colons of DSS treated mice were observed compared to DSS+GED mice and controls. The tissue levels of the main markers of fibrosis resulted significantly increased in DSS mice and restored by administration of GED. GED seems to prevents ECM colonic deposition and to improve the intestinal fibrotic lesions by its ability in controlling TGFβ/Smads pathway signalling activation., Italian Journal of Anatomy and Embryology, Vol 119, No 1 (Supplement) 2014

Intestinal fibrosis is a common complication of inflammatory bowel disease (IBD) in which chronic inflammation leads to abnormal deposition of extracellular matrix components (ECM) causing obstruction and loss of function of the intestinal tract involved (1). Fibrogenesis is mainly regulates by trasforming growth factor (TGF) β/Smad pathway and a key antagonist of this signaling is represented by peroxisome proliferator-activated receptor (PPAR)-γ. As the anti-inflammatory drugs currently used in IBD are unable to improve intestinal fibrosis the exploration of new therapeutical approaches has now became crucial (2). Aim of this study is to evaluate the antifibrotic action of a novel PPARγ agonist, GED-0507-34-LEVO (GED), in colon fibrosis in mice. Chronic colitis and fibrosis were induced in C57BL/6 mice by administration of 2,5% (w/v) dextrane sulphate sodium (DSS) in drinking water for 5 days followed by 7 days of water for 3 cycles. Mice were divided into 3 groups: DSS, DSS+GED and control. 30mg/Kg/mice of GED was daily administrated by oral gavage starting from the second DSS cycle. Samples from colon were excised and processed to assess macroscopic lesions, histological and morphometrical aspects and immunohistochemical and immunoblotting analysis for TGFβ1, CTGF, collagen types I-III, Smad3,α-SMA. Evident shortening and dilation in the most of colons of DSS treated mice were observed. Macroscopic and microscopic findings were significantly improved in DSS mice+GED compared with control mice. The tissue levels of collagen and α-SMA, specific markers of fibrosis, resulted significantly increased in mice receving DSS compared to control mice, as well as the expression of TGFβ1, CTGF, Smad3. DSS+GED group showed reduced expression of all markers involved. GED significantly improves the intestinal fibrotic lesions in DSS chronic colitis murine model and controls the pivotal molecular events leading to fibrosis., Italian Journal of Anatomy and Embryology, Vol 118, No 2 (Supplement) 2013