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

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1104 ◽  
Author(s):  
Dolores Ortiz-Masiá ◽  
Laura Gisbert-Ferrándiz ◽  
Cristina Bauset ◽  
Sandra Coll ◽  
Céline Mamie ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Epithelial Cells ◽  
Wnt Signaling ◽  
Intestinal Inflammation ◽  
Intestinal Epithelial Cells ◽  
Fistula Tract ◽  
Intestinal Epithelial ◽  
Mesenchymal Transition ◽  
Ht29 Cells

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.

scholarly journals Herbs-Partitioned Moxibustion Combined with Acupuncture Inhibits TGF-β1-Smad-Snail-Induced Intestinal Epithelial Mesenchymal Transition in Crohn’s Disease Model Rats

2019 ◽  
Vol 2019 ◽  
pp. 1-9
Author(s):  
Yin Shi ◽  
Tao Li ◽  
Jing Zhou ◽  
Yuwei Li ◽  
Liu Chen ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Epithelial Cells ◽  
Epithelial Mesenchymal Transition ◽  
Intestinal Epithelial Cells ◽  
Mrna Levels ◽  
Intestinal Epithelial ◽  
Cell Marker ◽  
Mesenchymal Transition ◽  
Intestinal Fibrosis

Crohn’s disease may cause excessive damage and repair in the intestinal epithelium due to its chronic relapsing intestinal inflammation. These factors may initiate the TGF-β 1-Smad pathway to activate the transcription factor of Snail, and the Snail-mediated pathway promotes the transformation of intestinal epithelial cells to mesenchymal cells, leading to intestinal fibrosis. Acupuncture and moxibustion have been demonstrated to prevent intestinal fibrosis in Crohn’s disease. However, it is not clear whether acupuncture and moxibustion can inhibit intestinal epithelial mesenchymal transformation in Crohn’s disease by affecting the TGF-β 1-Smad-Snail pathway. This study indicated that abnormal increased expressions of TGFβ1, TβR2, Smad3, and Snail were significantly downregulated by herbs-partitioned moxibustion at Tianshu (ST25) and Qihai (RN6) and acupuncture at Zusanli (ST36) and Shangjuxu (ST37). In addition, protein and mRNA levels of E-cadherin, the epithelial cell marker, were significantly increased. Protein and mRNA levels of fibronectin, the mesenchymal cell marker, were decreased in the intestinal tissue. Moreover, the number of mesenchymal cells in the intestinal mucosa can be reversely transformed to intestinal epithelial cells. Therefore, herbs-partitioned moxibustion combined with acupuncture can prevent intestinal epithelial mesenchymal transition by inhibiting abnormal expression of TGFβ1, TβR2, Smad3, and Snail in the TGF-β1-Smad-Snail pathway in Crohn’s disease.

scholarly journals The Oxidoreductase DsbA Plays a Key Role in the Ability of the Crohn's Disease-Associated Adherent-Invasive Escherichia coli Strain LF82 To Resist Macrophage Killing

2007 ◽  
Vol 189 (13) ◽  
pp. 4860-4871 ◽  
Author(s):  
Marie-Agnès Bringer ◽  
Nathalie Rolhion ◽  
Anne-Lise Glasser ◽  
Arlette Darfeuille-Michaud
Keyword(s):  
Escherichia Coli ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Epithelial Cells ◽  
Intestinal Epithelial Cells ◽  
Coli Strain ◽  
Intestinal Epithelial ◽  
Type 1 Pili ◽  
K 12

ABSTRACT Adherent-invasive Escherichia coli (AIEC) isolated from Crohn's disease patients is able to adhere to and invade intestinal epithelial cells and to replicate in mature phagolysosomes within macrophages. Here, we show that the dsbA gene, encoding a periplasmic oxidoreductase, was required for AIEC strain LF82 to adhere to intestinal epithelial cells and to survive within macrophages. The LF82-ΔdsbA mutant did not express flagella and, probably as a consequence of this, did not express type 1 pili. The role of DsbA in adhesion is restricted to the loss of flagella and type 1 pili, as forced contact between bacteria and cells and induced expression of type 1 pili restored the wild-type phenotype. In contrast, the dsbA gene is essential for AIEC LF82 bacteria to survive within macrophages, irrespective of the loss of flagella and type 1 pilus expression, and the survival ability of LF82-ΔdsbA was as low as that of the nonpathogenic E. coli K-12, which was efficiently killed by macrophages. We also provide evidence that the dsbA gene is needed for LF82 bacteria to grow and survive in an acidic and nutrient-poor medium that partly mimics the harsh environment of the phagocytic vacuole. In addition, under such stress conditions dsbA transcription is highly up-regulated. Finally, the CpxRA signaling pathway does not play a role in regulation of dsbA expression in AIEC LF82 bacteria under conditions similar to those of mature phagolysosomes.

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