Succinate Activates EMT in Intestinal Epithelial Cells through SUCNR1: A Novel Protagonist in Fistula Development

Abstract

The pathogenesis of Crohn’s disease-associated fibrostenosis and fistulas imply the epithelial-to-mesenchymal transition (EMT) process. As succinate and its receptor (SUCNR1) are involved in intestinal inflammation and fibrosis, we investigated their relevance in EMT and Crohn’s disease (CD) fistulas. Succinate levels and SUCNR1-expression were analyzed in intestinal resections from non-Inflammatory Bowel Disease (non-IBD) subjects and CD patients with stenosing-B2 or penetrating-B3 complications and in a murine heterotopic-transplant model of intestinal fibrosis. EMT, as increased expression of Snail1, Snail2 and vimentin and reduction in E-cadherin, was analyzed in tissues and succinate-treated HT29 cells. The role played by SUCNR1 was studied by silencing its gene. Succinate levels and SUCNR1 expression are increased in B3-CD patients and correlate with EMT markers. SUCNR1 is detected in transitional cells lining the fistula tract and in surrounding mesenchymal cells. Grafts from wild type (WT) mice present increased succinate levels, SUCNR1 up-regulation and EMT activation, effects not observed in SUCNR1−/− tissues. SUCNR1 activation induces the expression of Wnt ligands, activates WNT signaling and induces a WNT-mediated EMT in HT29 cells. In conclusion, succinate and its receptor are up-regulated around CD-fistulas and activate Wnt signaling and EMT in intestinal epithelial cells. These results point to SUCNR1 as a novel pharmacological target for fistula prevention.

Vitamin D receptor inhibits EMT via regulation of the epithelial mitochondrial function in intestinal fibrosis

“…We evaluated the effects of the VDR gene on the human intestinal epithelial tumor cell line HT29 by establishing a well-characterized model of TGF-β1-induced EMT ( 27 , 28 ). In HT29 cells, knockdown of VDR expression decreased epithelial integrity ( Fig.…”

Metabolomics as a Promising Resource Identifying Potential Biomarkers for Inflammatory Bowel Disease

“…In the first study, the authors reported a significant increase in succinate in CD patients compared with control subjects [17]. In addition, in a second study, the same authors expanded their observations, and they have recently reported that succinate levels are even increased in CD patients with a penetrating behaviour (B3-CD patients) compared with CD patients with a stricturing behaviour (B2-CD patients) [18]. This difference in one TCA cycle intermediate reveals the importance of studying the metabolomic patterns specifically in intestinal resections of IBD patients.…”

Succinate Pathway in Head and Neck Squamous Cell Carcinoma: Potential as a Diagnostic and Prognostic Marker

“…Remarkably, it has become evident over the last decade that succinate also functions as an extracellular signaling metabolite via engagement with its cognate receptor succinate receptor 1, SUCNR1 (also known as GPR91). While its role in cancer has been poorly studied, SUCNR1 has been proposed as a tumor driver, as succinate-SUCNR1 signaling has been related to epithelial-to-mesenchymal transition [ 14 ], angiogenesis [ 15 ] and tumor-associated macrophage polarization [ 16 ]. Moreover, SUCNR1 expression seems to be closely related to immune status in ovarian cancer [ 17 ].…”