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03 09, 2023;13 (1): 3953.

Decreased Paneth cell α-defensins promote fibrosis in a choline-deficient L-amino acid-defined high-fat diet-induced mouse model of nonalcoholic steatohepatitis via disrupting intestinal microbiota.

Shunta Nakamura, Kiminori Nakamura, Yuki Yokoi, Yu Shimizu, Shuya Ohira, Mizu Hagiwara, Zihao Song, Li Gan, Tomoyasu Aizawa, Daigo Hashimoto, Takanori Teshima, Andre J Ouellette, Tokiyoshi Ayabe
Author Information
  1. Shunta Nakamura: Graduate School of Life Science, Hokkaido University, Sapporo, Japan.
  2. Kiminori Nakamura: Graduate School of Life Science, Hokkaido University, Sapporo, Japan. kiminori@sci.hokudai.ac.jp.
  3. Yuki Yokoi: Graduate School of Life Science, Hokkaido University, Sapporo, Japan.
  4. Yu Shimizu: Department of Cell Biological Science, Faculty of Advanced Life Science, Hokkaido University, Kita-21, Nishi-11, Kita-ku, Sapporo, Hokkaido, 001-0021, Japan.
  5. Shuya Ohira: Graduate School of Life Science, Hokkaido University, Sapporo, Japan.
  6. Mizu Hagiwara: Graduate School of Life Science, Hokkaido University, Sapporo, Japan.
  7. Zihao Song: Graduate School of Life Science, Hokkaido University, Sapporo, Japan.
  8. Li Gan: Graduate School of Life Science, Hokkaido University, Sapporo, Japan.
  9. Tomoyasu Aizawa: Graduate School of Life Science, Hokkaido University, Sapporo, Japan.
  10. Daigo Hashimoto: Department of Hematology, Faculty of Medicine, Hokkaido University, Sapporo, Japan.
  11. Takanori Teshima: Department of Hematology, Faculty of Medicine, Hokkaido University, Sapporo, Japan.
  12. Andre J Ouellette: Department of Pathology and Laboratory Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  13. Tokiyoshi Ayabe: Graduate School of Life Science, Hokkaido University, Sapporo, Japan. ayabe@sci.hokudai.ac.jp.
PMID: 36894646 DOI: 10.1038/s41598-023-30997-y

Abstract

Nonalcoholic steatohepatitis (NASH) is a chronic liver disease characterized by fibrosis that develops from fatty liver. Disruption of intestinal microbiota homeostasis, dysbiosis, is associated with fibrosis development in NASH. An antimicrobial peptide α-defensin secreted by Paneth cells in the small intestine is known to regulate composition of the intestinal microbiota. However, involvement of α-defensin in NASH remains unknown. Here, we show that in diet-induced NASH model mice, decrease of fecal α-defensin along with dysbiosis occurs before NASH onset. When α-defensin levels in the intestinal lumen are restored by intravenous administration of R-Spondin1 to induce Paneth cell regeneration or by oral administration of α-defensins, liver fibrosis is ameliorated with dissolving dysbiosis. Furthermore, R-Spondin1 and α-defensin improved liver pathologies together with different features in the intestinal microbiota. These results indicate that decreased α-defensin secretion induces liver fibrosis through dysbiosis, further suggesting Paneth cell α-defensin as a potential therapeutic target for NASH.

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MeSH Term

Animals
Mice
alpha-Defensins
Amino Acids
Choline
Diet, High-Fat
Dysbiosis
Gastrointestinal Microbiome
Liver Cirrhosis
Mice, Inbred C57BL
Non-alcoholic Fatty Liver Disease
Paneth Cells

Chemicals

alpha-Defensins
Amino Acids
Choline
Journal Article Research Support, Non-U.S. Gov't
Article has an altmetric score of 12

Word Cloud

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