Department of Physiology and Biophysics, University of California, Irvine, California.
Department of Medicine, University of California, Irvine, California.
Am J Physiol Cell Physiol. 2022 Dec 1;323(6):C1664-C1680. doi: 10.1152/ajpcell.00458.2022. Epub 2022 Nov 7.
The aim of this study was to examine the effect of TNFα (i.e., a predominant proinflammatory cytokine produced during chronic gut inflammation) on colonic uptake of thiamin pyrophosphate (TPP) and free thiamin, forms of vitamin B1 that are produced by the gut microbiota and are absorbed via distinct carrier-mediated systems. We utilized human-derived colonic epithelial CCD841 and NCM460 cells, human differentiated colonoid monolayers, and mouse intact colonic tissue preparations together with an array of cellular/molecular approaches in our investigation. The results showed that exposure of colonic epithelial cells to TNFα leads to a significant inhibition in TPP and free thiamin uptake. This inhibition was associated with: ) a significant suppression in the level of expression of the colonic TPP transporter (cTPPT; encoded by ), as well as thiamin transporters-1 & 2 (THTR-1 & -2; encoded by & , respectively); ) marked inhibition in activity of the , , and promoters; and ) significant suppression in level of expression of nuclear factors that are needed for activity of these promoters (i.e., CREB-1, Elf-3, NF-1A, SP-1). Furthermore, the inhibitory effects were found to be mediated via JNK and ERK1/2 signaling pathways. We also examined the level of expression of cTPPT and THTR-1 & -2 in colonic tissues of patients with active ulcerative colitis and found the levels to be significantly lower than in healthy controls. These findings demonstrate that exposure of colonocytes to TNFα suppresses TPP and free thiamin uptake at the transcriptional level via JNK- and Erk1/2-mediated pathways.
本研究旨在探讨 TNFα（一种在慢性肠道炎症期间产生的主要促炎细胞因子）对肠道摄取焦磷酸硫胺素（TPP）和游离硫胺素的影响，TPP 和游离硫胺素是肠道微生物群产生的维生素 B1 形式，通过不同的载体介导系统吸收。我们利用人源结肠上皮 CCD841 和 NCM460 细胞、人分化结肠类器官单层和完整的小鼠结肠组织准备，以及一系列细胞/分子方法进行研究。结果表明，TNFα 暴露导致 TPP 和游离硫胺素摄取显著抑制。这种抑制与：）结肠 TPP 转运蛋白（cTPPT；由 编码）以及硫胺素转运蛋白-1 和 -2（THTR-1 和 -2；分别由 和 编码）的表达水平显著下调有关；）、和 启动子的活性显著抑制；以及）这些启动子所需的核因子表达水平显著下调（即 CREB-1、Elf-3、NF-1A、SP-1）。此外，发现抑制作用是通过 JNK 和 ERK1/2 信号通路介导的。我们还检查了活性溃疡性结肠炎患者结肠组织中 cTPPT 和 THTR-1 和 -2 的表达水平，发现其水平明显低于健康对照组。这些发现表明，结肠细胞暴露于 TNFα 会通过 JNK-和 Erk1/2 介导的途径在转录水平上抑制 TPP 和游离硫胺素的摄取。
