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ABSTRACT:
PROVIDER: PRJNA998544 | ENA |
REPOSITORIES: ENA
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Project description:Morphine and its pharmacological derivatives are the most prescribed analgesics for moderate to severe pain management. However, chronic use of morphine reduces pathogen clearance and induces bacterial translocation across the gut barrier. The enteric microbiome has been shown to play a critical role in the preservation of the mucosal barrier function and metabolic homeostasis. Here, we show for the first time, using bacterial 16s rDNA sequencing, that chronic morphine treatment significantly alters the gut microbial composition and induces preferential expansion of the gram-positive pathogenic and reduction of bile-deconjugating bacterial strains. A significant reduction in both primary and secondary bile acid levels was seen in the gut, but not in the liver with morphine treatment. Morphine induced microbial dysbiosis and gut barrier disruption was rescued by transplanting placebo-treated microbiota into morphine-treated animals, indicating that microbiome modulation could be exploited as a therapeutic strategy for patients using morphine for pain management. In this study, we establish a link between the two phenomena, namely gut barrier compromise and dysregulated bile acid metabolism. We show for the first time that morphine fosters significant gut microbial dysbiosis and disrupts cholesterol/bile acid metabolism. Changes in the gut microbial composition is strongly correlated to disruption in host inflammatory homeostasis13,14 and in many diseases (e.g. cancer/HIV infection), persistent inflammation is known to aid and promote the progression of the primary morbidity. We show here that chronic morphine, gut microbial dysbiosis, disruption of cholesterol/bile acid metabolism and gut inflammation; have a linear correlation. This opens up the prospect of devising minimally invasive adjunct treatment strategies involving microbiome and bile acid modulation and thus bringing down morphine-mediated inflammation in the host.
2016-06-01 | E-MTAB-3722 | biostudies-arrayexpress
Project description:Here, we extensively characterize noradrenaline (NA) mediated transcriptomic response during acute stress in the mouse hippocampus. Combining for the first time bulk mRNA-sequencing and selective pharmacological manipulations of the NA system. We show that the NA mediates robust stress associated transcriptomic alterations across the dorsal and ventral hippocampus via β-adrenergic receptors
2023-02-02 | GSE218315 | GEO
Project description:We investigated a drug-induced liver injury (DILI) model in rats induced by methapyrilene (MPy) administration. MPy, a former antihistamine and anticholinergic drug, was withdrawn in the 1970ties due to its ability to initiate hepatocarcinogenesis and is now used to induce hepatobiliary injury and biliary epithelial cell hyperplasia. Male Wistar rats (8–10 weeks old, weighing 170–200 g) were randomly assigned to three dosing groups (n=6 per group and time-point) and dosed with MPy at 0, 30 and 80 mg/kg/day by oral gavage. After 4, 8 or 15 days, or after 14 days followed by a recovery period of 10 days (day 24) rats were sacrificed. Increased levels of ALAT, ASAT, AP and ɣ-GT as well as bili-t and total bile acids indicated liver damage (AP and ɣGT indicating biliary effects). They were detectable on day 7 at the high dose of 80 mg/kg MPy and persisted until day 15 at end of treatment. Histopathologically, vacuolation and necrosis of the hepatocytes (predominantly in the periportal region) were seen starting on day 3 - especially in animals treated with 80 mg/kg MPy. These findings were accompanied by periportal mononuclear inflammatory cell filtration. Bile duct proliferation, bile duct hyperplasia and increased numbers of mitoses of hepatocytes were evident at all treatment time points. The frequency and severity of these findings increased with dose and duration of the treatment. Gene expression analysis in liver tissues revealed highly significant transcriptional changes in the high dose group, detectable on day 4 and intensifying over time. Besides genes associated with apoptosis (CASP4, CASP12), detoxification (CYB4B) and proliferation (p21, CCNG1) several were related to bile acid metabolism or transport. For example, bile acid exporters OATP1, NTCP, OATP4 and MOAT1/ OATPB as well as the putative bile acid metabolizing enzymes AMACR, BAAT and ACOX2 were found down regulated in response to MPy treatment. In contrast, mRNAs encoding putative bile acid importers MRP2 and ABCC4 / MRP4 were found up regulated. Most of the deregulated levels returned to control values during the recovery phase except OATP1, MOAT1/ OATPB, which remained slightly elevated. Interestingly, OATP4 followed an inverse trend of deregulation after 10 days of recovery, presumably due to overcompensation. Overall, the expression changes found associated with bile acid metabolism or transport could be linked to detected bile acid level alterations in liver and plasma.
2017-07-31 | GSE95470 | GEO
Project description:Specific bile acids are potent signaling molecules that modulate metabolic pathways affecting lipid, glucose and bile acid homeostasis, and the microbiota. Bile acids are synthesized from cholesterol in the liver, and the key enzymes involved in bile acid synthesis (Cyp7a1, Cyp8b1) are regulated transcriptionally by the nuclear receptor FXR. We have identified an FXR-regulated pathway upstream of a transcriptional repressor that controls multiple bile acid metabolism genes. We identify MafG as an FXR target gene and show that hepatic MAFG overexpression represses genes of the bile acid synthetic pathway and modifies the biliary bile acid composition. In contrast, loss-of-function studies using MafG(+/-) mice causes de-repression of the same genes with concordant changes in biliary bile acid levels. Finally, we identify functional MafG response elements in bile acid metabolism genes using ChIP-seq analysis. Our studies identify a molecular mechanism for the complex feedback regulation of bile acid synthesis controlled by FXR.
2016-02-04 | GSE77529 | GEO
Project description:Biliary reverse cholesterol transport (RCT) plays a crucial role in cholesterol clearance and regulation of atherogenesis. San-wei-tan-xiang capsule (SWTX), a traditional Chinese medicine, has shown potential in inhibiting atherogenesis by increasing high-density lipoprotein (HDL) cholesterol levels and promoting macrophage-mediated cholesterol efflux. However, the specific role of HDL-driven cholesterol metabolism in the anti-atherogenic effects of SWTX remains unclear. In this study, liquid chromatography coupled with tandem mass spectrometry was used to analyze the circulating metabolic profile, and RNA sequencing was performed on liver samples from ApoE−/− mice fed a cholesterol-enriched diet. We found that SWTX treatment induced significantly differential expression of metabolites and genes involved in cholesterol and lipid metabolism, as well as bile secretion pathways, which are critical for HDL-driven biliary RCT. Furthermore, alterations in L-carnitine and choline metabolism induced by SWTX treatment was involved in the atheroprotective effects of SWTX. Notably, SWTX treatment led to a significant increase in the expression of cholesterol 7α-hydroxylase (CYP7A1), a key enzyme involved in bile acid synthesis during atherogenesis. Additionally, the expression of CYP7A1 and CYP7A1-mediated bile acid secretion were enhanced by the addition of choline in hepatic cells, suggesting that SWTX-induced elevation of choline metabolic products may contribute to the upregulation of CYP7A1 and CYP7A1-mediated biliary RCT. Overall, SWTX demonstrated its ability to attenuate atherosclerotic plaque formation, which can be attributed to alterations in carnitine and choline metabolism, as well as the modulation of CYP7A1-mediated HDL-driven biliary RCT.
2024-06-12 | GSE236672 | GEO
Project description:Many patients suffer from chronic diarrhoea after surgical treatment for cancer in the right side of the colon.
The investigators’ main hypothesis is that colon cancer patients with chronic diarrhoea have a higher risk of bile acid malabsorption compared with colon cancer patients without diarrhoea.
The investigators also expect that a part of the cases of bile acid malabsorption is caused by underlying bacterial overgrowth in the small bowel.
The investigators assume that patients with severe bile acid malabsorption have a lower value of FGF19 in the blood compared to patients with moderate or none bile acid malabsorption.
Furthermore, it is assumed that patients with chronic diarrhoea and documented bile acid malabsorption after surgical treatment for right-sided colon cancer will get improved bowel function when treated with a bile acid binder, or antibiotics in case of bacterial overgrowth.
| 2309640 | ecrin-mdr-crc
Project description:The disruption of cholesterol homeostasis leads to an increase in cholesterol levels which results in the development of cardiovascular disease. Mitogen Inducible Gene 6 (Mig-6) is an immediate early response gene that can be induced by various mitogens, stresses, and hormones. To identify the metabolic role of Mig-6 in the liver, we conditionally ablated Mig-6 in the liver using the Albumin-Cre mouse model (Albcre/+Mig-6f/f; Mig-6d/d). Mig-6d/d mice exhibit hepatomegaly and fatty liver. Serum levels of total, LDL, and HDL cholesterol and hepatic lipid were significantly increased in the Mig-6d/d mice. The daily excretion of fecal bile acids was significantly decreased in the Mig-6d/d mice. DNA microarray analysis of mRNA isolated from the livers of these mice showed alterations in genes that regulate lipid metabolism, bile acid, and cholesterol synthesis, while the expression of genes that regulate biliary excretion of bile acid and triglyceride synthesis showed no difference in the Mig-6d/d mice compared to Mig-6f/f controls. These results indicate that Mig-6 plays an important role in cholesterol homeostasis and bile acid synthesis. Mice with liver specific conditional ablation of Mig-6 develop hepatomegaly and increased intrahepatic lipid and provide a novel model system to investigate the genetic and molecular events involved in the regulation of cholesterol homeostasis and bile acid synthesis. Defining the molecular mechanisms by which Mig-6 regulates cholesterol homeostasis will provide new insights into the development of more effective ways for the treatment and prevention of cardiovascular disease. Eight week old Mig-6f/f vs Mig-6d/d male mice after undergoing a 24 hour fast
2011-08-30 | E-GEOD-31752 | biostudies-arrayexpress
Project description:DNA microarray was applied to characterize the whole-genome expression profiles of placentas during ICP development. Pregnant women were categorized evenly into three groups: healthy group; mild ICP, with serum bile-acid concentration ranging from 10M-bM-^@M-^S40 uM; and severe ICP, with bile-acid concentration >40 uM.
2013-04-18 | E-GEOD-46157 | biostudies-arrayexpress