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Escherichia coli Promotes Endothelial to Mesenchymal Transformation of Liver Sinusoidal Endothelial Cells and Exacerbates Nonalcoholic Fatty Liver Disease Via Its Flagellin

BACKGROUND&AIMS: Gut bacteria translocate into the liver through a disrupted gut vascular barrier, which is an early and common event in the development of nonalcoholic fatty liver disease (NAFLD). Liver sinusoidal endothelial cells (LSECs) are directly exposed to translocated gut microbiota in port...

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Autores principales: Shen, Bo, Gu, Tianyi, Shen, Zhenyang, Zhou, Cui, Guo, Yuecheng, Wang, Junjun, Li, Binghang, Xu, Xianjun, Li, Fei, Zhang, Qidi, Cai, Xiaobo, Dong, Hui, Lu, Lungen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10598062/
https://www.ncbi.nlm.nih.gov/pubmed/37572735
http://dx.doi.org/10.1016/j.jcmgh.2023.08.001
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author Shen, Bo
Gu, Tianyi
Shen, Zhenyang
Zhou, Cui
Guo, Yuecheng
Wang, Junjun
Li, Binghang
Xu, Xianjun
Li, Fei
Zhang, Qidi
Cai, Xiaobo
Dong, Hui
Lu, Lungen
author_facet Shen, Bo
Gu, Tianyi
Shen, Zhenyang
Zhou, Cui
Guo, Yuecheng
Wang, Junjun
Li, Binghang
Xu, Xianjun
Li, Fei
Zhang, Qidi
Cai, Xiaobo
Dong, Hui
Lu, Lungen
author_sort Shen, Bo
collection PubMed
description BACKGROUND&AIMS: Gut bacteria translocate into the liver through a disrupted gut vascular barrier, which is an early and common event in the development of nonalcoholic fatty liver disease (NAFLD). Liver sinusoidal endothelial cells (LSECs) are directly exposed to translocated gut microbiota in portal vein blood. Escherichia coli, a commensal gut bacterium with flagella, is markedly enriched in the gut microbiota of patients with NAFLD. However, the impact of E coli on NAFLD progression and its underlying mechanisms remains unclear. METHODS: The abundance of E coli was analyzed by using 16S ribosomal RNA sequencing in a cohort of patients with NAFLD and healthy controls. The role of E coli was assessed in NAFLD mice after 16 weeks of administration, and the features of NAFLD were evaluated. Endothelial to mesenchymal transition (EndMT) in LSECs induced by E coli was analyzed through Western blotting and immunofluorescence. RESULTS: The abundance of gut Enterobacteriaceae increased in NAFLD patients with severe fat deposition and fibrosis. Importantly, translocated E coli in the liver aggravated hepatic steatosis, inflammation, and fibrosis in NAFLD mice. Mechanistically, E coli induced EndMT in LSECs through the TLR5/MYD88/TWIST1 pathway during NAFLD development. The toll-like receptor 5 inhibitor attenuated E coli–induced EndMT in LSECs and liver injury in NAFLD mice. Interestingly, flagellin-deficient E coli promoted less EndMT in LSECs and liver injury in NAFLD mice. CONCLUSIONS: E coli promoted the development of NAFLD and promoted EndMT in LSECs through toll-like receptor 5/nuclear factor kappa B–dependent activation of TWIST1 mediated by flagellin. Therapeutic interventions targeting E coli and/or flagellin may represent a promising candidate for NAFLD treatment.
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spelling pubmed-105980622023-10-26 Escherichia coli Promotes Endothelial to Mesenchymal Transformation of Liver Sinusoidal Endothelial Cells and Exacerbates Nonalcoholic Fatty Liver Disease Via Its Flagellin Shen, Bo Gu, Tianyi Shen, Zhenyang Zhou, Cui Guo, Yuecheng Wang, Junjun Li, Binghang Xu, Xianjun Li, Fei Zhang, Qidi Cai, Xiaobo Dong, Hui Lu, Lungen Cell Mol Gastroenterol Hepatol Original Research BACKGROUND&AIMS: Gut bacteria translocate into the liver through a disrupted gut vascular barrier, which is an early and common event in the development of nonalcoholic fatty liver disease (NAFLD). Liver sinusoidal endothelial cells (LSECs) are directly exposed to translocated gut microbiota in portal vein blood. Escherichia coli, a commensal gut bacterium with flagella, is markedly enriched in the gut microbiota of patients with NAFLD. However, the impact of E coli on NAFLD progression and its underlying mechanisms remains unclear. METHODS: The abundance of E coli was analyzed by using 16S ribosomal RNA sequencing in a cohort of patients with NAFLD and healthy controls. The role of E coli was assessed in NAFLD mice after 16 weeks of administration, and the features of NAFLD were evaluated. Endothelial to mesenchymal transition (EndMT) in LSECs induced by E coli was analyzed through Western blotting and immunofluorescence. RESULTS: The abundance of gut Enterobacteriaceae increased in NAFLD patients with severe fat deposition and fibrosis. Importantly, translocated E coli in the liver aggravated hepatic steatosis, inflammation, and fibrosis in NAFLD mice. Mechanistically, E coli induced EndMT in LSECs through the TLR5/MYD88/TWIST1 pathway during NAFLD development. The toll-like receptor 5 inhibitor attenuated E coli–induced EndMT in LSECs and liver injury in NAFLD mice. Interestingly, flagellin-deficient E coli promoted less EndMT in LSECs and liver injury in NAFLD mice. CONCLUSIONS: E coli promoted the development of NAFLD and promoted EndMT in LSECs through toll-like receptor 5/nuclear factor kappa B–dependent activation of TWIST1 mediated by flagellin. Therapeutic interventions targeting E coli and/or flagellin may represent a promising candidate for NAFLD treatment. Elsevier 2023-08-11 /pmc/articles/PMC10598062/ /pubmed/37572735 http://dx.doi.org/10.1016/j.jcmgh.2023.08.001 Text en © 2023 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Research
Shen, Bo
Gu, Tianyi
Shen, Zhenyang
Zhou, Cui
Guo, Yuecheng
Wang, Junjun
Li, Binghang
Xu, Xianjun
Li, Fei
Zhang, Qidi
Cai, Xiaobo
Dong, Hui
Lu, Lungen
Escherichia coli Promotes Endothelial to Mesenchymal Transformation of Liver Sinusoidal Endothelial Cells and Exacerbates Nonalcoholic Fatty Liver Disease Via Its Flagellin
title Escherichia coli Promotes Endothelial to Mesenchymal Transformation of Liver Sinusoidal Endothelial Cells and Exacerbates Nonalcoholic Fatty Liver Disease Via Its Flagellin
title_full Escherichia coli Promotes Endothelial to Mesenchymal Transformation of Liver Sinusoidal Endothelial Cells and Exacerbates Nonalcoholic Fatty Liver Disease Via Its Flagellin
title_fullStr Escherichia coli Promotes Endothelial to Mesenchymal Transformation of Liver Sinusoidal Endothelial Cells and Exacerbates Nonalcoholic Fatty Liver Disease Via Its Flagellin
title_full_unstemmed Escherichia coli Promotes Endothelial to Mesenchymal Transformation of Liver Sinusoidal Endothelial Cells and Exacerbates Nonalcoholic Fatty Liver Disease Via Its Flagellin
title_short Escherichia coli Promotes Endothelial to Mesenchymal Transformation of Liver Sinusoidal Endothelial Cells and Exacerbates Nonalcoholic Fatty Liver Disease Via Its Flagellin
title_sort escherichia coli promotes endothelial to mesenchymal transformation of liver sinusoidal endothelial cells and exacerbates nonalcoholic fatty liver disease via its flagellin
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10598062/
https://www.ncbi.nlm.nih.gov/pubmed/37572735
http://dx.doi.org/10.1016/j.jcmgh.2023.08.001
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