Dysregulated meta-organismal metabolism of aromatic amino acids in alcohol-associated liver disease.
Journal
Hepatology communications
ISSN: 2471-254X
Titre abrégé: Hepatol Commun
Pays: United States
ID NLM: 101695860
Informations de publication
Date de publication:
01 11 2023
01 11 2023
Historique:
received:
30
06
2023
accepted:
26
07
2023
medline:
13
10
2023
pubmed:
11
10
2023
entrez:
11
10
2023
Statut:
epublish
Résumé
Chronic alcohol consumption impairs gut barrier function and perturbs the gut microbiome. Although shifts in bacterial communities in patients with alcohol-associated liver disease (ALD) have been characterized, less is known about the interactions between host metabolism and circulating microbe-derived metabolites during the progression of ALD. A large panel of gut microbiome-derived metabolites of aromatic amino acids was quantified by stable isotope dilution liquid chromatography with online tandem mass spectrometry in plasma from healthy controls (n = 29), heavy drinkers (n = 10), patients with moderate (n = 16) or severe alcohol-associated hepatitis (n = 40), and alcohol-associated cirrhosis (n = 10). The tryptophan metabolites, serotonin and indole-3-propionic acid, and tyrosine metabolites, p-cresol sulfate, and p-cresol glucuronide, were decreased in patients with ALD. Patients with severe alcohol-associated hepatitis and alcohol-associated cirrhosis had the largest decrease in concentrations of tryptophan and tyrosine-derived metabolites compared to healthy control. Western blot analysis and interrogation of bulk RNA sequencing data from patients with various liver pathologies revealed perturbations in hepatic expression of phase II metabolism enzymes involved in sulfonation and glucuronidation in patients with severe forms of ALD. We identified several metabolites decreased in ALD and disruptions of hepatic phase II metabolism. These results indicate that patients with more advanced stages of ALD, including severe alcohol-associated hepatitis and alcohol-associated cirrhosis, had complex perturbations in metabolite concentrations that likely reflect both changes in the composition of the gut microbiome community and the ability of the host to enzymatically modify the gut-derived metabolites.
Sections du résumé
BACKGROUND
Chronic alcohol consumption impairs gut barrier function and perturbs the gut microbiome. Although shifts in bacterial communities in patients with alcohol-associated liver disease (ALD) have been characterized, less is known about the interactions between host metabolism and circulating microbe-derived metabolites during the progression of ALD.
METHODS
A large panel of gut microbiome-derived metabolites of aromatic amino acids was quantified by stable isotope dilution liquid chromatography with online tandem mass spectrometry in plasma from healthy controls (n = 29), heavy drinkers (n = 10), patients with moderate (n = 16) or severe alcohol-associated hepatitis (n = 40), and alcohol-associated cirrhosis (n = 10).
RESULTS
The tryptophan metabolites, serotonin and indole-3-propionic acid, and tyrosine metabolites, p-cresol sulfate, and p-cresol glucuronide, were decreased in patients with ALD. Patients with severe alcohol-associated hepatitis and alcohol-associated cirrhosis had the largest decrease in concentrations of tryptophan and tyrosine-derived metabolites compared to healthy control. Western blot analysis and interrogation of bulk RNA sequencing data from patients with various liver pathologies revealed perturbations in hepatic expression of phase II metabolism enzymes involved in sulfonation and glucuronidation in patients with severe forms of ALD.
CONCLUSIONS
We identified several metabolites decreased in ALD and disruptions of hepatic phase II metabolism. These results indicate that patients with more advanced stages of ALD, including severe alcohol-associated hepatitis and alcohol-associated cirrhosis, had complex perturbations in metabolite concentrations that likely reflect both changes in the composition of the gut microbiome community and the ability of the host to enzymatically modify the gut-derived metabolites.
Identifiants
pubmed: 37820283
doi: 10.1097/HC9.0000000000000284
pii: 02009842-202311010-00005
pmc: PMC10578770
pii:
doi:
Substances chimiques
Amino Acids, Aromatic
0
Tryptophan
8DUH1N11BX
Tyrosine
42HK56048U
Types de publication
Comparative Study
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK120679
Pays : United States
Organisme : NIDDK NIH HHS
ID : U01 DK061732
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL144651
Pays : United States
Organisme : NHLBI NIH HHS
ID : P01 HL147823
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL103866
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK130227
Pays : United States
Organisme : NIAAA NIH HHS
ID : U01 AA021890
Pays : United States
Organisme : NIAAA NIH HHS
ID : U01 AA026980
Pays : United States
Organisme : NIAAA NIH HHS
ID : U01 AA026976
Pays : United States
Organisme : NIAAA NIH HHS
ID : K08 AA028794
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK113196
Pays : United States
Organisme : NIAAA NIH HHS
ID : P50 AA024333
Pays : United States
Organisme : NIAAA NIH HHS
ID : R21 AA026398
Pays : United States
Organisme : NHLBI NIH HHS
ID : R56 HL141744
Pays : United States
Organisme : NIAAA NIH HHS
ID : U01 AA021893
Pays : United States
Organisme : NIAAA NIH HHS
ID : U01 AA021901
Pays : United States
Organisme : NIGMS NIH HHS
ID : P20 GM113226
Pays : United States
Organisme : NIDDK NIH HHS
ID : U01 DK062470
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM119174
Pays : United States
Organisme : NIAAA NIH HHS
ID : P50 AA024337
Pays : United States
Informations de copyright
Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.
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