Human gut metagenome
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1058098 | ENA |
REPOSITORIES: ENA
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Project description:Intrahepatic cholestasis of pregnancy (ICP) is strongly associated withan increased risk of adverse perinatal outcomes. Total bile acid (TBA) levels in the late second or third trimester are a major factor in the diagnosis. Here, we sought to establish the miRNA expression profile of plasma exosomes of ICP and identify possible biomarkers for the diagnosis of ICP.
2022-08-09 | GSE210764 | GEO
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
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:The liver is the central organ critically regulating the balance of the metabolically potent yet toxic bile acids in the body. While genomic association studies have pointed to hepatic Sel1L – a critical component of mammalian Hrd1 ER-associated degradation (ERAD) machinery – as an influencer of serum bile acid levels, physiological relevance and mechanistic insights of ERAD in bile homeostasis remain unexplored. Using hepatocyte-specific Sel1L-deficient mouse models, we report that hepatic Sel1L-Hrd1 ERAD critically manages bile homeostasis in the body. Mice with hepatocyte-specific Sel1L developed intrahepatic cholestasis, with significant overload of bile acids in the liver and circulation under basal condition, and were hypersensitive to dietary bile acid challenge. By contrast, biliary bile acid and phosphatidylcholine levels were reduced, pointing to an export defect from hepatocytes. Unbiased proteomics analysis followed by biochemical assays revealed significant accumulation of the bile-stabilizing phosphatidylcholine exporter ATP-binding cassette 4 (Abcb4) in the ER of Sel1L-deficient livers, a gene associated with Progressive Familial Intrahepatic Cholestasis type III. Indeed, Abcb4 was a substrate of Sel1L-Hrd1 ERAD. Hence, hepatic Sel1L-Hrd1 ERAD maintains bile equilibrium via quality control of Abcb4 maturation in the ER.
2023-03-11 | PXD035243 | Pride
Project description:We used microarrays to provide a transcriptomic signature of different types of cholestasis evoked by 3 different drugs and obstructive surgery Adverse outcome pathways (AOPs) have been recently introduced as tools to map the mechanisms underlying toxic events relevant for chemical risk assessment. AOPs particularly depict the linkage between a molecular initiating event and an adverse outcome through a number of intermediate key events. An AOP has been previously introduced for cholestatic liver injury. The objective of this study was to test the robustness of this AOP for different types of cholestatic insult and the in vitro to in vivo extrapolation. For this purpose, in vitro samples from human hepatoma HepaRG cell cultures were exposed to cholestatic drugs (i.e. intrahepatic cholestasis), while in vivo samples were obtained from livers of cholestatic mice (i.e. extrahepatic cholestasis). The occurrence of cholestasis in vitro was confirmed through analysis of bile transporter functionality and bile acid analysis. Transcriptomic analysis revealed inflammation and oxidative stress as key events in both types of cholestatic liver injury. Major transcriptional differences between intrahepatic and extrahepatic cholestatic liver insults were observed at the level of cell death and metabolism. Novel key events identified by pathway analysis included endoplasmic reticulum stress in intrahepatic cholestasis, and autophagy and necroptosis in both intrahepatic as extrahepatic cholestasis. This study demonstrates that AOPs constitute dynamic tools that should be frequently updated with new input information.
2020-06-16 | GSE152494 | GEO
Project description:Intrahepatic cholestasis of pregnancy (ICP) is estimated to impact between 0.4% and 5% of pregnancies worldwide. This disease is associated with elevated maternal bile acids and frequently untoward neonatal outcomes such as respiratory distress and asphyxia. Multiple candidate genes have been implicated, but none have provided insight into the mechanisms of neonatal respiratory distress and death. Herein our studies demonstrate that maternal cholestasis (due to Abcb11 deficiency) produces 100% neonatal death within 24h due to atelectasis producing pulmonary hypoxia, which recapitulates the respiratory distress and asphyxia of human ICP. We show that these neonates have elevated pulmonary bile acids that are associated with disrupted structure of pulmonary surfactant. Maternal absence of Nr1i2 superimposed upon Abcb11 deficiency strongly increased neonatal survival and is directly related to reduced maternal bile acid concentrations. The mechanism accounting for reduced serum bile acids in the mothers deficient in both Nr1i2 and Abcb11 appears related to disrupted reabsorption of intestinal bile acids due to changes in transporter expression. These findings provide novel insights into pulmonary failure by revealing bile acids capability to disrupt the structure of surfactant producing collapsed alveoli, pulmonary failure and ultimately death. These findings have important implications for neonatal health especially when maternal bile acids are elevated during pregnancy and highlight a potential pathway and targets amenable to therapeutic intervention to ameliorate this condition.
2015-09-23 | GSE70179 | GEO
Project description:Gut microbiota and bile acid metabolism in infantile cholestasis
| PRJEB33641 | ENA
Project description:Intrahepatic cholestasis of pregnancy (ICP) is estimated to impact between 0.4% and 5% of pregnancies worldwide. This disease is associated with elevated maternal bile acids and frequently untoward neonatal outcomes such as respiratory distress and asphyxia. Multiple candidate genes have been implicated, but none have provided insight into the mechanisms of neonatal respiratory distress and death. Herein our studies demonstrate that maternal cholestasis (due to Abcb11 deficiency) produces 100% neonatal death within 24h due to atelectasis producing pulmonary hypoxia, which recapitulates the respiratory distress and asphyxia of human ICP. We show that these neonates have elevated pulmonary bile acids that are associated with disrupted structure of pulmonary surfactant. Maternal absence of Nr1i2 superimposed upon Abcb11 deficiency strongly increased neonatal survival and is directly related to reduced maternal bile acid concentrations. The mechanism accounting for reduced serum bile acids in the mothers deficient in both Nr1i2 and Abcb11 appears related to disrupted reabsorption of intestinal bile acids due to changes in transporter expression. These findings provide novel insights into pulmonary failure by revealing bile acids capability to disrupt the structure of surfactant producing collapsed alveoli, pulmonary failure and ultimately death. These findings have important implications for neonatal health especially when maternal bile acids are elevated during pregnancy and highlight a potential pathway and targets amenable to therapeutic intervention to ameliorate this condition. We used microarrays to measure changes in gene expression profiles in lung tissues from Abcb11+/- lungs after interbreeding C57BL/6 wild-type female or C57BL/6 Abcb11-/- female mice against either C57BL/6 wild-type male mice or C57BL/6 Abcb11-/- male mice to create only heterozygote offspring. We also measured profiles in liver tissues from age-matched C57BL/6 wild-type and C57BL/6 Abcb11-/- mice. Lung tissues were collected from day E17.5, E18.5 and neonatal (N0) mice. Liver tissues were collected from 1.5-month-old C57BL/6 wildtype and Abcb11-/- mice.
2015-09-23 | E-GEOD-70179 | biostudies-arrayexpress
Project description:Chronic jet lag induces spontaneous hepatocellular carcinoma (HCC) in wild-type mice following a pathophysiological pathway very similar to that observed in obese humans. This process initiates with non-alcoholic fatty liver disease (NAFLD), progresses to steatohepatitis and fibrosis before HCC detection, and is driven by persistent genome-wide gene deregulation that induces global liver metabolic dysfunction. Nuclear receptor-controlled cholesterol/bile acid and xenobiotic metabolism are found among top deregulated pathways. Ablation of the bile acid receptor FXR dramatically increases intrahepatic bile acid levels and jet-lag-induced HCC, while loss of CAR, a well-known liver tumor promoter, inhibits NAFLD-induced hepatocarcinogenesis. Circadian disruption activates CAR by promoting cholestasis, peripheral clock disruption, and sympathetic dysfunction. Thus, FXR and CAR are clock-controlled therapeutic targets for spontaneous HCC
2016-11-23 | GSE75475 | GEO
Project description:H4K12 Lactylation-activated c-JUN signaling aggravates bile acid dysfunction in intrahepatic cholestasis during pregnancy
| PRJNA884413 | ENA