Chapter 4—The Importance of Metabolomics Insights
In the previous chapter of this guide, you learned a bit more about metabolites, the metabolome, and how to study the metabolome through metabolomics analyses. But why study the metabolome in the first place? In this chapter, we’ll discuss why metabolomics is an attractive option on many levels, and provide a brief introduction to the academic, clinical, and commercial applications of metabolomics studies.
What are Some of the Benefits of Metabolomic Studies?
Because metabolomics datasets provide phenotypic information, they are a powerful tool for adding context and direction to any research study. For example, enzyme kinetics studies (which are a critical component of drug development) can benefit from metabolomic profiling of the small molecules (ie, the cofactors and substrates) that interact with enzymes and impact their activity, helping troubleshoot studies that aren’t working as expected and giving direction on where to go next.
Metabolomics datasets can also advance precision medicine research and development by shedding light on the person-to-person differences that impact how and why treatment strategies work or not. This can be something as simple as differential exposure to environmental components, such as pollution, that can impact drug effectiveness, or something as inherently unique as the way each individual metabolizes nutrients or medicines. Megan Showalter, PhD, Strategic Account Manager at Metabolon, provides an example we are probably all familiar with: “The globally accepted recommendation is that everyone take a certain dose of fish oil for heart and brain health, but we all metabolize it a bit differently. Metabolomics can help determine whether different people will benefit from different doses—or from fish oil, period.”
Additional aspects of metabolomics studies that make them a great option for human medicine—personalized or not—is their application in next-generation disease diagnostics and their discovery potential for biomarkers. Several cancer biomarkers have already been identified using metabolomics, and the required samples can be collected in a non-invasive manner. Urine, breath, sweat, saliva, and fecal samples can all be collected painlessly and used to detect a range of diseases such as cancer, infectious diseases, neurodegenerative diseases, and more. These same samples can also be used for biomarker discovery, along with blood. And although blood collection isn’t non-invasive per se, it is certainly far less invasiveness than traditional solid tissue biopsy.
Metabolomics as Part of Multi-omics Approaches
Because the small molecules detected via metabolomics studies can be impacted by the genome, transcriptome, proteome, and environment, metabolomics is the only true reflection of phenotype at any given point in time. Any changes in or interactions between gene expression, protein expression, and the environment can be directly observed through the metabolome, making metabolomics the most complex and informative of all the omics techniques.
While each omic approach on its own provides useful information, combining different approaches can reveal important biological and physiological signatures that can help elucidate the mechanisms behind specific disease etiologies, drug responses, and more. For a more in-depth discussion of metabolomics in the context of other omics approaches and why metabolomics is a critical component of multi-omics studies, refer to Chapter 2 of this guide.
Applications of Metabolomics
Academic research, which can also be called “bench science” or “basic science research” lays the foundational knowledge required to better understand biological systems and to make progress outside of the laboratory. The early stages of drug discovery, biomarker identification, microbial-host interactions in health and disease (for humans, plants, and animals), and more, typically start in the academic laboratory.
One of the hottest areas of research today is the human microbiome and its role in human health and disease. While the potential for leveraging the human microbiome to optimize human health has been recognized for several years, its therapeutic potential has been limited by knowledge gaps in precisely how the human microbiome interacts with its host. By adding metabolomics components to their (traditionally DNA-based) studies, researchers are beginning to understand how the microbiome impacts our immune systems,1 digestive system,2 metabolism,3 skin, and brain function. These studies are laying the foundation for pre-clinical and, eventually, clinical studies that will make testing and addressing the microbiome in the clinic as common as measuring blood pressure.
Histone modification4 is also a growing area of academic research, because it plays such an integral role in life—from basic biological processes like DNA repair to complex physiologies like disease etiology. Several metabolomics studies have reported crucial relationships between metabolites and histone modifications, and how fluctuations in these relationships can impact diseases such as cancer.5 Basic research like this that provides mechanistic understanding often drives drug discovery work, to eventually result in effective therapeutics used in clinical practice.
Metabolic signatures have been used clinically to some capacity for over 30 years (and in some cases, even longer). For example: the heel-prick test done on babies after their birth detects certain inborn errors in metabolism; cholesterol tests measure lipid metabolites; and the Warburg effect6 is a well-documented metabolic hallmark of cancer. But these are all tests or signatures applied to a global population—there is nothing individualized about them. They are performed and read in the exact same way for everyone.
Metabolomics, by definition, is the high-throughput measurement of hundreds to thousands of metabolites at a time from multiple samples at once. This makes it the perfect tool for advancing precision medicine, which accounts for patient-specific variables that impact health and disease. Metabolomics provides a deep look into the metabolites present in any given sample at any given time, so it can be used to characterize metabolic anomalies associated with disease, discover and validate new therapeutic targets and biomarkers, and dictate personalized therapeutic approaches for patients based on their own unique metabolic profiles.
Metabolomics can also help direct dosing strategies for clinical trials and help troubleshoot failed interventions. In one case study, investigators managed to turn a failed phase II trial into a successful phase III trial using metabolomics to re-design the trial parameters. In another case study, metabolomics was integrated into a clinical trial design so investigators could gain insight on a precision treatment for pulmonary arterial hypertension. These are just two examples of many.
There are several commercial applications for metabolomics, including pharmaceutical, cosmetic, nutritional science, and agriculture. Pharmaceuticals are a significant opportunity area for metabolomics, which can provide early information on drug toxicity7 and pharmacokinetics to increase the chances of a drug proceeding through clinical trials and gaining regulatory approval through the FDA and EMA. Cosmetics also stand to benefit from metabolomics studies, which are being used to drive research into personalized skin care and, similar to drug toxicity studies, can characterize cosmetic product toxicity and activity8—a particularly important factor for companies that do not engage in animal testing.
Metabolomics can also be used to assist food breeders in optimizing for traits such as flavor9 and selecting the cultivars most likely to succeed commercially—as well as prevent large-scale losses by detecting food adulteration and contamination10. Other research groups and companies are leveraging microbial metabolomics to improve fertilizers, while still more are using metabolomics to better understand nutrition and address malnutrition on a global scale. It is also being used to drive innovation in animal nutrition, which can impact not only the health of our beloved pets but also the health of animals intended for food (and, therefore, our own health).
1. Zheng D, Liwinski T, Elinav E. Interaction between microbiota and immunity in health and disease. Cell Res. 2020;30(6):492-506. doi:10.1038/s41422-020-0332-7
2. Vernocchi P, Del Chierico F, Putignani L. Gut Microbiota Metabolism and Interaction with Food Components. Int J Mol Sci. 2020;21(10):3688. Published 2020 May 23. doi:10.3390/ijms21103688
3. Jin Q, Black A, Kales SN, Vattem D, Ruiz-Canela M, Sotos-Prieto M. Metabolomics and Microbiomes as Potential Tools to Evaluate the Effects of the Mediterranean Diet. Nutrients. 2019;11(1):207. Published 2019 Jan 21. doi:10.3390/nu11010207
4. Greer EL, Shi Y. Histone methylation: a dynamic mark in health, disease and inheritance. Nat Rev Genet. 2012;13(5):343-357. Published 2012 Apr 3. doi:10.1038/nrg3173
5. Simithy J, Sidoli S, Garcia BA. Integrating Proteomics and Targeted Metabolomics to Understand Global Changes in Histone Modifications. Proteomics. 2018;18(18):e1700309. doi:10.1002/pmic.201700309
6. Liberti MV, Locasale JW. The Warburg Effect: How Does it Benefit Cancer Cells? [published correction appears in Trends Biochem Sci. 2016 Mar;41(3):287] [published correction appears in Trends Biochem Sci. 2016 Mar;41(3):287]. Trends Biochem Sci. 2016;41(3):211-218. doi:10.1016/j.tibs.2015.12.001
7. Ramirez T, Daneshian M, Kamp H, et al. Metabolomics in toxicology and preclinical research. ALTEX. 2013;30(2):209-225. doi:10.14573/altex.2013.2.209
8. Jacques C, Jamin EL, Jouanin I, et al. Safety assessment of cosmetics by read across applied to metabolomics data of in vitro skin and liver models. Arch Toxicol. 2021;95(10):3303-3322. doi:10.1007/s00204-021-03136-7
9. Klevorn CM, Dean LL, Johanningsmeier SD. Metabolite Profiles of Raw Peanut Seeds Reveal Differences between Market-Types. J Food Sci. 2019;84(3):397-405. doi:10.1111/1750-3841.14450
10. Selamat J, Rozani NAA, Murugesu S. Application of the Metabolomics Approach in Food Authentication. Molecules. 2021;26(24):7565. Published 2021 Dec 14. doi:10.3390/molecules26247565
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