Gut bacterial metabolites modulate endoplasmic reticulum stress.
ER stress
Intestinal epithelial homeostasis
Microbial metabolites
Unfolded protein response
Journal
Genome biology
ISSN: 1474-760X
Titre abrégé: Genome Biol
Pays: England
ID NLM: 100960660
Informations de publication
Date de publication:
15 10 2021
15 10 2021
Historique:
received:
07
08
2020
accepted:
10
09
2021
entrez:
16
10
2021
pubmed:
17
10
2021
medline:
29
1
2022
Statut:
epublish
Résumé
The endoplasmic reticulum (ER) is a membranous organelle that maintains proteostasis and cellular homeostasis, controlling the fine balance between health and disease. Dysregulation of the ER stress response has been implicated in intestinal inflammation associated with inflammatory bowel disease (IBD), a chronic condition characterized by changes to the mucosa and alteration of the gut microbiota. While the microbiota and microbially derived metabolites have also been implicated in ER stress, examples of this connection remain limited to a few observations from pathogenic bacteria. Furthermore, the mechanisms underlying the effects of bacterial metabolites on ER stress signaling have not been well established. Utilizing an XBP1s-GFP knock-in reporter colorectal epithelial cell line, we screened 399 microbiome-related metabolites for ER stress pathway modulation. We find both ER stress response inducers (acylated dipeptide aldehydes and bisindole methane derivatives) and suppressors (soraphen A) and characterize their activities on ER stress gene transcription and translation. We further demonstrate that these molecules modulate the ER stress pathway through protease inhibition or lipid metabolism interference. Our study identified novel links between classes of gut microbe-derived metabolites and the ER stress response, suggesting the potential for these metabolites to contribute to gut ER homeostasis and providing insight into the molecular mechanisms by which gut microbes impact intestinal epithelial cell homeostasis.
Sections du résumé
BACKGROUND
The endoplasmic reticulum (ER) is a membranous organelle that maintains proteostasis and cellular homeostasis, controlling the fine balance between health and disease. Dysregulation of the ER stress response has been implicated in intestinal inflammation associated with inflammatory bowel disease (IBD), a chronic condition characterized by changes to the mucosa and alteration of the gut microbiota. While the microbiota and microbially derived metabolites have also been implicated in ER stress, examples of this connection remain limited to a few observations from pathogenic bacteria. Furthermore, the mechanisms underlying the effects of bacterial metabolites on ER stress signaling have not been well established.
RESULTS
Utilizing an XBP1s-GFP knock-in reporter colorectal epithelial cell line, we screened 399 microbiome-related metabolites for ER stress pathway modulation. We find both ER stress response inducers (acylated dipeptide aldehydes and bisindole methane derivatives) and suppressors (soraphen A) and characterize their activities on ER stress gene transcription and translation. We further demonstrate that these molecules modulate the ER stress pathway through protease inhibition or lipid metabolism interference.
CONCLUSIONS
Our study identified novel links between classes of gut microbe-derived metabolites and the ER stress response, suggesting the potential for these metabolites to contribute to gut ER homeostasis and providing insight into the molecular mechanisms by which gut microbes impact intestinal epithelial cell homeostasis.
Identifiants
pubmed: 34654459
doi: 10.1186/s13059-021-02496-8
pii: 10.1186/s13059-021-02496-8
pmc: PMC8518294
doi:
Substances chimiques
Aldehydes
0
Dipeptides
0
Indoles
0
Macrolides
0
Tunicamycin
11089-65-9
soraphen A
122547-72-2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
292Subventions
Organisme : NIDDK NIH HHS
ID : P30 DK043351
Pays : United States
Organisme : NIH HHS
ID : P30 DK043351
Pays : United States
Informations de copyright
© 2021. The Author(s).
Références
Science. 2004 Oct 15;306(5695):457-61
pubmed: 15486293
J Nat Prod. 2003 Nov;66(11):1520-3
pubmed: 14640534
J Nat Prod. 1994 Nov;57(11):1587-90
pubmed: 7853008
J Clin Invest. 2002 Nov;110(10):1389-98
pubmed: 12438434
Nat Microbiol. 2018 Mar;3(3):337-346
pubmed: 29311644
Cell. 2017 Jan 26;168(3):517-526.e18
pubmed: 28111075
J Antibiot (Tokyo). 2007 Sep;60(9):547-53
pubmed: 17917237
Breast Cancer Res Treat. 2019 Aug;177(1):29-40
pubmed: 31119568
Appl Microbiol Biotechnol. 2011 Feb;89(4):1001-8
pubmed: 20972782
Nat Rev Microbiol. 2015 Feb;13(2):71-82
pubmed: 25534809
J Clin Invest. 2001 Mar;107(5):585-93
pubmed: 11238559
Cell Metab. 2009 Jul;10(1):13-26
pubmed: 19583950
Cell. 2019 Aug 22;178(5):1041-1056
pubmed: 31442399
Mol Cell. 2007 Jul 6;27(1):53-66
pubmed: 17612490
Science. 2008 Jun 13;320(5882):1492-6
pubmed: 18556558
Mol Cancer Ther. 2004 Mar;3(3):247-60
pubmed: 15026545
Biochem Pharmacol. 2011 Mar 1;81(5):649-60
pubmed: 21184748
Genes Dev. 1998 Apr 1;12(7):982-95
pubmed: 9531536
Front Microbiol. 2018 Nov 01;9:2625
pubmed: 30443243
Science. 2006 Aug 25;313(5790):1137-40
pubmed: 16931765
Endocrinology. 2006 Jul;147(7):3398-407
pubmed: 16601139
Diabetologia. 2010 Jun;53(6):1120-30
pubmed: 20349222
Mol Cell Biol. 2003 Nov;23(21):7448-59
pubmed: 14559994
Chem Pharm Bull (Tokyo). 1994 Dec;42(12):2449-51
pubmed: 7697760
Trends Cell Biol. 1998 Oct;8(10):397-403
pubmed: 9789328
J Clin Invest. 2002 Feb;109(4):525-32
pubmed: 11854325
Nat Genet. 2008 Aug;40(8):955-62
pubmed: 18587394
Cell. 2001 Dec 28;107(7):881-91
pubmed: 11779464
Nat Microbiol. 2019 Feb;4(2):293-305
pubmed: 30531976
Am J Pathol. 2009 May;174(5):1786-98
pubmed: 19359519
Hepatology. 2011 Jul;54(1):229-39
pubmed: 21503947
Immunol Cell Biol. 2012 Mar;90(3):260-70
pubmed: 22249202
Nat Cell Biol. 2000 Jun;2(6):326-32
pubmed: 10854322
Cell. 2008 Sep 5;134(5):743-56
pubmed: 18775308
Nat Genet. 2010 Apr;42(4):332-7
pubmed: 20228799
Science. 2015 Jul 24;349(6246):1254766
pubmed: 26206939
Cancer Lett. 1997 Nov 25;120(1):53-63
pubmed: 9570386
J Cell Biol. 2012 Jun 25;197(7):857-67
pubmed: 22733998
Cancer Res. 2004 Sep 1;64(17):5994-6001
pubmed: 15342379
Blood Cancer J. 2012 Jul;2(7):e79
pubmed: 22852048
Mol Biol Cell. 1999 Nov;10(11):3787-99
pubmed: 10564271
Nature. 1999 Jan 21;397(6716):271-4
pubmed: 9930704
Nature. 1996 Apr 4;380(6573):403-9
pubmed: 8602240
J Immunol. 2009 Jul 15;183(2):1368-74
pubmed: 19553530
Cancer Lett. 2000 Apr 14;151(2):169-79
pubmed: 10738111
Biochem Biophys Res Commun. 2008 Nov 7;376(1):96-9
pubmed: 18760995
Science. 2017 Sep 8;357(6355):1047-1052
pubmed: 28751470
Am J Respir Cell Mol Biol. 2018 Aug;59(2):225-236
pubmed: 29465261
Diabetes. 2010 Jan;59(1):6-16
pubmed: 19808896
Genes Dev. 2016 Jul 15;30(14):1589-97
pubmed: 27474437
Mol Biol Cell. 1997 Sep;8(9):1805-14
pubmed: 9307975
Science. 2021 Jan 1;371(6524):
pubmed: 33384352
Cell Host Microbe. 2014 Mar 12;15(3):382-392
pubmed: 24629344
Mol Cell. 2000 May;5(5):897-904
pubmed: 10882126
Chem Rev. 1997 Feb 5;97(1):133-172
pubmed: 11848867