Disruption of autophagy by increased 5-HT alters gut microbiota and enhances susceptibility to experimental colitis and Crohn’s disease
| Autor: | Yun Han Kwon, Gregory R. Steinberg, Sabah Haq, Usha Chauhan, John H. Brumell, Francine Côté, Jensine Grondin, John Marshall, Huaqing Wang, Waliul I. Khan, Michael G. Surette, Suhrid Banskota, Irfan I. Khan, Dana J. Philpott |
|---|---|
| Přispěvatelé: | Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
[SDV]Life Sciences [q-bio]
Diseases and Disorders Disease Gut flora Microbiology Pathogenesis 03 medical and health sciences 0302 clinical medicine Medicine 5-HT receptor ComputingMilieux_MISCELLANEOUS 030304 developmental biology 0303 health sciences Crohn's disease Multidisciplinary biology business.industry Autophagy Experimental colitis SciAdv r-articles Life Sciences biology.organism_classification medicine.disease 3. Good health Immunology 030211 gastroenterology & hepatology Biomedicine and Life Sciences business Intracellular Research Article |
| Zdroj: | Science Advances Science Advances, American Association for the Advancement of Science (AAAS), 2021, 7 (45), ⟨10.1126/sciadv.abi6442⟩ |
| ISSN: | 2375-2548 |
| DOI: | 10.1126/sciadv.abi6442⟩ |
| Popis: | Description Elevated gut serotonin inhibits autophagy via mTOR promoting a disrupted microbiota and enhanced susceptibility to colitis. 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|