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
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...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-03-01
|
| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-30997-y |
| _version_ | 1797865001766092800 |
|---|---|
| author | 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_facet | 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_sort | Shunta Nakamura |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-09T23:01:02Z |
| format | Article |
| id | doaj.art-ad3288f42a2948a6ac84fd4142d11a39 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-09T23:01:02Z |
| publishDate | 2023-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-ad3288f42a2948a6ac84fd4142d11a392023-03-22T10:58:22ZengNature PortfolioScientific Reports2045-23222023-03-0113111510.1038/s41598-023-30997-yDecreased 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 microbiotaShunta Nakamura0Kiminori Nakamura1Yuki Yokoi2Yu Shimizu3Shuya Ohira4Mizu Hagiwara5Zihao Song6Li Gan7Tomoyasu Aizawa8Daigo Hashimoto9Takanori Teshima10Andre J. Ouellette11Tokiyoshi Ayabe12Graduate School of Life Science, Hokkaido UniversityGraduate School of Life Science, Hokkaido UniversityGraduate School of Life Science, Hokkaido UniversityDepartment of Cell Biological Science, Faculty of Advanced Life Science, Hokkaido UniversityGraduate School of Life Science, Hokkaido UniversityGraduate School of Life Science, Hokkaido UniversityGraduate School of Life Science, Hokkaido UniversityGraduate School of Life Science, Hokkaido UniversityGraduate School of Life Science, Hokkaido UniversityDepartment of Hematology, Faculty of Medicine, Hokkaido UniversityDepartment of Hematology, Faculty of Medicine, Hokkaido UniversityDepartment of Pathology and Laboratory Medicine, Keck School of Medicine, University of Southern CaliforniaGraduate School of Life Science, Hokkaido UniversityAbstract 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.https://doi.org/10.1038/s41598-023-30997-y |
| spellingShingle | 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 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 Scientific Reports |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| url | https://doi.org/10.1038/s41598-023-30997-y |
| work_keys_str_mv | AT shuntanakamura decreasedpanethcelladefensinspromotefibrosisinacholinedeficientlaminoaciddefinedhighfatdietinducedmousemodelofnonalcoholicsteatohepatitisviadisruptingintestinalmicrobiota AT kiminorinakamura decreasedpanethcelladefensinspromotefibrosisinacholinedeficientlaminoaciddefinedhighfatdietinducedmousemodelofnonalcoholicsteatohepatitisviadisruptingintestinalmicrobiota AT yukiyokoi decreasedpanethcelladefensinspromotefibrosisinacholinedeficientlaminoaciddefinedhighfatdietinducedmousemodelofnonalcoholicsteatohepatitisviadisruptingintestinalmicrobiota AT yushimizu decreasedpanethcelladefensinspromotefibrosisinacholinedeficientlaminoaciddefinedhighfatdietinducedmousemodelofnonalcoholicsteatohepatitisviadisruptingintestinalmicrobiota AT shuyaohira decreasedpanethcelladefensinspromotefibrosisinacholinedeficientlaminoaciddefinedhighfatdietinducedmousemodelofnonalcoholicsteatohepatitisviadisruptingintestinalmicrobiota AT mizuhagiwara decreasedpanethcelladefensinspromotefibrosisinacholinedeficientlaminoaciddefinedhighfatdietinducedmousemodelofnonalcoholicsteatohepatitisviadisruptingintestinalmicrobiota AT zihaosong decreasedpanethcelladefensinspromotefibrosisinacholinedeficientlaminoaciddefinedhighfatdietinducedmousemodelofnonalcoholicsteatohepatitisviadisruptingintestinalmicrobiota AT ligan decreasedpanethcelladefensinspromotefibrosisinacholinedeficientlaminoaciddefinedhighfatdietinducedmousemodelofnonalcoholicsteatohepatitisviadisruptingintestinalmicrobiota AT tomoyasuaizawa decreasedpanethcelladefensinspromotefibrosisinacholinedeficientlaminoaciddefinedhighfatdietinducedmousemodelofnonalcoholicsteatohepatitisviadisruptingintestinalmicrobiota AT daigohashimoto decreasedpanethcelladefensinspromotefibrosisinacholinedeficientlaminoaciddefinedhighfatdietinducedmousemodelofnonalcoholicsteatohepatitisviadisruptingintestinalmicrobiota AT takanoriteshima decreasedpanethcelladefensinspromotefibrosisinacholinedeficientlaminoaciddefinedhighfatdietinducedmousemodelofnonalcoholicsteatohepatitisviadisruptingintestinalmicrobiota AT andrejouellette decreasedpanethcelladefensinspromotefibrosisinacholinedeficientlaminoaciddefinedhighfatdietinducedmousemodelofnonalcoholicsteatohepatitisviadisruptingintestinalmicrobiota AT tokiyoshiayabe decreasedpanethcelladefensinspromotefibrosisinacholinedeficientlaminoaciddefinedhighfatdietinducedmousemodelofnonalcoholicsteatohepatitisviadisruptingintestinalmicrobiota |