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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:Alterations in Bile Acid Physiology in Wilson Disease
| PRJNA1210982 | ENA
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 MPy, a former antihistamine and anticholinergic drug, was withdrawn in the 1970ties due to its ability to initiate hepatocarcinogenesis and is now used to induce hepatobiliary injury and biliary epithelial cell hyperplasia.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:Summary Ex vivo liver normothermic machine perfusion (NMP) does not fully recapitulate physiological liver function due to the absence of the enterohepatic circulation as only infusion of the bile acid taurocholate (TCA) is applied in most protocols. In this study we characterized the de novo bile acid synthesis and cholesterol homeostasis during liver NMP. We hypothesized that addition of a more diverse pool of (conjugated)bile acids during liver NMP would decrease the metabolic burden of de novo synthesis and thereby improve liver function during NMP. Method First, human and porcine livers were perfused for 360 min at 37°C and perfusate containing TCA (gene expression at t=0min and t=360min was measured by RNAseq). Next, the infusion of different conjugated bile acid mixes was assessed during porcine and human liver perfusion. Perfusate, bile and tissue samples were obtained to study liver viability, functionality, gene expression (qPCR), cholesterol and bile acid levels. Result During human and porcine perfusions with TCA infusion, composition of bile was comparable to literature however, synthesis rates were above physiological average and a decrease over time in cholesterol perfusate levels was observed. Additionally, over time a decreased expression of bile acid synthesis related genes, increased gene expression of cholesterol metabolism related genes and decreased expression in bile acid-dependent uptake and efflux transporters were detected (RNAseq). Upon infusion of a conjugated bile acid mix lower AST and ALT values and stable cholesterol homeostasis was] observed after 720 min of perfusion. Perfused human livers showed appropriate function and good functioning livers showed rapid bile acid clearance from the perfusate into the bile. Conclusion This study reveals new insights that infusion of (un)conjugated bile acids in NMP alleviated the burden of the de novo bile acid synthesis and improved liver function.
2025-10-14 | GSE279712 | GEO
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: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:Background: Myosin 5b (Myo5b) is a motor protein critical for trafficking proteins to the apical surface of intestinal epithelial cells. Inactivating mutations in MYO5B cause Microvillus Inclusion Disease (MVID), a congenital diarrhea disorder that often leads to liver cholestasis. While Myo5b’s role in the intestine is well characterized, its function in the liver remains unclear. Methods & Results: To define the hepatic consequences of Myo5b loss, we analyzed germline Myo5b knockout (KO) mice. Bulk RNA-seq of KO livers revealed significant transcriptomic alterations, notably downregulation of genes linked to cell proliferation. Immunostaining confirmed reduced Ki67, phospho-histone H3, and cyclin D1 expression, along with impaired growth of liver organoids in Myo5b deficient mice. Histology and lipid staining showed steatosis and enlarged lipid droplets, with gene signatures favoring lipogenesis and ketogenesis in mice lacking Myo5b. Myo5b KO livers also displayed disrupted zonated gene expression and loss of zone 1 and zone 3 markers. Bile acid profiling revealed reduced hepatic bile acid levels, decreased expression of classical pathway genes (Cyp7a1, Cyp7b1), and compensatory upregulation of Cyp27a1. In the ileum, we observed mislocalization of the apical bile acid transporter ASBT and decreased levels of basolateral OSTβ, leading to impaired enterohepatic recycling and increased luminal bile acids. Conclusions: These findings reveal a previously unrecognized role for Myo5b in liver proliferation, metabolic zonation, and bile acid homeostasis, highlighting its importance in maintaining hepatobiliary function.
2026-01-11 | GSE315772 | 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