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Host Gasdermin D restrains systemic endotoxemia by capturing Proteobacteria in the colon of high-fat diet-feeding mice
Gasdermin D (GSDMD) functions as a key pyroptotic executor through its secreted N-terminal domain (GSDMD-N). However, the functional relevance and mechanistic basis of the precise roles of host colonic GSDMD in high-fat diet (HFD)-induced gut dysbiosis and systemic endotoxemia remain elusive. In thi...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Taylor & Francis
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8288038/ https://www.ncbi.nlm.nih.gov/pubmed/34275417 http://dx.doi.org/10.1080/19490976.2021.1946369 |
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author | Shi, Yujie Zou, Yixin Xiong, Yonghong Zhang, Shiyao Song, Mingming An, Xiaofei Liu, Chang Zhang, Wenxiang Chen, Siyu |
author_facet | Shi, Yujie Zou, Yixin Xiong, Yonghong Zhang, Shiyao Song, Mingming An, Xiaofei Liu, Chang Zhang, Wenxiang Chen, Siyu |
author_sort | Shi, Yujie |
collection | PubMed |
description | Gasdermin D (GSDMD) functions as a key pyroptotic executor through its secreted N-terminal domain (GSDMD-N). However, the functional relevance and mechanistic basis of the precise roles of host colonic GSDMD in high-fat diet (HFD)-induced gut dysbiosis and systemic endotoxemia remain elusive. In this study, we demonstrate that HFD feeding triggers GSDMD-N secretion of both T-lymphocytes and enterocytes in mouse colons. GSDMD deficiency aggravates HFD-induced systemic endotoxemia, gut barrier impairment, and colonic inflammation. More importantly, active GSDMD-N kills the Proteobacteria phylum via directly interacting with Cardiolipin. Mechanistically, we identify that the Glu236 (a known residue for GSDMD protein cleavage) is a bona fide important site for the bacterial recognition of GSDMD. Collectively, our findings explain the mechanism by which colonic GSDMD-N maintains low levels of HFD-induced metabolic endotoxemia. A GSDMD-N mimetic containing an exposed Glu236 site could be an attractive strategy for the treatment of HFD-induced metabolic endotoxemia. |
format | Online Article Text |
id | pubmed-8288038 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Taylor & Francis |
record_format | MEDLINE/PubMed |
spelling | pubmed-82880382021-08-02 Host Gasdermin D restrains systemic endotoxemia by capturing Proteobacteria in the colon of high-fat diet-feeding mice Shi, Yujie Zou, Yixin Xiong, Yonghong Zhang, Shiyao Song, Mingming An, Xiaofei Liu, Chang Zhang, Wenxiang Chen, Siyu Gut Microbes Research Paper Gasdermin D (GSDMD) functions as a key pyroptotic executor through its secreted N-terminal domain (GSDMD-N). However, the functional relevance and mechanistic basis of the precise roles of host colonic GSDMD in high-fat diet (HFD)-induced gut dysbiosis and systemic endotoxemia remain elusive. In this study, we demonstrate that HFD feeding triggers GSDMD-N secretion of both T-lymphocytes and enterocytes in mouse colons. GSDMD deficiency aggravates HFD-induced systemic endotoxemia, gut barrier impairment, and colonic inflammation. More importantly, active GSDMD-N kills the Proteobacteria phylum via directly interacting with Cardiolipin. Mechanistically, we identify that the Glu236 (a known residue for GSDMD protein cleavage) is a bona fide important site for the bacterial recognition of GSDMD. Collectively, our findings explain the mechanism by which colonic GSDMD-N maintains low levels of HFD-induced metabolic endotoxemia. A GSDMD-N mimetic containing an exposed Glu236 site could be an attractive strategy for the treatment of HFD-induced metabolic endotoxemia. Taylor & Francis 2021-07-18 /pmc/articles/PMC8288038/ /pubmed/34275417 http://dx.doi.org/10.1080/19490976.2021.1946369 Text en © 2021 The Author(s). Published with license by Taylor & Francis Group, LLC. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Paper Shi, Yujie Zou, Yixin Xiong, Yonghong Zhang, Shiyao Song, Mingming An, Xiaofei Liu, Chang Zhang, Wenxiang Chen, Siyu Host Gasdermin D restrains systemic endotoxemia by capturing Proteobacteria in the colon of high-fat diet-feeding mice |
title | Host Gasdermin D restrains systemic endotoxemia by capturing Proteobacteria in the colon of high-fat diet-feeding mice |
title_full | Host Gasdermin D restrains systemic endotoxemia by capturing Proteobacteria in the colon of high-fat diet-feeding mice |
title_fullStr | Host Gasdermin D restrains systemic endotoxemia by capturing Proteobacteria in the colon of high-fat diet-feeding mice |
title_full_unstemmed | Host Gasdermin D restrains systemic endotoxemia by capturing Proteobacteria in the colon of high-fat diet-feeding mice |
title_short | Host Gasdermin D restrains systemic endotoxemia by capturing Proteobacteria in the colon of high-fat diet-feeding mice |
title_sort | host gasdermin d restrains systemic endotoxemia by capturing proteobacteria in the colon of high-fat diet-feeding mice |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8288038/ https://www.ncbi.nlm.nih.gov/pubmed/34275417 http://dx.doi.org/10.1080/19490976.2021.1946369 |
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