Special Issue "The Application of Metabolomics in Clinical Practice: Challenges and Opportunities"

A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Endocrinology and Clinical Metabolic Research".

Deadline for manuscript submissions: closed (15 October 2021).

Special Issue Editors

Dr. Michele Mussap
E-Mail Website
Guest Editor
Department of Surgical Sciences, School of Medicine, University of Cagliari, Cittadella Universitaria S.S. 554, 09042 Monserrato, Italy
Interests: hypertension; infection; sepsis; neonatology; clinical nephrology
Dr. Luigi Atzori
E-Mail Website
Guest Editor
Department of Biomedical Sciences, Clinical Metabolomics Unit, University of Cagliari, Cittadella Universitaria S.S. 554, 09042 Monserrato, Italy
Interests: applications of metabolomics in biomedical field; Identification of disease markers
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Currently, patient care is switching from a reductionist approach to precision medicine, characterized by the collection of individual longitudinal clinical data and multi-omics profiling along with tailored therapeutic treatments. Diseases are no longer seen as the sum of structural and functional multiorgan damage and complications; rather, they should be evaluated as the full spectrum of associated phenotypic abnormalities due to multiple factors, such as genetic and epigenetic changes, the pathogenesis of the disease, the host immune response, the gut microbiota, the microenvironment, and both the beneficial and adverse effects of the therapeutic interventions. In this context, metabolomics plays a strategic role in depicting the individual molecular phenotype and discovering insights into cellular metabolic processes that are not identifiable when each component is investigated individually. The challenge of this Special Issue of Metabolites is to promote the transition of metabolomics from research to clinical settings with the contribution of timely reviews discussing current applications of metabolomics in clinical practice and research articles presenting results related with the introduction of metabolomics and new biomarkers in specific human diseases and in clinical testing; original data on metabolomics for the monitoring of drug efficacy and toxicity are within the scope of this Special Issue.

Dr. Michele Mussap
Dr. Luigi Atzori
Guest Editors

Manuscript Submission Information

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Keywords

  • metabolomics
  • precision medicine
  • brain–gut axis
  • clinical testing
  • pharmacometabolomics

Published Papers (8 papers)

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Research

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Article
Plasma Metabolome Normalization in Rheumatoid Arthritis Following Initiation of Methotrexate and the Identification of Metabolic Biomarkers of Efficacy
Metabolites 2021, 11(12), 824; https://doi.org/10.3390/metabo11120824 - 30 Nov 2021
Viewed by 214
Abstract
Methotrexate (MTX) efficacy in the treatment of rheumatoid arthritis (RA) is variable and unpredictable, resulting in a need to identify biomarkers to guide drug therapy. This study evaluates changes in the plasma metabolome associated with response to MTX in RA with the goal [...] Read more.
Methotrexate (MTX) efficacy in the treatment of rheumatoid arthritis (RA) is variable and unpredictable, resulting in a need to identify biomarkers to guide drug therapy. This study evaluates changes in the plasma metabolome associated with response to MTX in RA with the goal of understanding the metabolic basis for MTX efficacy towards the identification of potential metabolic biomarkers of MTX response. Plasma samples were collected from healthy control subjects (n = 20), and RA patients initiating MTX therapy (n = 20, 15 mg/week) before and after 16 weeks of treatment. The samples were analyzed by a semi-targeted metabolomic analysis, and then analyzed by univariate and multivariate methods, as well as an enrichment analysis. An MTX response was defined as a clinically significant reduction in the disease activity score in 28 joints (DAS-28) of greater than 1.2; achievement of clinical remission, defined as a DAS-28 < 2.6, was also utilized as an additional measure of response. In this study, RA is associated with an altered plasma metabolome that is normalized following initiation of MTX therapy. Metabolite classes found to be altered in RA and corrected by MTX therapy were diverse and included triglycerides (p = 1.1 × 10−16), fatty acids (p = 8.0 × 10−12), and ceramides (p = 9.8 × 10−13). Stratification based on responses to MTX identified various metabolites differentially impacted in responders and non-responders including glucosylceramides (GlcCer), phosphatidylcholines (PC), sphingomyelins (SM), phosphatidylethanolamines (PE), choline, inosine, hypoxanthine, guanosine, nicotinamide, and itaconic acid (p < 0.05). In conclusion, RA is associated with significant alterations to the plasma metabolome displaying at least partial normalization following 16 weeks of MTX therapy. Changes in multiple metabolites were found to be associated with MTX efficacy, including metabolites involved in fatty acid/lipid, nucleotide, and energy metabolism. Full article
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Article
Application of Sebum Lipidomics to Biomarkers Discovery in Neurodegenerative Diseases
Metabolites 2021, 11(12), 819; https://doi.org/10.3390/metabo11120819 - 29 Nov 2021
Viewed by 279
Abstract
Lipidomics is strategic in the discovery of biomarkers of neurodegenerative diseases (NDDs). The skin surface lipidome bears the potential to provide biomarker candidates in the detection of pathological processes occurring in distal organs. We investigated the sebum composition to search diagnostic and, possibly, [...] Read more.
Lipidomics is strategic in the discovery of biomarkers of neurodegenerative diseases (NDDs). The skin surface lipidome bears the potential to provide biomarker candidates in the detection of pathological processes occurring in distal organs. We investigated the sebum composition to search diagnostic and, possibly, prognostic, biomarkers of Alzheimer’s disease (AD) and Parkinson’s disease (PD). The observational study included 64 subjects: 20 characterized as “probable AD with documented decline”, 20 as “clinically established PD”, and 24 healthy subjects (HS) of comparable age. The analysis of sebum by GCMS and TLC retrieved the amounts (µg) of 41 free fatty acids (FFAs), 7 fatty alcohols (FOHs), vitamin E, cholesterol, squalene, and total triglycerides (TGs) and wax esters (WEs). Distributions of sebum lipids in NDDs and healthy conditions were investigated with multivariate ANOVA-simultaneous component analysis (ASCA). The deranged sebum composition associated with the PD group showed incretion of most composing lipids compared to HS, whereas only two lipid species (vitamin E and FOH14:0) were discriminant of AD samples and presented lower levels than HS sebum. Thus, sebum lipid biosynthetic pathways are differently affected in PD and AD. The characteristic sebum bio-signatures detected support the value of sebum lipidomics in the biomarkers search in NDDs. Full article
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Article
A Metabolomics Investigation of the Metabolic Changes of Raji B Lymphoma Cells Undergoing Apoptosis Induced by Zinc Ions
Metabolites 2021, 11(10), 689; https://doi.org/10.3390/metabo11100689 - 07 Oct 2021
Viewed by 742
Abstract
Zinc plays a pivotal role in the function of cells and can induce apoptosis in various cancer cells, including Raji B lymphoma. However, the metabolic mechanism of Zn-induced apoptosis in Raji cells has not been explored. In this study, we performed global metabolic [...] Read more.
Zinc plays a pivotal role in the function of cells and can induce apoptosis in various cancer cells, including Raji B lymphoma. However, the metabolic mechanism of Zn-induced apoptosis in Raji cells has not been explored. In this study, we performed global metabolic profiling using UPLC−Orbitrap−MS to assess the apoptosis of Raji cells induced by Zn ions released from ZnO nanorods. Multivariate analysis and database searches identified altered metabolites. Furthermore, the differences in the phosphorylation of 1380 proteins were also evaluated by Full Moon kinase array to discover the protein associated Zn−induced apoptosis. From the results, a prominent increase in glycerophosphocholine and fatty acids was observed after Zn ion treatment, but only arachidonic acid was shown to induce apoptosis. The kinase array revealed that the phosphorylation of p53, GTPase activation protein, CaMK2a, PPAR−γ, and PLA−2 was changed. From the pathway analysis, metabolic changes showed earlier onset than protein signaling, which were related to choline metabolism. LC−MS analysis was used to quantify the intracellular choline concentration, which decreased after Zn treatment, which may be related to the choline consumption required to produce choline-containing metabolites. Overall, we found that choline metabolism plays an important role in Zn-induced Raji cell apoptosis. Full article
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Article
Analysis of Metabolic Markers in Patients with Chronic Heart Failure before and after LVAD Implantation
Metabolites 2021, 11(9), 615; https://doi.org/10.3390/metabo11090615 - 09 Sep 2021
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Abstract
Chronic heart failure (HF) is a clinical syndrome characterized by functional impairments of the myocardium. Metabolic and clinical changes develop with disease progression. In an advanced state, left ventricular assist devices (LVADs) are implanted for mechanical unloading. Our study aimed to assess the [...] Read more.
Chronic heart failure (HF) is a clinical syndrome characterized by functional impairments of the myocardium. Metabolic and clinical changes develop with disease progression. In an advanced state, left ventricular assist devices (LVADs) are implanted for mechanical unloading. Our study aimed to assess the effects of LVAD implantation on the metabolic phenotypes and their potential to reverse the latter in patients with advanced HF. Plasma metabolites were analyzed by LC–MS/MS in 20 patients with ischemic cardiomyopathy (ICM), 20 patients with dilative cardiomyopathy (DCM), and 20 healthy controls. Samples were collected in HF patients before, 30 days after, and >100 days after LVAD implantation. Out of 188 measured metabolites, 63 were altered in HF. Only three metabolites returned to pre-LVAD concentrations 100 days after LVAD implantation. Pre-LVAD differences between DCM and ICM were mainly observed for amino acids and biogenic amines. This study shows a reversal of metabolite abnormalities in HF as a result of LVAD implantation. The etiology of the underlying disease plays an essential role in defining which specific metabolic parameter is altered in HF and reversed by LVAD implantation. Our findings provide a detailed insight into the disease pattern of ICM and DCM and the potential for reversibility of metabolic abnormalities in HF. Full article
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Article
Serum Metabolite Profile Associated with Sex-Dependent Visceral Adiposity Index and Low Bone Mineral Density in a Mexican Population
Metabolites 2021, 11(9), 604; https://doi.org/10.3390/metabo11090604 - 06 Sep 2021
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Abstract
Recent evidence shows that obesity correlates negatively with bone mass. However, traditional anthropometric measures such as body mass index could not discriminate visceral adipose tissue from subcutaneous adipose tissue. The visceral adiposity index (VAI) is a reliable sex-specified indicator of visceral adipose distribution [...] Read more.
Recent evidence shows that obesity correlates negatively with bone mass. However, traditional anthropometric measures such as body mass index could not discriminate visceral adipose tissue from subcutaneous adipose tissue. The visceral adiposity index (VAI) is a reliable sex-specified indicator of visceral adipose distribution and function. Thus, we aimed to identify metabolomic profiles associated with VAI and low bone mineral density (BMD). A total of 602 individuals from the Health Workers Cohort Study were included. Forty serum metabolites were measured using the targeted metabolomics approach, and multivariate regression models were used to test associations of metabolomic profiles with anthropometric, clinical, and biochemical parameters. The analysis showed a serum amino acid signature composed of glycine, leucine, arginine, valine, and acylcarnitines associated with high VAI and low BMD. In addition, we found a sex-dependent VAI in pathways related to primary bile acid biosynthesis, branched-chain amino acids, and the biosynthesis of pantothenate and coenzyme A (CoA). In conclusion, a metabolic profile differs by VAI and BMD status, and these changes are gender-dependent. Full article
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Review

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Review
Metabolomics in Autoimmune Diseases: Focus on Rheumatoid Arthritis, Systemic Lupus Erythematous, and Multiple Sclerosis
Metabolites 2021, 11(12), 812; https://doi.org/10.3390/metabo11120812 - 29 Nov 2021
Viewed by 283
Abstract
The metabolomics approach represents the last downstream phenotype and is widely used in clinical studies and drug discovery. In this paper, we outline recent advances in the metabolomics research of autoimmune diseases (ADs) such as rheumatoid arthritis (RA), multiple sclerosis (MuS), and systemic [...] Read more.
The metabolomics approach represents the last downstream phenotype and is widely used in clinical studies and drug discovery. In this paper, we outline recent advances in the metabolomics research of autoimmune diseases (ADs) such as rheumatoid arthritis (RA), multiple sclerosis (MuS), and systemic lupus erythematosus (SLE). The newly discovered biomarkers and the metabolic mechanism studies for these ADs are described here. In addition, studies elucidating the metabolic mechanisms underlying these ADs are presented. Metabolomics has the potential to contribute to pharmacotherapy personalization; thus, we summarize the biomarker studies performed to predict the personalization of medicine and drug response. Full article
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Review
Metabolomic Laboratory-Developed Tests: Current Status and Perspectives
Metabolites 2021, 11(7), 423; https://doi.org/10.3390/metabo11070423 - 26 Jun 2021
Cited by 1 | Viewed by 1212
Abstract
Laboratory-developed tests (LDTs) are a subset of in vitro diagnostic devices, which the US Food and Drug Administration defines as “tests that are manufactured by and used within a single laboratory”. The review describes the emergence and history of LDTs. The current state [...] Read more.
Laboratory-developed tests (LDTs) are a subset of in vitro diagnostic devices, which the US Food and Drug Administration defines as “tests that are manufactured by and used within a single laboratory”. The review describes the emergence and history of LDTs. The current state and development prospects of LDTs based on metabolomics are analyzed. By comparing LDTs with the scientific metabolomics study of human bio samples, the characteristic features of metabolomic LDT are shown, revealing its essence, strengths, and limitations. The possibilities for further developments and scaling of metabolomic LDTs and their potential significance for healthcare are discussed. The legal aspects of LDT regulation in the United States, European Union, and Singapore, demonstrating different approaches to this issue, are also provided. Based on the data presented in the review, recommendations were made on the feasibility and ways of further introducing metabolomic LDTs into practice. Full article
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Review
Metabolomics: A Scoping Review of Its Role as a Tool for Disease Biomarker Discovery in Selected Non-Communicable Diseases
Metabolites 2021, 11(7), 418; https://doi.org/10.3390/metabo11070418 - 25 Jun 2021
Cited by 2 | Viewed by 1173
Abstract
Metabolomics is a branch of ‘omics’ sciences that utilises a couple of analytical tools for the identification of small molecules (metabolites) in a given sample. The overarching goal of metabolomics is to assess these metabolites quantitatively and qualitatively for their diagnostic, therapeutic, and [...] Read more.
Metabolomics is a branch of ‘omics’ sciences that utilises a couple of analytical tools for the identification of small molecules (metabolites) in a given sample. The overarching goal of metabolomics is to assess these metabolites quantitatively and qualitatively for their diagnostic, therapeutic, and prognostic potentials. Its use in various aspects of life has been documented. We have also published, howbeit in animal models, a few papers where metabolomic approaches were used in the study of metabolic disorders, such as metabolic syndrome, diabetes, and obesity. As the goal of every research is to benefit humankind, the purpose of this review is to provide insights into the applicability of metabolomics in medicine vis-à-vis its role in biomarker discovery for disease diagnosis and management. Here, important biomarkers with proven diagnostic and therapeutic relevance in the management of disease conditions, such as Alzheimer’s disease, dementia, Parkinson’s disease, inborn errors of metabolism (IEM), diabetic retinopathy, and cardiovascular disease, are noted. The paper also discusses a few reasons why most metabolomics-based laboratory discoveries are not readily translated to the clinic and how these could be addressed going forward. Full article
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