Bile acid-receptor TGR5 deficiency worsens liver injury in alcohol-fed mice by inducing intestinal microbiota dysbiosis
Résumé
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.
Mots clés
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
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
Domaines
Sciences du Vivant [q-bio]
Origine : Publication financée par une institution