Bile acid-receptor TGR5 deficiency worsens liver injury in alcohol-fed mice by inducing intestinal microbiota dysbiosis.
JHEP Rep
; 3(2): 100230, 2021 Apr.
Article
em En
| MEDLINE
| ID: mdl-33665587
ABSTRACT
BACKGROUND & AIMS:
Bile-acid metabolism and the intestinal microbiota are impaired in alcohol-related liver disease. Activation of the bile-acid receptor TGR5 (or GPBAR1) controls both biliary homeostasis and inflammatory processes. We examined the role of TGR5 in alcohol-induced liver injury in mice.METHODS:
We used TGR5-deficient (TGR5-KO) and wild-type (WT) female mice, fed alcohol or not, to study the involvement of liver macrophages, the intestinal microbiota (16S sequencing), and bile-acid profiles (high-performance liquid chromatography coupled to tandem mass spectrometry). Hepatic triglyceride accumulation and inflammatory processes were assessed in parallel.RESULTS:
TGR5 deficiency worsened liver injury, as shown by greater steatosis and inflammation than in WT mice. Isolation of liver macrophages from WT and TGR5-KO alcohol-fed mice showed that TGR5 deficiency did not increase the pro-inflammatory phenotype of liver macrophages but increased their recruitment to the liver. TGR5 deficiency induced dysbiosis, independently of alcohol intake, and transplantation of the TGR5-KO intestinal microbiota to WT mice was sufficient to worsen alcohol-induced liver inflammation. Secondary bile-acid levels were markedly lower in alcohol-fed TGR5-KO than normally fed WT and TGR5-KO mice. Consistent with these results, predictive analysis showed the abundance of bacterial genes involved in bile-acid transformation to be lower in alcohol-fed TGR5-KO than WT mice. This altered bile-acid profile may explain, in particular, why bile-acid synthesis was not repressed and inflammatory processes were exacerbated.CONCLUSIONS:
A lack of TGR5 was associated with worsening of alcohol-induced liver injury, a phenotype mainly related to intestinal microbiota dysbiosis and an altered bile-acid profile, following the consumption of alcohol. LAYSUMMARY:
Excessive chronic alcohol intake can induce liver disease. Bile acids are molecules produced by the liver and can modulate disease severity. We addressed the specific role of TGR5, a bile-acid receptor. We found that TGR5 deficiency worsened alcohol-induced liver injury and induced both intestinal microbiota dysbiosis and bile-acid pool remodelling. Our data suggest that both the intestinal microbiota and TGR5 may be targeted in the context of human alcohol-induced liver injury.
ALD, alcohol-related liver diseases; ALT, alanine aminotransferase; Alc, alcohol; Alcoholic liver disease; BA, bile acids; BHI, brain heart infusion; Bile acid; C57, conventional mice; C57C57, conventional mice transplanted with their own IM; CA, cholic acid; CCL, CC motif chemokine ligands; CDCA, chenodeoxycholic acid; Col1a1, collagen type-I alpha-1 chain; DCA, deoxycholic acid; Dysbiosis; FDR, false-discovery rate; FXR, farnesoid X receptor; Gut-liver axis; IM, intestinal microbiota; Inflammation; KC, Kupffer cells; KO, knockout; Kupffer cells; LCA, lithocholic acid; LDA, linear discriminative analysis; LEfsE, LDA effect size; MCA, muricholic acid; MO, monocytes/macrophages; Microbiome; NFkB, nuclear factor-kappa B; OTU, operational taxonomic unit; PCA, principal component analysis; PCoA, principal coordinate analysis; PICRUSt, phylogenetic investigation of communities by reconstruction of unobserved states; RIN, RNA integrity number; TBA, total bile acids; TG, triglycerides; TGF, transforming growth factor; TIMP1, tissue inhibitor of metalloproteinase 1; TNF, tumour necrosis factor; UDCA, ursodeoxycholic acid; WT, wild-type; WTKO, WT mice transplanted with the IM of TGR5-KO mice; alpha-SMA, alpha-smooth muscle actin; mMMP9, matrix metallopeptidase 9
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Base de dados:
MEDLINE
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article