An introduction to metabolomics and its potential application in veterinary science

Metabolomics has been found to be applicable to a wide range of fields, including the study of gene function, toxicology, plant sciences, environmental analysis, clinical diagnostics, nutrition, and the discrimination of organism genotypes. This approach combines high-throughput sample analysis with computer-assisted multivariate pattern-recognition techniques. It is increasingly being deployed in toxico- and pharmacokinetic studies in the pharmaceutical industry, especially during the safety assessment of candidate drugs in human medicine. However, despite the potential of this technique to reduce both costs and the numbers of animals used for research, examples of the application of metabolomics in veterinary research are, thus far, rare. Here we give an introduction to metabolomics and discuss its potential in the field of veterinary science.     

Metabolomics through the lens of precision cardiovascular medicine

Metabolomics, which targets at the extensive characterization and quantitation of global metabolites from both endogenous and exogenous sources, has emerged as a novel technological avenue to advance the field of precision medicine principally driven by genomics-oriented approaches. In particular,metabolomics has revealed the cardinal roles that the environment exerts in driving the progression of major diseases threatening public health. Herein, the existent and potential applications of metabolomics in two key areas of precision cardiovascular medicine will be critically discussed: 1) the use of metabolomics in unveiling novel disease biomarkers and pathological pathways; 2) the contribution of metabolomics in cardiovascular drug development. Major issues concerning the statistical handling of big data generated by metabolomics, as well as its interpretation, will be briefly addressed. Finally, the need for integration of various omics branches and adopting a multi-omics approach to precision medicine will be discussed.     

Toward the implementation of metabolomic assessments of human health and nutrition

Metabolomics is emerging as an exciting post-genomic science with applications that span the scope of biotechnology and medicine. Although metabolomics is still in its infancy, it has already been used to identify the function of genes, describe the effects of toxicological, pharmaceutical, nutritional and environmental interventions, and to build integrated databases of metabolite concentrations across human and research animal populations. Metabolomics provides nutrition with an invaluable tool for determining the distributions of metabolite concentrations in humans, the relationship of these metabolite concentrations to disease, and the extent to which nutrition can modulate metabolite concentrations.     

Metabolomics for phytomedicine research and drug development

Metabolomics, including both targeted and global metabolite profiling strategies, is fast becoming the approach of choice across a broad range of sciences including systems biology, drug discovery, molecular and cell biology, and other medical and agricultural sciences. New analytical and bioinformatics technologies and techniques are continually being created or optimized, significantly increasing the crossdisciplinary capabilities of this new biology. The metabolomes of medicinal plants are particularly a valuable natural resource for the evidence-based development of new phytotherapeutics and nutraceuticals. Comparative metabolomics platforms are evolving into novel technologies for monitoring disease development, drug metabolism, and chemical toxicology. An efficient multidisciplinary marriage of these emerging metabolomics techniques with agricultural biotechnology will greatly benefit both basic and applied medical research.     

Understanding mouse models of disease through metabolomics

Metabolomics is widely applicable to a number of fields including toxicology, plant metabolism and functional genomics. In the area of functional genomics, a number of studies have demonstrated the potential of this approach, which combines high-throughput metabolite profiling with computer-assisted pattern recognition approaches. In this review, recent applications of metabolomics to understanding mouse models of disease are considered. This includes studies on the impact of mouse strain on disease models, as well as metabolic profiling of cardiovascular, metabolic and neurodegenerative diseases. This versatile tool is set to increase in popularity as functional genomic approaches produce more mouse models for phenotyping.     

Recent and potential developments of biofluid analyses in metabolomics

Metabolomics, one of the ‘omic’ sciences in systems biology, is the global assessment and validation of endogenous small-molecule metabolites within a biologic system. Analysis of these key metabolites in body fluids has become an important role to monitor the state of biological organisms and is a widely used diagnostic tool for disease. A majority of these metabolites are being applied to metabolic profiling of the biological samples, for example, plasma and whole blood, serum, urine, saliva, cerebrospinal fluid, synovial fluid, semen, and tissue homogenates. However, the recognition of the need for a holistic approach to metabolism led to the application of metabolomics to biological fluids for disease diagnostics. A recent surge in metabolomic applications which are probably more accurate than routine clinical practice, dedicated to characterizing the biological fluids. While developments in the analysis of biofluid samples encompassing an important impediment, it must be emphasized that these biofluids are complementary. Metabolomics provides potential advantages that classical diagnostic approaches do not, based on following discovery of a suite of clinically relevant biomarkers that are simultaneously affected by the disease. Emerging as a promising biofocus, metabolomics will drive biofluid analyses and offer great benefits for public health in the long-term.     

Metabolomics for mitochondrial and cancer studies

Metabolomics, a high-throughput global metabolite analysis, is a burgeoning field, and in recent times has shown substantial evidence to support its emerging role in cancer diagnosis, cancer recurrence, and prognosis, as well as its impact in identifying novel cancer biomarkers and developing cancer therapeutics. Newly evolving advances in disease diagnostics and therapy will further facilitate future growth in the field of metabolomics, especially in cancer, where there is a dire need for sensitive and more affordable diagnostic tools and an urgency to develop effective therapies and identify reliable biomarkers to predict accurately the response to a therapy. Here, we review the application of metabolomics in cancer and mitochondrial studies and its role in enabling the understanding of altered metabolism and malignant transformation during cancer growth and metastasis. The recent developments in the area of metabolic flux analysis may help to close the gap between clinical metabolomics research and the development of cancer metabolome. In the era of personalized medicine with more and more patient specific targeted therapies being used, we need reliable, dynamic, faster, and yet sensitive biomarkers both to track the disease and to develop and evolve therapies during the course of treatment. Recent advances in metabolomics along with the novel strategies to analyze, understand, and construct the metabolic pathways opens this window of opportunity in a very cost-effective manner.     

Metabolomics enables precision medicine: “A White Paper,Community Perspective”

Introduction: Background to metabolomics

Metabolomics is the comprehensive study of the metabolome, the repertoire of biochemicals (or small molecules) present in cells, tissues, and body fluids. The study of metabolism at the global or “-omics” level is a rapidly growing field that has the potential to have a profound impact upon medical practice. At the center of metabolomics, is the concept that a person’s metabolic state provides a close representation of that individual’s overall health status. This metabolic state reflects what has been encoded by the genome, and modified by diet, environmental factors, and the gut microbiome. The metabolic profile provides a quantifiable readout of biochemical state from normal physiology to diverse pathophysiologies in a manner that is often not obvious from gene expression analyses. Today, clinicians capture only a very small part of the information contained in the metabolome, as they routinely measure only a narrow set of blood chemistry analytes to assess health and disease states. Examples include measuring glucose to monitor diabetes, measuring cholesterol and high density lipoprotein/low density lipoprotein ratio to assess cardiovascular health, BUN and creatinine for renal disorders, and measuring a panel of metabolites to diagnose potential inborn errors of metabolism in neonates.

Objectives of White Paper—expected treatment outcomes and metabolomics enabling tool for precision medicine

We anticipate that the narrow range of chemical analyses in current use by the medical community today will be replaced in the future by analyses that reveal a far more comprehensive metabolic signature. This signature is expected to describe global biochemical aberrations that reflect patterns of variance in states of wellness, more accurately describe specific diseases and their progression, and greatly aid in differential diagnosis. Such future metabolic signatures will: (1) provide predictive, prognostic, diagnostic, and surrogate markers of diverse disease states; (2) inform on underlying molecular mechanisms of diseases; (3) allow for sub-classification of diseases, and stratification of patients based on metabolic pathways impacted; (4) reveal biomarkers for drug response phenotypes, providing an effective means to predict variation in a subject’s response to treatment (pharmacometabolomics); (5) define a metabotype for each specific genotype, offering a functional read-out for genetic variants: (6) provide a means to monitor response and recurrence of diseases, such as cancers: (7) describe the molecular landscape in human performance applications and extreme environments. Importantly, sophisticated metabolomic analytical platforms and informatics tools have recently been developed that make it possible to measure thousands of metabolites in blood, other body fluids, and tissues. Such tools also enable more robust analysis of response to treatment. New insights have been gained about mechanisms of diseases, including neuropsychiatric disorders, cardiovascular disease, cancers, diabetes and a range of pathologies. A series of ground breaking studies supported by National Institute of Health (NIH) through the Pharmacometabolomics Research Network and its partnership with the Pharmacogenomics Research Network illustrate how a patient’s metabotype at baseline, prior to treatment, during treatment, and post-treatment, can inform about treatment outcomes and variations in responsiveness to drugs (e.g., statins, antidepressants, antihypertensives and antiplatelet therapies). These studies along with several others also exemplify how metabolomics data can complement and inform genetic data in defining ethnic, sex, and gender basis for variation in responses to treatment, which illustrates how pharmacometabolomics and pharmacogenomics are complementary and powerful tools for precision medicine.

Conclusions: Key scientific concepts and recommendations for precision medicine

Our metabolomics community believes that inclusion of metabolomics data in precision medicine initiatives is timely and will provide an extremely valuable layer of data that compliments and informs other data obtained by these important initiatives. Our Metabolomics Society, through its “Precision Medicine and Pharmacometabolomics Task Group”, with input from our metabolomics community at large, has developed this White Paper where we discuss the value and approaches for including metabolomics data in large precision medicine initiatives. This White Paper offers recommendations for the selection of state of-the-art metabolomics platforms and approaches that offer the widest biochemical coverage, considers critical sample collection and preservation, as well as standardization of measurements, among other important topics. We anticipate that our metabolomics community will have representation in large precision medicine initiatives to provide input with regard to sample acquisition/preservation, selection of optimal omics technologies, and key issues regarding data collection, interpretation, and dissemination. We strongly recommend the collection and biobanking of samples for precision medicine initiatives that will take into consideration needs for large-scale metabolic phenotyping studies.

     

New insights into cardiovascular and lipid metabolomics

Metabolomics is the study of metabolite profiles in biological samples, particularly urine, saliva, blood plasma and fat biopsies. The metabolome is now considered by some to be the most predictive phenotype: consequently, the comprehensive and quantitative study of metabolites is a desirable tool for diagnosing disease, identifying new therapeutic targets and enabling appropriate treatments. A wealth of information about metabolites has been accumulated with global profiling tools and several candidate technologies for metabolomic studies are now available. Many high-throughput metabolomics methodologies are currently under development and have yet to be applied in clinical practice on a routine basis. In the cardiovascular field, few recent metabolomic studies have been reported so far. This minireview provides an updated overview of alternative technical approaches for metabolomics studies and reviews initial applications of metabolomics that relate to both cardiovascular disease and lipid metabolism research.     

Stable isotope-resolved metabolomics (SIRM) in cancer research with clinical application to nonsmall cell lung cancer

Metabolomics provides a readout of the state of metabolism in cells or tissue and their responses to external perturbations. For this reason, the approach has great potential in clinical diagnostics. Clinical metabolomics using stable isotope resolved metabolomics (SIRM) for pathway tracing represents an important new approach to obtaining metabolic parameters in human cancer subjects in situ. Here we provide an overview of the technology development of labeling from cells in culture and mouse models. The high throughput analytical methods NMR and mass spectrometry, especially Fourier transform ion cyclotron resonance, for analyzing the resulting metabolite isotopomers and isotopologues are described with examples of applications in cancer biology. Special technical considerations for clinical applications of metabolomics using stable isotope tracers are described. The whole process from concept to analysis will be exemplified by our on-going study of nonsmall cell lung cancer (NSCLC) metabolomics. This powerful new approach has already provided important new insights into metabolic adaptations in lung cancer cells, including the upregulation of anaplerosis via pyruvate carboxylation in NSCLC.     

A Metabolomic Approach to Understanding the Metabolic Link between Obesity and Diabetes

Obesity and diabetes arise from an intricate interplay between both genetic and environmental factors. It is well recognized that obesity plays an important role in the development of insulin resistance and diabetes. Yet, the exact mechanism of the connection between obesity and diabetes is still not completely understood. Metabolomics is an analytical approach that aims to detect and quantify small metabolites. Recently, there has been an increased interest in the application of metabolomics to the identification of disease biomarkers, with a number of well-known biomarkers identified. Metabolomics is a potent approach to unravel the intricate relationships between metabolism, obesity and progression to diabetes and, at the same time, has potential as a clinical tool for risk evaluation and monitoring of disease. Moreover, metabolomics applications have revealed alterations in the levels of metabolites related to obesity-associated diabetes. This review focuses on the part that metabolomics has played in elucidating the roles of metabolites in the regulation of systemic metabolism relevant to obesity and diabetes. It also explains the possible metabolic relation and association between the two diseases. The metabolites with altered profiles in individual disorders and those that are specifically and similarly altered in both disorders are classified, categorized and summarized.     

Applications of Metabolomics for Kidney Disease Research

Metabolomics is one of the relative newcomers of the omics techniques and is likely the one most closely related to actual real-time disease pathophysiology. Hence, it has the power to yield not only specific biomarkers but also insight into the pathophysiology of disease. Despite this power, metabolomics as applied to kidney disease is still in its early adolescence and has not yet reached the mature stage of clinical application, i.e., specific biomarker and therapeutic target discovery. On the other hand, the insight gained from hints into what makes these diseases tick, as is evident from the metabolomics pathways which have been found to be altered in kidney cancer, are now beginning to bear fruit in leading to potential therapeutic targets. It is quite likely that, with greater numbers of clinical materials and with more investigators jumping into the field, metabolomics may well change the course of kidney disease research.     

Emerging issues: nutritional awareness in environmental toxicology

Based on recent evidence, we hypothesize that nutrition can modulate the toxicity of environmental pollutants and thus modulate health and disease outcome associated with chemical insults. For example, certain dietary fats may increase the risk to environmental insult induced by polychlorinated biphenyls (PCBs), and fruits and vegetables, rich in antioxidant and anti-inflammatory nutrients or bioactive compounds, may provide protection. Nutritional awareness in environmental toxicology is critical, because of opportunities to develop dietary guidelines which specifically target exposed populations. Nutrition may provide the most sensible means to develop primary prevention strategies of diseases associated with environmental toxicology.     

The utility of metabolomics in natural product and biomarker characterization

BackgroundMetabolomics is a well-established rapidly developing research field involving quantitative and qualitative metabolite assessment within biological systems. Recent improvements in metabolomics technologies reveal the unequivocal value of metabolomics tools in natural products discovery, gene-function analysis, systems biology and diagnostic platforms.Scope of reviewWe review here some of the prominent metabolomics methodologies employed in data acquisition and analysis of natural products and disease-related biomarkers.Major conclusionsThis review demonstrates that metabolomics represents a highly adaptable technology with diverse applications ranging from environmental toxicology to disease diagnosis. Metabolomic analysis is shown to provide a unique snapshot of the functional genetic status of an organism by examining its biochemical profile, with relevance toward resolving phylogenetic associations involving horizontal gene transfer and distinguishing subgroups of genera possessing high genetic homology, as well as an increasing role in both elucidating biosynthetic transformations of natural products and detecting preclinical biomarkers of numerous disease states.General significanceThis review expands the interest in multiplatform combinatorial metabolomic analysis. The applications reviewed range from phylogenetic assignment, biosynthetic transformations of natural products, and the detection of preclinical biomarkers.     

MetaboLights: towards a new COSMOS of metabolomics data management

Exciting funding initiatives are emerging in Europe and the US for metabolomics data production, storage, dissemination and analysis. This is based on a rich ecosystem of resources around the world, which has been build during the past ten years, including but not limited to resources such as MassBank in Japan and the Human Metabolome Database in Canada. Now, the European Bioinformatics Institute has launched MetaboLights, a database for metabolomics experiments and the associated metadata (http://www.ebi.ac.uk/metabolights). It is the first comprehensive, cross-species, cross-platform metabolomics database maintained by one of the major open access data providers in molecular biology. In October, the European COSMOS consortium will start its work on Metabolomics data standardization, publication and dissemination workflows. The NIH in the US is establishing 6?C8 metabolomics services cores as well as a national metabolomics repository. This communication reports about MetaboLights as a new resource for Metabolomics research, summarises the related developments and outlines how they may consolidate the knowledge management in this third large omics field next to proteomics and genomics.     

Metabolomics and its application to studying metal toxicity

Here we explain the omics approach of metabolomics and how it can be applied to study a physiological response to toxic metal exposure. This review aims to educate the metallomics field to the tool of metabolomics. Metabolomics is becoming an increasingly used tool to compare natural and challenged states of various organisms, from disease states in humans to toxin exposure to environmental systems. This approach is key to understanding and identifying the cellular or biochemical targets of metals and the underlying physiological response. Metabolomics steps are described and overviews of its application to metal toxicity to organisms are given. As this approach is very new there are yet only a small number of total studies and therefore only a brief overview of some metal metabolomics studies is described. A frank critical evaluation of the approach is given to provide newcomers to the method a clear idea of the challenges and the rewards of applying metabolomics to their research.