scholarly journals Recent Advances of Microbiome-Associated Metabolomics Profiling in Liver Disease: Principles, Mechanisms, and Applications

2021 ◽  
Vol 22 (3) ◽  
pp. 1160
Author(s):  
Ganesan Raja ◽  
Haripriya Gupta ◽  
Yoseph Asmelash Gebru ◽  
Gi Soo Youn ◽  
Ye Rin Choi ◽  
...  
Keyword(s):  
Liver Disease ◽  
Metabolic Pathways ◽  
High Throughput Screening ◽  
Proof Of Concept ◽  
Metabolic Factors ◽  
Metabolomics Data ◽  
Liver Health ◽  
Activity Screening ◽  
Cellular Microenvironments ◽  
Endogenous Metabolites

Advances in high-throughput screening of metabolic stability in liver and gut microbiota are able to identify and quantify small-molecule metabolites (metabolome) in different cellular microenvironments that are closest to their phenotypes. Metagenomics and metabolomics are largely recognized to be the “-omics” disciplines for clinical therapeutic screening. Here, metabolomics activity screening in liver disease (LD) and gut microbiomes has significantly delivered the integration of metabolomics data (i.e., a set of endogenous metabolites) with metabolic pathways in cellular environments that can be tested for biological functions (i.e., phenotypes). A growing literature in LD and gut microbiomes reports the use of metabolites as therapeutic targets or biomarkers. Although growing evidence connects liver fibrosis, cirrhosis, and hepatocellular carcinoma, the genetic and metabolic factors are still mainly unknown. Herein, we reviewed proof-of-concept mechanisms for metabolomics-based LD and gut microbiotas’ role from several studies (nuclear magnetic resonance, gas/lipid chromatography, spectroscopy coupled with mass spectrometry, and capillary electrophoresis). A deeper understanding of these axes is a prerequisite for optimizing therapeutic strategies to improve liver health.

scholarly journals Quantitative genome-scale analysis of human liver reveals dysregulation of glycosphingolipid pathways in progressive nonalcoholic fatty liver disease

2021 ◽  
Author(s):  
Partho Sen ◽  
Olivier Govaere ◽  
Tim Sinioja ◽  
Aidan McGlinchey ◽  
Dawei Geng ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Metabolic Pathways ◽  
Fatty Liver Disease ◽  
Human Liver ◽  
Integrative Approach ◽  
Metabolomics Data ◽  
Nonalcoholic Fatty Liver ◽  
Genome Scale

ABSTRACTNonalcoholic fatty liver disease (NAFLD) is a well defined chronic liver diseases closely related with metabolic disorders. The prevalence of NAFLD is rapidly increasing worldwide, while the pathology and the underlying mechanisms driving NAFLD are not fully understood. In NAFLD, a series of metabolic changes takes place in the liver. However, the alteration of the metabolic pathways in the human liver along the progression of NAFLD, i.e., the transition from nonalcoholic steatosis (NAFL) to steatohepatitis (NASH) through cirrhosis remains to be discovered. Here, we sought to examine the metabolic pathways of the human liver across the full histological spectrum of NAFLD. We analyzed the whole liver tissue transcriptomic (RNA-Seq) and serum metabolomics data obtained from a large, prospectively enrolled cohort of histologically characterized patients derived from the European NAFLD Registry (n=206), and developed genome-scale metabolic models (GEMs) of human hepatocytes at different stages of NAFLD. The integrative approach employed in this study has enabled us to understand the regulation of the metabolic pathways of human liver in NAFL, and with progressive NASH-associated fibrosis (F0–F4). Our study identified several metabolic signatures in the liver and blood of these patients, specifically highlighting the alteration of vitamins (A, E) and glycosphingolipids (GSLs), and their link with complex glycosaminoglycans (GAGs) in advanced fibrosis. The study provides insights into the underlying pathways of the progressive fibrosing steatohepatitis. Furthermore, by applying genome-scale metabolic modeling (GSMM), we were able to identify the metabolic differences among carriers of widely validated genetic variants associated with NAFLD / NASH disease severity in three genes (PNPLA3, TM6SF2 and HSD17B13).

scholarly journals Markers of Intestinal Permeability Are Rapidly Improved by Alcohol Withdrawal in Patients with Alcohol-Related Liver Disease

Nutrients ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1659
Author(s):  
Finn Jung ◽  
Katharina Burger ◽  
Raphaela Staltner ◽  
Annette Brandt ◽  
Sebastian Mueller ◽  
...  
Keyword(s):  
Liver Disease ◽  
Liver Damage ◽  
Alcohol Withdrawal ◽  
Barrier Function ◽  
Binding Protein ◽  
Intestinal Barrier ◽  
Intestinal Barrier Function ◽  
Fatty Acid Binding ◽  
Liver Health ◽  
Related Liver Disease

Changes in intestinal microbiome and barrier function are critical in the development of alcohol-related liver disease (ALD). Here, we determined the effects of a one-week alcohol withdrawal on parameters of intestinal barrier function in heavy drinkers with ALD in comparison to healthy non-drinkers (controls). In serum samples of 17 controls (m = 10/f = 7) and 37 age-matched ALD patients (m = 26/f = 11) undergoing a one-week alcohol withdrawal, markers of liver health and intestinal barrier function were assessed. Liver damage, e.g., fibrosis and hepatic steatosis, were assessed using FibroScan. Before alcohol withdrawal, markers of liver damage, lipopolysaccharide binding protein (LBP) and overall TLR4/TLR2 ligands in serum were significantly higher in ALD patients than in controls, whereas intestinal fatty acid binding protein (I-FABP) and zonulin protein concentrations in serum were lower. All parameters, with the exception of LBP, were significantly improved after alcohol withdrawal; however, not to the level of controls. Our data suggest that one-week of abstinence improves markers of intestinal barrier function and liver health in ALD patients.

scholarly journals Gaussian graphical modeling of the serum exposome and metabolome reveals interactions between environmental chemicals and endogenous metabolites

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Vincent Bessonneau ◽  
Roy R. Gerona ◽  
Jessica Trowbridge ◽  
Rachel Grashow ◽  
Thomas Lin ◽  
...  
Keyword(s):  
Graphical Models ◽  
Association Studies ◽  
Environmental Chemicals ◽  
Gaussian Graphical Models ◽  
Metabolomics Data ◽  
Health And Nutrition ◽  
Novel Approach ◽  
Disease Causation ◽  
Women Firefighters ◽  
Endogenous Metabolites

AbstractGiven the complex exposures from both exogenous and endogenous sources that an individual experiences during life, exposome-wide association studies that interrogate levels of small molecules in biospecimens have been proposed for discovering causes of chronic diseases. We conducted a study to explore associations between environmental chemicals and endogenous molecules using Gaussian graphical models (GGMs) of non-targeted metabolomics data measured in a cohort of California women firefighters and office workers. GGMs revealed many exposure-metabolite associations, including that exposures to mono-hydroxyisononyl phthalate, ethyl paraben and 4-ethylbenzoic acid were associated with metabolites involved in steroid hormone biosynthesis, and perfluoroalkyl substances were linked to bile acids—hormones that regulate cholesterol and glucose metabolism—and inflammatory signaling molecules. Some hypotheses generated from these findings were confirmed by analysis of data from the National Health and Nutrition Examination Survey. Taken together, our findings demonstrate a novel approach to discovering associations between chemical exposures and biological processes of potential relevance for disease causation.

scholarly journals cAMP metabolism controls caspase-11 inflammasome activation and pyroptosis in sepsis

2019 ◽  
Vol 5 (5) ◽  
pp. eaav5562 ◽  
Author(s):  
Ruochan Chen ◽  
Ling Zeng ◽  
Shan Zhu ◽  
Jiao Liu ◽  
Herbert J. Zeh ◽  
...  
Keyword(s):  
Metabolic Pathways ◽  
Inflammatory Responses ◽  
Poly I:C ◽  
Inflammasome Activation ◽  
Proof Of Concept ◽  
Potential Therapeutic Target ◽  
Camp Metabolism ◽  
Camp Hydrolysis ◽  
Insight Into

The ability of cytosolic lipopolysaccharide (LPS) to activate caspase-11–dependent nonclassical inflammasome is intricately controlled to avoid excessive inflammatory responses. However, very little is known about the regulatory role of various metabolic pathways in the control of caspase-11 activation. Here, we demonstrate that l-adrenaline can act on receptor ADRA2B to inhibit the activation of the caspase-11 inflammasome by cytosolic LPS or Escherichia coli infection in macrophages. l-adrenaline–induced cAMP production via the enzyme ADCY4 promotes protein kinase A (PKA) activation, which then blocks the caspase-11–mediated proteolytic maturation of interleukin-1β, gasdermin D (GSDMD) cleavage, and consequent DAMP release. Inhibition of PDE8A-mediated cAMP hydrolysis limits caspase-11 inflammasome activation and pyroptosis in macrophages. Consequently, pharmacological modulation of the ADRA2B-ADCY4-PDE8A-PKA axis, knockout of caspase-11 (Casp11−/−), or Gsdmd inactivation (GsdmdI105N/I105N) similarly protects against LPS-induced lethality in poly(I:C)-primed mice. Our results provide previously unidentified mechanistic insight into immune regulation by cAMP and represent a proof of concept that immunometabolism constitutes a potential therapeutic target in sepsis.

scholarly journals Effects of Oral Vitamin C Supplementation on Liver Health and Associated Parameters in Patients With Non-Alcoholic Fatty Liver Disease: A Randomized Clinical Trial

2021 ◽  
Vol 8 ◽  
Author(s):  
Zhangya He ◽  
Xiaomin Li ◽  
Hexiang Yang ◽  
Pei Wu ◽  
Shanshan Wang ◽  
...  
Keyword(s):  
Liver Disease ◽  
Glucose Metabolism ◽  
Vitamin C ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Alcoholic Fatty Liver ◽  
Hmw Adiponectin ◽  
Liver Health ◽  
Glutamyl Transferase ◽  
Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is now recognized as the most prevalent hepatic disorder worldwide, and an unhealthy lifestyle is the leading risk factor for its occurrence. Vitamin C (VC) has been suggested to protect NAFLD, whereas evidence from randomized controlled trials (RCTs) is sparse. In this study, we aimed to investigate the potential benefits of VC supplementation daily on liver health and associated parameters in patients with NAFLD. In this double-blind, RCT, 84 patients with NAFLD, aged 18–60 years old, were assigned to 12 weeks of oral treatment with either low (250 mg/day, n = 26), medium (1,000 mg/day, n = 30), or high (2,000 mg/day, n = 28) doses of VC supplements. After the intervention, the Medium group had a more significant decrease in aspartate aminotransferase [Medium, −5.00 (−10.25, −1.75) vs. High, −2.50 (−7.75, 0.00), P = 0.02] and alanine aminotransferase [Medium, −8.00 (−18.00, −1.75) vs. High, −3.50 (−13.75, 4.25), P = 0.05; Medium vs. Low, −3.00 (−9.00, 5.50), P = 0.031]. The levels of other indicators of liver health, such as gamma-glutamyl transferase, alkaline phosphatase, total bilirubin, and direct bilirubin were decreased after the intervention but comparable among the three groups and so did the parameters of glucose metabolism, such as fasting insulin, fasting glucose, and homeostasis model assessment for insulin resistance. The plasma level of VC in patients and total adiponectin and high molecular weight (HMW) adiponectin levels were also elevated but not in a dose-dependent manner. Meanwhile, analysis of fecal microbiota composition showed an increase in the alpha diversity (Abundance-based Coverage Estimator (ACE), Shannon, chao1, and Simpson) both in the Low and the Medium groups. A total of 12 weeks of VC supplementation, especially 1,000 mg/day, improved liver health and glucose metabolism in patients with NAFLD. The elevated plasma levels of VC, total and HMW adiponectin, and the improvement of intestinal microbiota may have made some contributions.

scholarly journals Dynamic Changes of the Fungal Microbiome in Alcohol Use Disorder

2021 ◽  
Vol 12 ◽  
Author(s):  
Phillipp Hartmann ◽  
Sonja Lang ◽  
Suling Zeng ◽  
Yi Duan ◽  
Xinlian Zhang ◽  
...  
Keyword(s):  
Liver Disease ◽  
Alcohol Use ◽  
Alcohol Use Disorder ◽  
Serum Levels ◽  
Amplicon Sequencing ◽  
Dynamic Changes ◽  
Alcohol Abstinence ◽  
Liver Health ◽  
Fungal Microbiome ◽  
Progressive Liver Disease

BackgroundAlcohol-associated liver disease (ALD) is an important cause of morbidity and mortality worldwide. The intestinal microbiota is involved in the development and progression of ALD; however, little is known about commensal fungi therein.MethodsWe studied the dynamic changes of the intestinal fungal microbiome, or mycobiome, in 66 patients with alcohol use disorder (AUD) and after 2 weeks of alcohol abstinence using internal transcribed spacer 2 (ITS2) amplicon sequencing of fecal samples.ResultsPatients with AUD had significantly increased abundance of the genera Candida, Debaryomyces, Pichia, Kluyveromyces, and Issatchenkia, and of the species Candida albicans and Candida zeylanoides compared with control subjects. Significantly improved liver health markers caspase-cleaved and intact cytokeratin 18 (CK18-M65) levels and controlled attenuation parameter (CAP) in AUD patients after 2 weeks of alcohol abstinence were associated with significantly lower abundance of the genera Candida, Malassezia, Pichia, Kluyveromyces, Issatchenkia, and the species C. albicans and C. zeylanoides. This was mirrored by significantly higher specific anti-C. albicans immunoglobulin G (IgG) and M (IgM) serum levels in AUD patients in relation to control participants, and significantly decreased anti-C. albicans IgG levels in AUD subjects after 2 weeks of abstinence. The intestinal abundance of the genus Malassezia was significantly higher in AUD subjects with progressive liver disease compared with non-progressive liver disease.ConclusionIn conclusion, improved liver health in AUD patients after alcohol abstinence was associated with lower intestinal abundances of Candida and Malassezia, and lower serum anti-C. albicans IgG levels. Intestinal fungi might serve as a therapeutic target to improve the outcome of patients in ALD.

scholarly journals Ultra-Performance Liquid Chromatography/Mass Spectrometry-Based Metabolomics for Discovering Potential Biomarkers and Metabolic Pathways of Colorectal Cancer in Mouse Model (ApcMin/+) and Revealing the Effect of Honokiol

2021 ◽  
Vol 11 ◽  
Author(s):  
Xin Chen ◽  
Bo-lun Shi ◽  
Run-zhi Qi ◽  
Xing Chang ◽  
Hong-gang Zheng
Keyword(s):  
Colorectal Cancer ◽  
Mouse Model ◽  
Metabolic Pathways ◽  
Molecular Mechanisms ◽  
Tca Cycle ◽  
Ultra Performance Liquid Chromatography ◽  
Therapeutic Effects ◽  
Anticancer Activities ◽  
Metabolic Disturbances ◽  
Endogenous Metabolites

Endogenous metabolites are a class of molecules playing diverse and significant roles in many metabolic pathways for disease. Honokiol (HNK), an active poly-phenolic compound, has shown potent anticancer activities. However, the detailed crucial mechanism regulated by HNK in colorectal cancer remains unclear. In the present study, we investigated the therapeutic effects and the underlying molecular mechanisms of HNK on colorectal cancer in a mouse model (ApcMin/+) by analyzing the urine metabolic profile based on metabolomics, which is a powerful tool for characterizing metabolic disturbances. We found that potential urine biomarkers were involved in the metabolism of compounds such as purines, tyrosines, tryptophans, etc. Moreover, we showed that a total of 27 metabolites were the most contribution biomarkers for intestinal tumors, and we found that the citrate cycle (TCA cycle) was regulated by HNK. In addition, it was suggested that the efficacy of HNK was achieved by affecting the multi-pathway system via influencing relevant metabolic pathways and regulating metabolic function. Our work also showed that high-throughput metabolomics can characterize the regulation of metabolic disorders as a therapeutic strategy to prevent colorectal cancer.

scholarly journals Cross-Platform Bayesian Optimization System for Autonomous Biological Assay Development

2021 ◽  
Vol 26 (6) ◽  
pp. 579-590
Author(s):  
Sam Elder ◽  
Carleen Klumpp-Thomas ◽  
Adam Yasgar ◽  
Jameson Travers ◽  
Shayne Frebert ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Assay Development ◽  
Bayesian Optimization ◽  
Biological Assay ◽  
Proof Of Concept ◽  
Screening Assay ◽  
High Throughput Screening Assay ◽  
Cross Platform ◽  
Assay Conditions

Current high-throughput screening assay optimization is often a manual and time-consuming process, even when utilizing design-of-experiment approaches. A cross-platform, Cloud-based Bayesian optimization-based algorithm was developed as part of the National Center for Advancing Translational Sciences (NCATS) ASPIRE (A Specialized Platform for Innovative Research Exploration) Initiative to accelerate preclinical drug discovery. A cell-free assay for papain enzymatic activity was used as proof of concept for biological assay development and system operationalization. Compared with a brute-force approach that sequentially tested all 294 assay conditions to find the global optimum, the Bayesian optimization algorithm could find suitable conditions for optimal assay performance by testing 21 assay conditions on average, with up to 20 conditions being tested simultaneously, as confirmed by repeated simulation. The algorithm could achieve a sevenfold reduction in costs for lab supplies and high-throughput experimentation runtime, all while being controlled from a remote site through a secure connection. Based on this proof of concept, this technology is expected to be applied to more complex biological assays and automated chemistry reaction screening at NCATS, and should be transferable to other institutions. Graphical Abstract

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