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Compromised Ileal Mucus Barrier Due to Impaired Epithelial Homeostasis Caused by Notch1 Signaling in Cirrhotic Rats

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Abstract

Background

In liver cirrhosis, intestinal mucus barrier is rarely studied.

Aims

This study aimed to investigate whether mucus barrier in ileum is altered in cirrhotic rats and its underlying mechanisms.

Methods

Thioacetamide was injected to induce liver cirrhosis in rats. Serum from portal vein blood, and ileum and liver tissues were obtained for further analysis. Goblet cell-like Ls174T cells were cultured for in vitro experiments.

Results

The ileal mucus was thin, loose, and porous with small bubbles in cirrhotic rats. mRNA expressions of Muc2 and TFF3 were also down-regulated in cirrhotic rats. Bacteria located near to crypts and LPS were increased in the serum from portal vein in cirrhotic rats. Smaller theca area and few goblet cells were found in cirrhotic rats compared with control. Increased proliferation of ileal epithelia was observed in cirrhotic rats. Notch1, Dll1, and Hes1 expressions were enhanced, and KLF4 expression was suppressed in ileum of cirrhotic rats. In Ls174T cells, EDTA and NICD plasmid induced NICD and Hes1 expression and suppressed KLF4 concomitantly, and mucus expression almost vanished in these cells. NICD plasmid induced more proliferation in Ls174T cells. Oppositely, after DBZ treatment, NICD and Hes1 were inhibited along with augmentation of KLF4 and increased mucous expression in Ls174T cells, while proliferation of the cells was suppressed.

Conclusions

In cirrhotic rats, mucus barrier was impaired. This might be attributed to increased proliferation and decreased differentiation of epithelia, which might be mediated by Notch1–Hes1–KLF4 signaling.

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Acknowledgments

This study was supported by the National Natural Science Foundation of China (U1702281, 81670551, and 81873584), the Chinesisch-Deutsches Zentrum fṻr Wissenschaftsfὅrderung (GZ1065), the Science and Technology Support Program of Sichuan Province (2016SZ0041), the Science and Technology Department of Sichuan Province (20YYJC3383), the National Key R&D Program of China (2017YFA0205404), the China Postdoctoral Science Foundation Grant (2019M653436), the and Post-Doctor Research Project, West China Hospital, Sichuan University (2019HXBH013). All the listed Grants support the expenses of performing experiments. No assistance with manuscript preparation was done.

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Authors and Affiliations

  1. Laboratory of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China

    Linhao Zhang, Yang Tai, Shihang Tang, Chong Zhao, Jinhang Gao & Chengwei Tang

  2. Department of Gastroenterology, West China Hospital, Sichuan University, Guo Xue Lane 37#, Chengdu, 610041, People’s Republic of China

    Linhao Zhang, Yang Tai, Shihang Tang, Huan Tong, Jinhang Gao & Chengwei Tang

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  1. Linhao Zhang
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Correspondence to Chengwei Tang.

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The animal experimentation was approved by institutional ethics committees. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

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Supplementary Fig. 1 Notch1 plasmid. Notch1 plasmid sequence information (PDF 64 kb)

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Zhang, L., Tai, Y., Tang, S. et al. Compromised Ileal Mucus Barrier Due to Impaired Epithelial Homeostasis Caused by Notch1 Signaling in Cirrhotic Rats. Dig Dis Sci 66, 131–142 (2021). https://doi.org/10.1007/s10620-020-06178-6

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  • DOI: https://doi.org/10.1007/s10620-020-06178-6

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