Divalent metal-ion transporter 1 is decreased in intestinal epithelial cells and contributes to the anemia in inflammatory bowel disease.

Wei Wu,Chong He,Yingzi Cong,Ruijin Wu,Changqin Liu,Zhanju Liu,Yinglei Miao,Yang Song,Leilei Fang

doi:10.1038/srep16344

Abstract

Divalent metal-ion transporter 1 (DMT1) has been found to play an important role in the iron metabolism and hemogenesis. However, little is known about the potential role of DMT1 in the pathogenesis of anemia from patients with inflammatory bowel disease (IBD). Herein, we investigated expression of DMT1 in the intestinal mucosa by quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry, and found that DMT1 was significantly decreased in the inflamed mucosa of active IBD patients compared with that in those patients at remission stage and healthy controls. To further study the mechanism, we cultured HCT 116 cell line in vitro. Expression of DMT1 in HCT116 was demonstrated to be markedly decreased under stimulation with TNF for 24 and 48 h, while JNK inhibitor (JNK-IN-7) could significantly reverse the decrease. Interestingly, anti-TNF therapy successfully improved anemia in clinical responsive Crohn’s disease patients, and DMT1 was found to be markedly up-regulated in intestinal mucosa. Taken together, our studies demonstrate that decreased expression of DMT1 in intestinal mucosa leads to compromised absorption and transportation of iron and that blockade of TNF could rescue anemia and promote DMT1 expression in gut mucosa. This work provides a therapeutic approach in the management of anemia in IBD.

Highlights

Iron absorption occurs in the upper digestive tract through intestinal epithelial cells or enterocytes[12]
Different pathogenic mechanisms have been reported to be involved in the cause of anemia in inflammatory bowel disease (IBD), including anemia of chronic disease, iron deficiency, chronic intestinal blood loss, vitamin B12 and folic acid[27]
We first determined the level of Hb was decreased in Chinese IBD patients, and found that there was a significantly negative relationship between C-reactive protein (CRP) and Hb, Crohn’s disease activity index (CDAI) or UCAI and Hb in patients with Crohn’s disease (CD) and ulcerative colitis (UC)

Summary

Introduction

Iron absorption occurs in the upper digestive tract through intestinal epithelial cells or enterocytes[12]. DMT1, named as SLC11A2, divalent cation transporter[1] (DCT1), and Nramp[2], is the main iron uptake transporter which mediates the transport of ferrous iron across the brush border membrane of intestinal epithelial cells[14], and functions as the main iron uptake transporter[15]. Another transporter protein heme carrier protein 1 (HCP1) which enables transmembrane transport of haem molecules into enterocytes is involved in iron absorption[16]. Our study provides evidence that DMT1 is the critical protein involved in the pathogenesis of anemia of IBD patients and may serve as a potential therapeutic target in the treatment of anemia in IBD

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Results

Conclusion