Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology, Trondheim, Norway.
Department of Gastroenterology and Hepatology, St. Olav's University Hospital, Trondheim, Norway.
Am J Physiol Gastrointest Liver Physiol. 2020 Dec 1;319(6):G761-G768. doi: 10.1152/ajpgi.00244.2020. Epub 2020 Sep 23.
Serotonin is a highly conserved and ubiquitous signaling molecule involved in a vast variety of biological processes. A majority of serotonin is produced in the gastrointestinal epithelium, where it is suggested to act as a prominent regulatory molecule in the inflammatory bowel diseases (IBDs) Crohn's disease (CD) and ulcerative colitis (UC). Extracellular and circulating serotonin levels are thought to be elevated during intestinal inflammation, but the underlying mechanisms have been poorly understood. The data on human material are limited, contradictory, and in need of further investigation and substantiating. In this study, we show a potent and significant downregulation of the dominant serotonin reuptake transporter (SERT) mRNA () in the epithelium from active CD ileitis, CD colitis, and UC colitis, compared with healthy controls. The mRNA of tryptophan hydroxylase 1, the rate-limiting enzyme in serotonin synthesis, was unregulated. Immunohistochemistry showed expression of the SERT protein in both the epithelium and the lamina propria and localized the downregulation to the epithelial monolayer. Laser capture microdissection followed by RNA sequencing confirmed downregulation of in the epithelial monolayer during intestinal inflammation. Patient-derived colon epithelial cell lines (colonoids) incubated with the proinflammatory cytokine tumor necrosis factor alpha (TNF-α) reduced SERT expression. In summary, these results show that intestinal inflammation potently reduces the expression of SERT in both CD and UC and that TNF-α alone is sufficient to induce a similar reduction in colonoids. The reduced serotonin reuptake capacity may contribute to the increased interstitial serotonin level associated with intestinal inflammation. The serotonin reuptake transporter is potently reduced in inflamed areas of Crohn's ileitis, Crohn's colitis, and ulcerative colitis. The changes are localized to the intestinal epithelium and can be induced by TNF-α. The serotonin synthesis through tryptophan hydroxylase 1 is unchanged. This regulation is suggested as a mechanism underlying the increased extracellular serotonin levels associated with intestinal inflammation.
血清素是一种高度保守且普遍存在的信号分子，参与了广泛的生物学过程。大多数血清素是在胃肠道上皮细胞中产生的，在那里它被认为是炎症性肠病（IBD）中克罗恩病（CD）和溃疡性结肠炎（UC）的主要调节分子。细胞外和循环中的血清素水平被认为在肠道炎症期间升高，但潜在机制尚未得到很好的理解。关于人类材料的数据有限，相互矛盾，需要进一步调查和证实。在这项研究中，我们显示了在活动性 CD 回肠炎、CD 结肠炎和 UC 结肠炎的上皮细胞中，主要的血清素再摄取转运体（SERT）mRNA （）显著下调，与健康对照组相比。血清素合成限速酶色氨酸羟化酶 1 的 mRNA 未受调节。免疫组织化学显示 SERT 蛋白在上皮细胞和固有层中均有表达，并将下调定位于上皮单层。激光捕获显微切割结合 RNA 测序证实，在肠道炎症期间，上皮单层中的下调。用促炎细胞因子肿瘤坏死因子-α（TNF-α）孵育的患者来源的结肠上皮细胞系（类器官）降低了 SERT 表达。总之，这些结果表明，肠道炎症强烈降低了 CD 和 UC 中 SERT 的表达，并且 TNF-α 单独足以诱导类器官中类似的减少。减少的血清素再摄取能力可能导致与肠道炎症相关的细胞外间隙血清素水平升高。在克罗恩病回肠炎、克罗恩病结肠炎和溃疡性结肠炎的炎症区域，血清素再摄取转运体强烈减少。这些变化局限于肠上皮细胞，可以被 TNF-α诱导。色氨酸羟化酶 1 的血清素合成不变。这种调节被认为是与肠道炎症相关的细胞外血清素水平升高的机制之一。
