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.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
09 03 2023
09 03 2023
Historique:
received:
01
09
2022
accepted:
06
03
2023
entrez:
9
3
2023
pubmed:
10
3
2023
medline:
14
3
2023
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 36894646
doi: 10.1038/s41598-023-30997-y
pii: 10.1038/s41598-023-30997-y
pmc: PMC9998432
doi:
Substances chimiques
alpha-Defensins
0
Amino Acids
0
Choline
N91BDP6H0X
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3953Informations de copyright
© 2023. The Author(s).
Références
J Biol Chem. 2007 Dec 28;282(52):37298-302
pubmed: 17986448
Front Immunol. 2020 Sep 09;11:2065
pubmed: 33013873
Cell. 2018 Mar 8;172(6):1198-1215
pubmed: 29522742
Sci Rep. 2021 May 10;11(1):9915
pubmed: 33972646
J Hepatol. 2014 Sep;61(3):617-25
pubmed: 24815875
Diabetologia. 2014 Apr;57(4):809-18
pubmed: 24356748
Anal Biochem. 2013 Dec 15;443(2):124-31
pubmed: 23994564
Biochem Biophys Res Commun. 2020 Jul 23;528(2):305-310
pubmed: 32475638
BMC Microbiol. 2019 Jun 13;19(1):130
pubmed: 31195972
Am J Physiol Gastrointest Liver Physiol. 2004 Jun;286(6):G1050-8
pubmed: 14715526
J Innate Immun. 2011;3(3):315-26
pubmed: 21099205
J Biol Chem. 1992 Nov 15;267(32):23216-25
pubmed: 1429669
Nature. 2003 Apr 3;422(6931):522-6
pubmed: 12660734
J Biol Chem. 2011 Nov 11;286(45):39336-48
pubmed: 21941003
Nutrients. 2020 Nov 20;12(11):
pubmed: 33233570
Microorganisms. 2020 Aug 12;8(8):
pubmed: 32806628
Arch Oral Biol. 2006 Feb;51(2):89-95
pubmed: 16076461
Mol Biol Evol. 2013 Apr;30(4):772-80
pubmed: 23329690
Front Cell Infect Microbiol. 2017 Sep 05;7:387
pubmed: 28929087
Hepatology. 2016 Jul;64(1):73-84
pubmed: 26707365
Nat Methods. 2016 Jul;13(7):581-3
pubmed: 27214047
Hepatology. 2019 Jun;69(6):2672-2682
pubmed: 30179269
Hepatology. 2017 May;65(5):1557-1565
pubmed: 28130788
J Pathol. 2011 Oct;225(2):276-84
pubmed: 21630271
Proc Natl Acad Sci U S A. 2004 Nov 2;101(44):15718-23
pubmed: 15505215
Infect Immun. 1994 Nov;62(11):5040-7
pubmed: 7927786
ISME J. 2011 Oct;5(10):1571-9
pubmed: 21472016
Life Sci Alliance. 2020 Apr 28;3(6):
pubmed: 32345659
J Cell Biochem. 2010 Aug 15;110(6):1447-56
pubmed: 20506389
J Microbiol Biotechnol. 2020 Feb 28;30(2):287-295
pubmed: 31635444
Biochem Biophys Res Commun. 2021 Mar 19;545:14-19
pubmed: 33529805
Front Immunol. 2020 Apr 15;11:646
pubmed: 32351509
J Biol Chem. 2002 Feb 1;277(5):3793-800
pubmed: 11724775
Nat Rev Gastroenterol Hepatol. 2018 Jul;15(7):397-411
pubmed: 29748586
Sci Rep. 2019 Feb 25;9(1):2710
pubmed: 30804449
Nature. 2006 Dec 21;444(7122):1022-3
pubmed: 17183309
Blood. 2012 Jul 5;120(1):223-31
pubmed: 22535662
Nat Commun. 2020 Oct 9;11(1):5104
pubmed: 33037214
Trends Immunol. 2018 Sep;39(9):677-696
pubmed: 29716793
Hepatol Commun. 2018 Dec 27;3(2):246-261
pubmed: 30766962
JCI Insight. 2020 Oct 15;5(20):
pubmed: 33055426
Biochem Biophys Res Commun. 2007 Aug 31;360(3):609-14
pubmed: 17617378
Annu Rev Pathol. 2018 Jan 24;13:321-350
pubmed: 29414249
Nutrients. 2019 Nov 18;11(11):
pubmed: 31752111
J Cell Biol. 1992 Aug;118(4):929-36
pubmed: 1500431
J Exp Med. 2017 Dec 4;214(12):3507-3518
pubmed: 29066578
Protein Expr Purif. 2015 Aug;112:21-8
pubmed: 25913370
Lancet. 2000 Apr 29;355(9214):1518-9
pubmed: 10801176
Science. 2005 Aug 19;309(5738):1256-9
pubmed: 16109882
J Exp Med. 2011 Feb 14;208(2):285-94
pubmed: 21282378
J Biol Chem. 2018 Jan 5;293(1):132-147
pubmed: 29133525
PLoS One. 2010 Mar 10;5(3):e9490
pubmed: 20224823
EMBO Mol Med. 2019 Feb;11(2):
pubmed: 30591521
Transpl Infect Dis. 2015 Oct;17(5):702-6
pubmed: 26198302
Nat Metab. 2019 Jan;1(1):34-46
pubmed: 32694818
Gut Microbes. 2015;6(3):173-81
pubmed: 25915459
Infect Immun. 2011 Jan;79(1):459-73
pubmed: 21041494
Hepatology. 2013 Feb;57(2):601-9
pubmed: 23055155
Biosci Microbiota Food Health. 2016;35(2):57-67
pubmed: 27200259
Nat Rev Gastroenterol Hepatol. 2020 May;17(5):279-297
pubmed: 32152478
Cell Mol Life Sci. 2011 Jul;68(13):2215-29
pubmed: 21560070
Nat Immunol. 2010 Jan;11(1):76-83
pubmed: 19855381
Hepatology. 2016 Jun;63(6):2032-43
pubmed: 26663351
Nat Immunol. 2000 Aug;1(2):113-8
pubmed: 11248802
Nat Biotechnol. 2019 Aug;37(8):852-857
pubmed: 31341288
J Exp Med. 2019 Nov 4;216(11):2602-2618
pubmed: 31420376
Hepatology. 2016 Mar;63(3):764-75
pubmed: 26600078