Haq Sabah, Wang Huaqing, Grondin Jensine, Banskota Suhrid, Marshall John K, Khan Irfan I, Chauhan Usha, Cote Francine, Kwon Yun Han, Philpott Dana, Brumell John H, Surette Michael, Steinberg Gregory R, Khan Waliul I
Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada.
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
Sci Adv. 2021 Nov 5;7(45):eabi6442. doi: 10.1126/sciadv.abi6442.
Autophagy, an essential intracellular recycling process, is linked to the pathogenesis of various diseases including Crohn’s disease (CD). Factors that lead to the development of impaired autophagy during intestinal inflammation remain largely unexplored. Here, we report the impact of the interaction between serotonin [5-hydroxytryptamine;(5-HT)] and autophagy in colitis in mouse and human studies. In mice, increased gut 5-HT inhibited autophagy and led to enhanced colitis susceptibility. Reciprocally, mice with reduced 5-HT exhibited up-regulated autophagy via the mammalian target of rapamycin pathway, which resulted in significantly decreased colitis. Deletion of autophagy gene, Atg7, in an epithelial-specific manner, in concert with reduced 5-HT, promoted the development of a colitogenic microbiota and abolished the protective effects conferred by reduced 5-HT. Notably, in control and patient peripheral blood mononuclear cells, we uncovered that 5-HT treatment inhibited autophagy. Our findings suggest 5-HT as a previously unidentified therapeutic target in intestinal inflammatory disorders such as CD that exhibits dysregulated autophagy.
自噬是一种重要的细胞内物质循环过程，与包括克罗恩病（CD）在内的多种疾病的发病机制相关。在肠道炎症期间导致自噬受损的因素在很大程度上仍未得到充分研究。在此，我们在小鼠和人体研究中报告了血清素[5-羟色胺；（5-HT）]与自噬之间的相互作用对结肠炎的影响。在小鼠中，肠道5-HT水平升高会抑制自噬，并导致结肠炎易感性增强。相反，5-HT水平降低的小鼠通过雷帕霉素靶蛋白途径表现出自噬上调，这导致结肠炎显著减轻。以上皮特异性方式缺失自噬基因Atg7，再加上5-HT水平降低，会促进致结肠炎微生物群的发展，并消除5-HT水平降低所赋予的保护作用。值得注意的是，在对照和患者外周血单核细胞中，我们发现5-HT处理会抑制自噬。我们的研究结果表明，5-HT是肠道炎症性疾病（如表现出自噬失调的CD）中一个此前未被识别的治疗靶点。
