An official website of the United States government
Chronic inflammation associated with inflammatory bowel disease (IBD) results in increased oxidative stress that damages the colonic microenvironment. A low level of serum bilirubin, an endogenous antioxidant, has been associated with increased risk for Crohn's disease (CD), but no study has tested another common IBD ulcerative colitis (UC). Bilirubin is metabolized in the liver by uridine glucuronosyltransferase 1A1 (UGT1A1) exclusively. Genetic variants cause functional changes in UGT1A1 which result in hyperbilirubinemia, which can be toxic to tissues if untreated and results in a characteristic jaundiced appearance. Approximately 10% of the Caucasian population is homozygous for the microsatellite polymorphism UGT1A1*28, which results in increased total serum bilirubin levels due to reduced transcriptional efficiency of UGT1A1 and an overall 70% reduction in UGT1A1 enzymatic activity. The aim of this study was to examine whether bilirubin levels are associated with the risk for ulcerative colitis (UC). Using the Informatics for Integrating Biology and the Bedside (i2b2), a large case-control population was identified from a single tertiary care center, Penn State Hershey Medical Center (PSU). Similarly, a validation cohort was identified at Virginia Commonwealth University Medical Center. Logistic regression analysis was performed to determine the risk of developing UC with lower concentrations of serum bilirubin. From the PSU cohort, a subset of terminal ileum tissue was obtained at the time of surgical resection to analyze UGT1A1 gene expression (which encodes the enzyme responsible for bilirubin metabolism). Similar to CD patients, UC patients also demonstrated reduced levels of total serum bilirubin. Upon segregating serum bilirubin levels into quartiles, risk of UC increased with reduced concentrations of serum bilirubin. These results were confirmed in our validation cohort. UGT1A1 gene expression was up-regulated in the terminal ileum of a subset of UC patients. Lower levels of the antioxidant bilirubin may reduce the capability of UC patients to remove reactive oxygen species leading to an increase in intestinal injury. One potential explanation for these lower bilirubin levels may be up-regulation of UGT1A1 gene expression, which encodes the only enzyme involved in conjugating bilirubin. Therapeutics that reduce oxidative stress may be beneficial for these patients.
more »
« less
Metabolome-wide association identifies altered metabolites and metabolic pathways in the serum of patients with cholangiocarcinoma
Background & Aims Metabolomic and lipidomic analyses provide an opportunity for novel biological insights. Cholangiocarcinoma (CCA) remains a highly lethal cancer with limited response to systemic, targeted, and immunotherapeutic approaches. Using a global metabolomics and lipidomics platform, this study aimed to discover and characterize metabolomic variations and associated pathway derangements in patients with CCA. Methods Leveraging a biospecimen collection, including samples from patients with digestive diseases and normal controls, global serum metabolomic and lipidomic profiling was performed on 213 patients with CCA and 98 healthy controls. The CCA cohort of patients included representation of intrahepatic, perihilar, and distal CCA tumours. Metabolome-wide association studies utilizing multivariable linear regression were used to perform case–control comparisons, followed by pathway enrichment analysis, CCA subtype analysis, and disease stage analysis. The impact of biliary obstruction was evaluated by repeating analyses in subsets of patients only with normal bilirubin levels. Results Of the 420 metabolites that discriminated patients with CCA from controls, decreased abundance of cysteine-glutathione disulfide was most closely associated with CCA. Additional conjugated bile acid species were found in increased abundance even in the absence of clinically relevant biliary obstruction denoted by elevated serum bilirubin levels. Pathway enrichment analysis also revealed alterations in caffeine metabolism and mitochondrial redox-associated pathways in the serum of patients with CCA. Conclusions The presented metabolomic and lipidomic profiling demonstrated multiple alterations in the serum of patients with CCA. These exploratory data highlight novel metabolic pathways in CCA and support future work in therapeutic targeting of these pathways and the development of a precision biomarker panel for diagnosis.
more »
« less
- Award ID(s):
- 2041339
- PAR ID:
- 10535818
- Publisher / Repository:
- JHEP Reports
- Date Published:
- Journal Name:
- JHEP Reports
- Volume:
- 6
- Issue:
- 6
- ISSN:
- 2589-5559
- Page Range / eLocation ID:
- 101068
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
null (Ed.)Background A better understanding of the pathophysiology involving coronary artery calcification (CAC) in patients on hemodialysis (HD) will help to develop new therapies. We sought to identify the differences in metabolomics profiles between patients on HD with and without CAC. Methods In this case-control study, nested within a cohort of 568 incident patients on HD, the cases were patients without diabetes with a CAC score >100 ( n =51), and controls were patients without diabetes with a CAC score of zero ( n =48). We measured 452 serum metabolites in each participant. Metabolites and pathway scores were compared using Mann–Whitney U tests, partial least squares–discriminant analyses, and pathway enrichment analyses. Results Compared with controls, cases were older (64±13 versus 42±12 years) and were less likely to be Black (51% versus 94%). We identified three metabolites in bile-acid synthesis (chenodeoxycholic, deoxycholic, and glycolithocholic acids) and one pathway (arginine/proline metabolism). After adjusting for demographics, higher levels of chenodeoxycholic, deoxycholic, and glycolithocholic acids were associated with higher odds of having CAC; comparing the third with the first tertile of each bile acid, the OR was 6.34 (95% CI, 1.12 to 36.06), 6.73 (95% CI, 1.20 to 37.82), and 8.53 (95% CI, 1.50 to 48.49), respectively. These associations were no longer significant after further adjustment for coronary artery disease and medication use. Per 1 unit higher in the first principal component score, arginine/proline metabolism was associated with CAC after adjusting for demographics (OR, 1.83; 95% CI, 1.06 to 3.15), and the association remained significant with additional adjustments for statin use (OR, 1.84; 95% CI, 1.04 to 3.27). Conclusions Among patients on HD without diabetes mellitus, chenodeoxycholic, deoxycholic, and glycolithocholic acids may be potential biomarkers for CAC, and arginine/proline metabolism is a plausible mechanism to study for CAC. These findings need to be confirmed in future studies.more » « less
-
Abstract Lipidomic profiling has been linked to the detection of cancers as dysregulation of lipid metabolism is closely associated with many disease states. Current work on chip‐based profiling has been limited and is largely hindered by issues associated with the chip's sophisticated fabrication processes. We report here the design and fabrication of a highly efficient microfluidic mixer/extractor by using three‐dimensional (3D) printing technology for on‐chip cell lysis/enrichment for lipidomic profiling with matrix‐assisted laser desorption/ionization mass spectrometry (MALDI‐MS). The platform consists of a micropillar mixer for flow‐through lysis and an on‐chip reservoir to separate phases where the lipid‐enriched layer was collected for subsequent MS analysis. The mass transfer between the two phases was simulated by a computational fluid dynamics study, and the efficiency in cell lysis in different extraction solvent systems was characterized by fluorescence microscopy. Results showed increased performance in extraction with the micropillar mixer as compared with the standard Bligh‐Dyer method. For lipid profiling ofC. reinhardtiicells by MALDI‐MS, over 65 lipid species from the monogalactosyldiacylglycerol, digalactosyldiacylglycerol, diacylglyceryltrimethylhomo‐Ser, and triacylglycerol lipid families have been identified. The effect of organic solvents on extraction and lipid profiles was also investigated, and the results indicated that the extractant formula has a diverse impact on the collection of certain types of lipid species, presenting useful guidance for the system to be applied to targeted enrichment of lipids with specific cells. The microfluidic chips by the 3D printing technique reported here offer new platforms potentially for clinical lipidomics and can provide a novel avenue in disease diagnosis.more » « less
-
Abstract Primary sclerosing cholangitis (PSC) is a complex bile duct disorder. Its etiology is incompletely understood, but environmental chemicals likely contribute to risk. Patients with PSC have an altered bile metabolome, which may be influenced by environmental chemicals. This novel study utilized state-of-the-art high-resolution mass spectrometry (HRMS) with bile samples to provide the first characterization of environmental chemicals and metabolomics (collectively, the exposome) in PSC patients located in the United States of America (USA) (n = 24) and Norway (n = 30). First, environmental chemical- and metabolome-wide association studies were conducted to assess geographic-based similarities and differences in the bile of PSC patients. Nine environmental chemicals (false discovery rate, FDR < 0.20) and 3143 metabolic features (FDR < 0.05) differed by site. Next, pathway analysis was performed to identify metabolomic pathways that were similarly and differentially enriched by the site. Fifteen pathways were differentially enriched (P < .05) in the categories of amino acid, glycan, carbohydrate, energy, and vitamin/cofactor metabolism. Finally, chemicals and pathways were integrated to derive exposure–effect correlation networks by site. These networks demonstrate the shared and differential chemical–metabolome associations by site and highlight important pathways that are likely relevant to PSC. The USA patients demonstrated higher environmental chemical bile content and increased associations between chemicals and metabolic pathways than those in Norway. Polychlorinated biphenyl (PCB)-118 and PCB-101 were identified as chemicals of interest for additional investigation in PSC given broad associations with metabolomic pathways in both the USA and Norway patients. Associated pathways include glycan degradation pathways, which play a key role in microbiome regulation and thus may be implicated in PSC pathophysiology.more » « less
-
ABSTRACT Biofilms are structured communities of tightly associated cells that constitute the predominant state of bacterial growth in natural and human-made environments. Although the core genetic circuitry that controls biofilm formation in model bacteria such as Bacillus subtilis has been well characterized, little is known about the role that metabolism plays in this complex developmental process. Here, we performed a time-resolved analysis of the metabolic changes associated with pellicle biofilm formation and development in B. subtilis by combining metabolomic, transcriptomic, and proteomic analyses. We report surprisingly widespread and dynamic remodeling of metabolism affecting central carbon metabolism, primary biosynthetic pathways, fermentation pathways, and secondary metabolism. Most of these metabolic alterations were hitherto unrecognized as biofilm associated. For example, we observed increased activity of the tricarboxylic acid (TCA) cycle during early biofilm growth, a shift from fatty acid biosynthesis to fatty acid degradation, reorganization of iron metabolism and transport, and a switch from acetate to acetoin fermentation. Close agreement between metabolomic, transcriptomic, and proteomic measurements indicated that remodeling of metabolism during biofilm development was largely controlled at the transcriptional level. Our results also provide insights into the transcription factors and regulatory networks involved in this complex metabolic remodeling. Following upon these results, we demonstrated that acetoin production via acetolactate synthase is essential for robust biofilm growth and has the dual role of conserving redox balance and maintaining extracellular pH. This report represents a comprehensive systems-level investigation of the metabolic remodeling occurring during B. subtilis biofilm development that will serve as a useful road map for future studies on biofilm physiology. IMPORTANCE Bacterial biofilms are ubiquitous in natural environments and play an important role in many clinical, industrial, and ecological settings. Although much is known about the transcriptional regulatory networks that control biofilm formation in model bacteria such as Bacillus subtilis , very little is known about the role of metabolism in this complex developmental process. To address this important knowledge gap, we performed a time-resolved analysis of the metabolic changes associated with bacterial biofilm development in B. subtilis by combining metabolomic, transcriptomic, and proteomic analyses. Here, we report a widespread and dynamic remodeling of metabolism affecting central carbon metabolism, primary biosynthetic pathways, fermentation pathways, and secondary metabolism. This report serves as a unique hypothesis-generating resource for future studies on bacterial biofilm physiology. Outside the biofilm research area, this work should also prove relevant to any investigators interested in microbial physiology and metabolism.more » « less
- Free Publicly Accessible Full Text
-
Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1016/j.jhepr.2024.101068
