期刊
SCIENCE ADVANCES
卷 7, 期 45, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abi6442
关键词
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资金
- Canadian Institutes of Health Research (CIHR) [PJT 156262]
- Canadian Association of Gastroenterology (CAG) doctoral fellowship
- Farncombe Student Award
- Diabetes Canada Investigator Award
- Tier 1 Canada Research Chair
- J. Bruce Duncan Chair in Metabolic Diseases
- Espervita Therapeutics
- Esperion Therapeutics
- Poxel Pharmaceuticals
- Novo Nordisk
This study revealed that gut 5-HT inhibited autophagy, leading to enhanced colitis susceptibility, while reduced 5-HT promoted autophagy and decreased colitis inflammation. Similar results were observed in control and patient blood samples, suggesting a potential therapeutic role of 5-HT in intestinal inflammatory disorders.
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.
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