Engineered bacteria producing aryl-hydrocarbon receptor agonists protect against ethanol-induced liver disease in mice.
alcohol-related liver disease
microbiome
microbiota
synthetic biology
Journal
Alcohol, clinical & experimental research
ISSN: 2993-7175
Titre abrégé: Alcohol Clin Exp Res (Hoboken)
Pays: United States
ID NLM: 9918609780906676
Informations de publication
Date de publication:
May 2023
May 2023
Historique:
revised:
10
02
2023
received:
28
07
2022
accepted:
27
02
2023
medline:
6
3
2023
pubmed:
6
3
2023
entrez:
5
3
2023
Statut:
ppublish
Résumé
Gut bacteria metabolize tryptophan into indoles. Intestinal levels of the tryptophan metabolite indole-3-acetic acid are reduced in patients with alcohol-associated hepatitis. Supplementation of indole-3-acetic acid protects against ethanol-induced liver disease in mice. The aim of this study was to evaluate the effect of engineered bacteria producing indoles as Aryl-hydrocarbon receptor (Ahr) agonists. C57BL/6 mice were subjected to chronic-plus-binge ethanol feeding and orally given PBS, control Escherichia coli Nissle 1917 (EcN) or engineered EcN-Ahr. The effects of EcN and EcN-Ahr were also examined in mice lacking Ahr in interleukin 22 (Il22)-producing cells. Through the deletion of endogenous genes trpR and tnaA, coupled with overexpression of a feedback-resistant tryptophan biosynthesis operon, EcN-Ahr were engineered to overproduce tryptophan. Additional engineering allowed conversion of this tryptophan to indoles including indole-3-acetic acid and indole-3-lactic acid. EcN-Ahr ameliorated ethanol-induced liver disease in C57BL/6 mice. EcN-Ahr upregulated intestinal gene expression of Cyp1a1, Nrf2, Il22, Reg3b, and Reg3g, and increased Il22-expressing type 3 innate lymphoid cells. In addition, EcN-Ahr reduced translocation of bacteria to the liver. The beneficial effect of EcN-Ahr was abrogated in mice lacking Ahr expression in Il22-producing immune cells. Our findings indicate that tryptophan metabolites locally produced by engineered gut bacteria mitigate liver disease via Ahr-mediated activation in intestinal immune cells.
Sections du résumé
BACKGROUND AND PURPOSE
OBJECTIVE
Gut bacteria metabolize tryptophan into indoles. Intestinal levels of the tryptophan metabolite indole-3-acetic acid are reduced in patients with alcohol-associated hepatitis. Supplementation of indole-3-acetic acid protects against ethanol-induced liver disease in mice. The aim of this study was to evaluate the effect of engineered bacteria producing indoles as Aryl-hydrocarbon receptor (Ahr) agonists.
METHODS
METHODS
C57BL/6 mice were subjected to chronic-plus-binge ethanol feeding and orally given PBS, control Escherichia coli Nissle 1917 (EcN) or engineered EcN-Ahr. The effects of EcN and EcN-Ahr were also examined in mice lacking Ahr in interleukin 22 (Il22)-producing cells.
RESULTS
RESULTS
Through the deletion of endogenous genes trpR and tnaA, coupled with overexpression of a feedback-resistant tryptophan biosynthesis operon, EcN-Ahr were engineered to overproduce tryptophan. Additional engineering allowed conversion of this tryptophan to indoles including indole-3-acetic acid and indole-3-lactic acid. EcN-Ahr ameliorated ethanol-induced liver disease in C57BL/6 mice. EcN-Ahr upregulated intestinal gene expression of Cyp1a1, Nrf2, Il22, Reg3b, and Reg3g, and increased Il22-expressing type 3 innate lymphoid cells. In addition, EcN-Ahr reduced translocation of bacteria to the liver. The beneficial effect of EcN-Ahr was abrogated in mice lacking Ahr expression in Il22-producing immune cells.
CONCLUSIONS
CONCLUSIONS
Our findings indicate that tryptophan metabolites locally produced by engineered gut bacteria mitigate liver disease via Ahr-mediated activation in intestinal immune cells.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
856-867Subventions
Organisme : NIAAA NIH HHS
ID : P50 AA011999
Pays : United States
Organisme : NIH HHS
ID : R37 AA020703
Pays : United States
Organisme : NIH HHS
ID : R01 AA24726
Pays : United States
Organisme : NIH HHS
ID : U01 AA026939
Pays : United States
Organisme : NIH HHS
ID : U01 AA026939-04S1
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK120515
Pays : United States
Organisme : NIAAA NIH HHS
ID : P50 AA011999
Pays : United States
Organisme : NIH HHS
ID : R37 AA020703
Pays : United States
Organisme : NIH HHS
ID : R01 AA24726
Pays : United States
Organisme : NIH HHS
ID : U01 AA026939
Pays : United States
Organisme : NIH HHS
ID : U01 AA026939-04S1
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK120515
Pays : United States
Informations de copyright
© 2023 Research Society on Alcohol. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.
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