The Candida albicans exotoxin candidalysin promotes alcohol-associated liver disease.
Adult
Aged
Animals
Candida albicans
/ metabolism
Case-Control Studies
Cells, Cultured
Disease Models, Animal
Exotoxins
/ analysis
Feces
/ microbiology
Female
Fungal Proteins
/ analysis
Gastrointestinal Microbiome
Hepatitis, Alcoholic
/ metabolism
Hepatocytes
/ drug effects
Humans
Lectins, C-Type
/ deficiency
Liver Diseases, Alcoholic
/ metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Middle Aged
Severity of Illness Index
Alcohol-related liver disease
Microbiome
Microbiota
Mycobiome
Journal
Journal of hepatology
ISSN: 1600-0641
Titre abrégé: J Hepatol
Pays: Netherlands
ID NLM: 8503886
Informations de publication
Date de publication:
03 2020
03 2020
Historique:
received:
23
05
2019
revised:
22
08
2019
accepted:
23
09
2019
pubmed:
14
10
2019
medline:
15
9
2021
entrez:
14
10
2019
Statut:
ppublish
Résumé
Alcohol-associated liver disease is a leading indication for liver transplantation and a leading cause of mortality. Alterations to the gut microbiota contribute to the pathogenesis of alcohol-associated liver disease. Patients with alcohol-associated liver disease have increased proportions of Candida spp. in the fecal mycobiome, yet little is known about the effect of intestinal Candida on the disease. Herein, we evaluated the contributions of Candida albicans and its exotoxin candidalysin in alcohol-associated liver disease. C. albicans and the extent of cell elongation 1 (ECE1) were analyzed in fecal samples from controls, patients with alcohol use disorder and those with alcoholic hepatitis. Mice colonized with different and genetically manipulated C. albicans strains were subjected to the chronic-plus-binge ethanol diet model. Primary hepatocytes were isolated and incubated with candidalysin. The percentages of individuals carrying ECE1 were 0%, 4.76% and 30.77% in non-alcoholic controls, patients with alcohol use disorder and patients with alcoholic hepatitis, respectively. Candidalysin exacerbates ethanol-induced liver disease and is associated with increased mortality in mice. Candidalysin enhances ethanol-induced liver disease independently of the β-glucan receptor C-type lectin domain family 7 member A (CLEC7A) on bone marrow-derived cells, and candidalysin does not alter gut barrier function. Candidalysin can damage primary hepatocytes in a dose-dependent manner in vitro and is associated with liver disease severity and mortality in patients with alcoholic hepatitis. Candidalysin is associated with the progression of ethanol-induced liver disease in preclinical models and worse clinical outcomes in patients with alcoholic hepatitis. Candidalysin is a peptide toxin secreted by the commensal gut fungus Candida albicans. Candidalysin enhances alcohol-associated liver disease independently of the β-glucan receptor CLEC7A on bone marrow-derived cells in mice without affecting intestinal permeability. Candidalysin is cytotoxic to primary hepatocytes, indicating a direct role of candidalysin on ethanol-induced liver disease. Candidalysin might be an effective target for therapy in patients with alcohol-associated liver disease.
Sections du résumé
BACKGROUND & AIMS
Alcohol-associated liver disease is a leading indication for liver transplantation and a leading cause of mortality. Alterations to the gut microbiota contribute to the pathogenesis of alcohol-associated liver disease. Patients with alcohol-associated liver disease have increased proportions of Candida spp. in the fecal mycobiome, yet little is known about the effect of intestinal Candida on the disease. Herein, we evaluated the contributions of Candida albicans and its exotoxin candidalysin in alcohol-associated liver disease.
METHODS
C. albicans and the extent of cell elongation 1 (ECE1) were analyzed in fecal samples from controls, patients with alcohol use disorder and those with alcoholic hepatitis. Mice colonized with different and genetically manipulated C. albicans strains were subjected to the chronic-plus-binge ethanol diet model. Primary hepatocytes were isolated and incubated with candidalysin.
RESULTS
The percentages of individuals carrying ECE1 were 0%, 4.76% and 30.77% in non-alcoholic controls, patients with alcohol use disorder and patients with alcoholic hepatitis, respectively. Candidalysin exacerbates ethanol-induced liver disease and is associated with increased mortality in mice. Candidalysin enhances ethanol-induced liver disease independently of the β-glucan receptor C-type lectin domain family 7 member A (CLEC7A) on bone marrow-derived cells, and candidalysin does not alter gut barrier function. Candidalysin can damage primary hepatocytes in a dose-dependent manner in vitro and is associated with liver disease severity and mortality in patients with alcoholic hepatitis.
CONCLUSIONS
Candidalysin is associated with the progression of ethanol-induced liver disease in preclinical models and worse clinical outcomes in patients with alcoholic hepatitis.
LAY SUMMARY
Candidalysin is a peptide toxin secreted by the commensal gut fungus Candida albicans. Candidalysin enhances alcohol-associated liver disease independently of the β-glucan receptor CLEC7A on bone marrow-derived cells in mice without affecting intestinal permeability. Candidalysin is cytotoxic to primary hepatocytes, indicating a direct role of candidalysin on ethanol-induced liver disease. Candidalysin might be an effective target for therapy in patients with alcohol-associated liver disease.
Identifiants
pubmed: 31606552
pii: S0168-8278(19)30599-9
doi: 10.1016/j.jhep.2019.09.029
pmc: PMC7031049
mid: NIHMS1545263
pii:
doi:
Substances chimiques
ECE1 protein, Candida albicans
0
Exotoxins
0
Fungal Proteins
0
Lectins, C-Type
0
dectin 1
0
Types de publication
Clinical Trial
Journal Article
Multicenter Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
391-400Subventions
Organisme : NIAAA NIH HHS
ID : R01 AA020703
Pays : United States
Organisme : BLRD VA
ID : I01 BX004594
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK120515
Pays : United States
Organisme : NIAAA NIH HHS
ID : R01 AA024726
Pays : United States
Organisme : NIAAA NIH HHS
ID : P50 AA011999
Pays : United States
Organisme : NIAAA NIH HHS
ID : U01 AA026939
Pays : United States
Informations de copyright
Published by Elsevier B.V.
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