Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Bile Acid Analogs with Anti-germination Activities for Prophylaxis of Clostridioides difficile Infection Alter Bile Acid Homeostasis in the Enterohepatic Cycle

ABSTRACT: We previously reported that two bile acid (BA) analogs CamSA and CA-Quin demon-strate potent anti-germination activity against Clostridioides difficile (C. difficile) spores, protecting rodents from C. difficile infections. Here we further evaluated the impact of these analogs on the hepatic transcriptome and BA homeostasis in vivo by focusing BA profiles on the liver, feces, and chyme as well as hepatic transcriptome after a 7-day treatment. The two compounds demonstrated similar impact on BA profiles among the three samples, with significantly increased BA excretion in feces. This change is aligned with significantly altered expression of genes involved in BA homeostasis in both liver and gut tissues. Also, both compounds increased levels of unconjugated BAs in the feces, indicating an elevated activity of gut microbiota (GM). Notably, fecal levels of anti-c. difficile germination chenodeoxycholate and pro-germination taurocholate are signifi-cantly increased and decreased by the treatments, respectively. While hepatic tran-scriptome did not show significant toxicity, altered genes are enriched in pathways as-sociated with GM activity and lipid metabolism. Overall, our study suggests that in vivo CamSA and CA-Quin treatment demonstrated minimal hepatoxicity but significantly altered BA homeostasis and potentially favorable improvement for GM profiles that together inhibit C. difficle germination.

ORGANISM(S): Mus musculus

PROVIDER: GSE309065 | GEO | 2025/09/28

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Postprandial FGF19 signaling-induced phosphorylation of FXR by Src modulates its activity in bile acid homeostasis

Project description:Farnesoid-X-Receptor (FXR) plays a central role in maintaining bile acid (BA) homeostasis by transcriptional control of numerous enterohepatic genes, including intestinal FGF19, a hormone that strongly represses hepatic BA synthesis. How activation of the FGF19 receptor at the membrane is transmitted to the nucleus for transcriptional regulation of BA levels and whether FGF19 signaling posttranslationally modulates function of FXR remain largely unknown. Here we show that FXR is phosphorylated at Y67 by non-receptor tyrosine kinase, Src, in response to postprandial FGF19, which is critical for its nuclear localization and transcriptional regulation of BA levels. Liver-specific expression of phospho-defective Y67F-FXR or Src-downregulation in mice result in impaired homeostatic responses to acute BA feeding, and exacerbate cholestatic pathologies upon drug-induced hepatobiliary insults. Also, the hepatic FGF19-Src-FXR pathway is defective in primary biliary cirrhosis patients. This study identifies Src-mediated FXR phosphorylation as a potential therapeutic target and biomarker for BA-related enterohepatic diseases.

2018-04-27 | GSE113707 | GEO

Bile Acid Analogs with Anti-germination Activities for Prophylaxis of Clostridioides difficile Infection Alter Bile Acid Homeostasis in the Enterohepatic Cycle

Project description:Bile Acid Analogs with Anti-germination Activities for Prophylaxis of Clostridioides difficile Infection Alter Bile Acid Homeostasis in the Enterohepatic Cycle

| PRJNA1333885 | ENA

Thyroid hormone-responsive miR-378 modulates cholesterol homeostasis by regulating hepatic bile acid synthesis

Project description:An improved mechanistic understanding of the thyroid hormone (TH) action on bile acid (BA) synthetic pathway, the major route for cholesterol elimination, will facilitate the identification of novel therapeutic targets for hypercholesterolemia. Here, we show that hepatic miR-378 is positively regulated by TH. Transient overexpression of miR-378 in the liver of mice reduces the serum cholesterol levels, which is accompanied with an upregulation of key enzymes involved in the intrahepatic conversion of cholesterol to BAs. Importantly, transgenic mice with liver-specific and moderate overexpression of miR-378 also display a decrease in serum cholesterol levels accompanied with an enhanced BA synthesis and are resistant to diet-induced hypercholesterolemia. In contrast, mice lacking miR-378 exhibit an elevation of serum cholesterol levels accompanied with an impaired BA synthesis. Mechanistic studies reveal that hepatic miR-378 regulates BA synthesis and cholesterol homeostasis through its direct target gene MAFG, which is a transcriptional repressor of BA synthetic genes. We also show that miR-378 serves as an essential component in either incoherent or coherent feed-forward loop to confer robust and precise controls on BA synthesis in response to TH signalling. Together, we identify a previously undescribed miR-378-mediated mechanism underlying the cholesterol-lowering effect of TH. Our findings not only add a new dimension to our understanding the regulation of BA synthesis by TH, but also provide new therapeutic regimens to manage serum cholesterol levels

2019-10-29 | GSE139491 | GEO

H4K12 Lactylation-activated c-JUN signaling aggravates bile acid dysfunction in intrahepatic cholestasis during pregnancy

Project description:The occurrence of hepatic cholestasis during pregnancy is accompanied by the disorders of glucose and lipid metabolism, especially the acceleration of glycolysis. Here, we reported a novel mechanism that the glycolysis metabolic intermediate lactate-induced histone 4 at K12 (H4K12) hyperlactylation aggravates bile acid (BA) dysfunction in intrahepatic cholestasis during pregnancy by activating c-JUN and in turn facilitating RXRɑ cytoplasmic relocalization. Lactylome analysis in livers of late pregnant sows with high levels of BA revealed induction of H4K12 hyperlactylation. Target correction of aberrant histone lactylation prevented the hepatic BA disorders in both sows and mice models. Mechanistically, H4K12la was enriched in promoter regions of c-JUN and activated its expression Moreover, activated c-JUN facilitated the RXRɑ phosphorylation and cytoplasmic relocalization, which resulted in the activation of whole BA synthesis pathway and inhibition of BA transport pathway. Inhibitor of the glycolysis pathway and lactate inhibitor as nutritional intervention ameliorated BA metabolic disorder in pregnant sows and cholestasis in mice. Our findings demonstrate the catalytic role of lactate on hepatic BA disorders in late pregnancy, we also provided a novel pattern of nutritional intervention to precisely target and regulate bile acid metabolism, and may open the new direction of nutritional epigenetic regulation of metabolic diseases.

2023-09-21 | GSE214238 | GEO

Hepatic thyroid hormone signalling modulates glucose homeostasis through the regulation of GLP-1 production via bile acid-mediated FXR antagonism

Project description:A greater understanding of the glucose homeostasis mediated by glucagon-like peptide-1 (GLP-1) will facilitate the development of novel glucose-lowering treatments. Here we show that improved glucose metabolism in hypothyroid mice after treatment of T3, the active form of thyroid hormone (TH), is accompanied with increased GLP-1 production and insulin secretion. Treatment of a GLP-1 receptor antagonist is able to attenuate the observed T3 effect on insulin and glucose levels, suggesting that GLP-1 is critically involved in the regulation of glucose homeostasis by T3. By using a mouse model lacking hepatic TH receptor β (TRβ) and a liver-specific TRβ-selective agonist, we demonstrate that TRβ-mediated hepatic TH signalling is not only required for the regulation of GLP-1 production by T3 but also the insulinotropic and glucose-lowering effects of T3. Accordingly, administration of the liver-targeted TRβ-selective agonist is capable of increasing GLP-1 and insulin levels and alleviating hyperglycemia in diet-induced obesity. Mechanistically, through suppressing CYP8B1 expression, T3 shapes the bile acid (BA) composition and increases the levels of Farnesoid X receptor (FXR)-antagonistic BAs, thereby potentiating the GLP-1 production and insulin secretion by repressing intestinal FXR signalling. Consistently, correlations between the T3 levels and either GLP-1 or FXR-antagonistic BA levels can be observed in euthyroid human subjects. Thus, our study reveals a previously undescribed role of hepatic TH signalling in glucose homeostasis through the regulation of GLP-1 production via BA-mediated FXR antagonism, which will underpin the development of novel therapeutics.

2022-09-23 | GSE184055 | GEO

Hepatic thyroid hormone signalling modulates glucose homeostasis through the regulation of GLP-1 production via bile acid-mediated FXR antagonism [RNA-seq]

2022-09-23 | GSE184261 | GEO

Disrupting bile acid metabolism by suppressing Fxr causes hepatocellular carcinoma induced by YAP activation

Project description:Bile acid (BA) production is a critical metabolic function of the liver, and its disruption leads to various liver diseases including hepatocellular carcinoma (HCC). However, the underlying molecular mechanism remained elusive. Here, we report that BA metabolism is directly controlled by a previously unidentified repressor function of YAP, a transcriptional activator known to promote HCC formation. We show in hepatocytes, activated YAP suppressed Fxr, a BA-sensing nuclear receptor that critically regulates BA production and export. The repressor function of activated YAP induced cholestasis damaged the liver, and altered liver and serum BA concentrations and composition. Specifically, YAP activation inhibited expression of an Fxr target gene, Bsep (Abcb11), impairing BA exportation and injuring hepatocytes. Elevated BA in the blood due to hepatocyte injury further activated hepatic YAP, resulting in a vicious cycle leading to HCC. In both mouse liver and human HCC patient samples, transcriptomic analysis negatively correlated YAP and Fxr activities. Mechanistically, Fxr was found to bind Teads in a DNA-binding-independent manner; and Teads recruited YAP to epigenetically reprogram Fxr by replacing the histone acetyltransferase, P300, with the histone deacetylase, HDAC1. Importantly, alleviating YAP repressor function in BA metabolism by activating Fxr with its agonist GW4064, inhibiting HDAC1 with Entinostat, or overexpressing Bsep, reduced cholestatic phenotypes including hepatic injury, fibrosis, and inflammation, alleviating the HCC caused by YAP activation. Our results identify Yap's transcriptional repressor role as a key driver of Yap-induced HCC and BA metabolism as a potential therapeutic target for HCC.

2025-02-10 | GSE272343 | GEO

Gut microbiota ameliorates hepatic fibrosis through modulating intestinal bile acid metabolism and hepatocyte pyroptosis (Hepatic fibrosis serum)

Project description:Hepatic fibrosis decreased feces bile acid level. Hepatic fibrosis increased serum bile acid. This result showed that hepatic fibrosis inhibited the excretion of bile acid in clinical patients. This result provided phenotype for hepatic fibrosis patients. Bile acid was important indexes for liver injury. TCDCA was important, and it play toxicity effect through ferroptosis and apoptosis. The research for other bile acid such CA, UDCA, TUDCA, TDCA, LCA, TLCA would be important. Hepatic fibrosis serum (sample 1) analysis is reported in the current study <a href='https://www.ebi.ac.uk/metabolights/MTBLS6732' rel='noopener noreferrer' target='_blank'>MTBLS6732</a>.Hepatic fibrosis feces (sample 2) analysis is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS6742' rel='noopener noreferrer' target='_blank'>MTBLS6742</a>.Hepatic fibrosis serum+feces (sample 3) analysis is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS6728' rel='noopener noreferrer' target='_blank'>MTBLS6728</a>.

2023-03-17 | MTBLS6732 | MetaboLights

Gut microbiota ameliorates hepatic fibrosis through modulating intestinal bile acid metabolism and hepatocyte pyroptosis (Hepatic fibrosis feces)

Project description:Hepatic fibrosis decreased feces bile acid level. Hepatic fibrosis increased serum bile acid. This result showed that hepatic fibrosis inhibited the excretion of bile acid in clinical patients. This result provided phenotype for hepatic fibrosis patients. Bile acid was important indexes for liver injury. TCDCA was important, and it play toxicity effect through ferroptosis and apoptosis. The research for other bile acid such CA, UDCA, TUDCA, TDCA, LCA, TLCA would be important. Hepatic fibrosis feces (sample 2) analysis is reported in the current study <a href='https://www.ebi.ac.uk/metabolights/MTBLS6742' rel='noopener noreferrer' target='_blank'>MTBLS6742</a>.Hepatic fibrosis serum (sample 1) analysis is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS6732' rel='noopener noreferrer' target='_blank'>MTBLS6732</a>.Hepatic fibrosis serum+feces (sample 3) analysis is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS6728' rel='noopener noreferrer' target='_blank'>MTBLS6728</a>.

2023-03-17 | MTBLS6742 | MetaboLights

Fibroblast growth factor 21 ameliorates cholestatic liver injury via a hepatic FGFR4-JNK pathway

Project description:Cholestasis is characterized by hepatic accumulation of cytotoxic bile acids (BAs), which often subsequentlyleads to liver injury, inflammation, fibrosis, and ultimately liver cirrhosis. Fibroblast growth factor 21 (FGF21) is a liver secreted hormone with pleiotropic effects on the homeostasis of glucose, lipid, and energy metabolism. However, whether hepatic FGF21 plays a role in cholestatic liver injury remains elusive. We found that serum and hepatic FGF21 levels were significantly increased in response to cholestatic liver injury. Hepatocyte-specific deletion of Fgf21 exacerbated hepatic accumulation of BAs, further accentuating liver injury. Consistently, administration of rFGF21 ameliorated cholestatic liver injury in α-naphthylisothiocyanate (ANIT)-treated and Mdr2 deficiency mice. Mechanically, FGF21 activated a hepatic FGFR4-JNK signaling pathway to decrease Cyp7a1 expression, thereby reducing hepatic BAs pool. Our study demonstrates that hepatic FGF21 functions as an adaptive stress-responsive signal to downregulate BA biosynthesis, thereby ameliorating cholestatic liver injury, and FGF21 analogs may represent a candidate therapy for cholestatic liver diseases.

2023-08-19 | GSE240733 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data