Metabolomics in Clinical and Medical Applications

Are you curious about the clinical and medical applicability of metabolomics analysis? We will discuss based on our recent metabolomics publications related to this settings. Our team of experts also present at the Mass Spectrometry & Advances in the Clinical Lab (MSACL) Conference 2023 in Monterey, California and excited to share the experience.

Tobacco and Urinary Biomarker

Dr. Britz-McKibbin, TMIC node leader at McMaster University, recently published the results of a large cohort study examining urine thiocyanate as a biomarker among 1000 people (self-reported never and current smokers) from 14 countries who participated in the Prospective Urban and Rural Epidemiological study.

Urinary thiocyanate was found to be a sensitive biomarker of active tobacco smoking in comparison to cotinine which may be evaluated using a low-cost capillary electrophoresis technique. This method offers a means of reducing bias that is present in the self-reports to figure out how dangerous smoking is in countries with different levels of socioeconomic development.

Using this more dependable and objective method, it was determined that Canadian tobacco consumers are exposed to higher levels of cyanide than smokers in low-income countries. While this finding may be startling, it is still understandable given the circumstances. Commonly smoked cigarettes in Canada are highly engineered products with less tar and nicotine, implying that they are less hazardous to human health. Nicotine-dependent heavy smokers compensate by smoking more aggressively with more frequent and deeper inhalations, which may cause more damage, such as increased exposure to cyanide which is extremely toxic to the heart, respiratory, and central nervous systems. McMaster University also featured this discovery in their research story section, Brighter World.

This large-scale population health study is published in the Nicotine & Tobacco Research journal with funding from the Natural Sciences and Engineering Research Council of Canada, Genome Canada, the Canada Foundation for Innovation, Hamilton Health Sciences New Investigator Fund, and an internal grant from the Population Health Research Institute.

BCG Vaccination for Tuberculosis

Another work from Britz-Mckibbin node examines the effects of subcutaneous Bacillus Calmette–Guérin (BCG) vaccination on the lungs, focusing on whether and how it leads to the formation of tissue-resident memory macrophages and trained innate immunity (TII). It was recorded in this open-access paper in Nature Immunology that named Parenteral BCG vaccine induces lung-resident memory macrophages and trained immunity via the gut–lung axis. [BCG is a vaccine for tuberculosis (TB) disease with the commonly delivered either enterally (i.e., by mouth) or parenterally (i.e., by needle injection under the skin)]

These findings indicate a pathway for the formation of innate immunological memory at distal mucosal tissues that is mediated by the gut microbiota. They are important for developing next-generation respiratory pathogen vaccines.

Inflammatory Bowel Disease Early Detection

Dr. Britz-McKibbin also published a patent earlier this year on a reliable, low-cost approach for the diagnosis of Crohn’s disease (CD) and ulcerative colitis (UC) utilizing urinary biomarkers. It provides a minimally invasive strategy for early identification. Inflammatory bowel disease (IBD), which includes CD and UC, is an idiopathic chronic gastrointestinal (GI) condition.

This method can also distinguish between UC and CD via distinct urine-based biomarkers and metabolic phenotypes of IBD patients. This benchmark allows for identifying the correct disease at an earlier stage and facilitating treatment monitoring. Also, it may eliminate the requirement for invasive procedures like colonoscopic imaging and tissue biopsies.

This technology is also registered with McMaster University as a non-invasive diagnosis and treatment monitoring of inflammatory bowel disease, putting this knowledge in the hands of those who can best apply it. This approach has several medical applications:

1. Non-invasive testing

2. Differential diagnosis of major pediatric inflammatory bowel disease subtypes

3. Prompt detection and treatment strategies

4. Improve IBD screening and diagnostic tests.

W.A.E. McBryde Medal

Credit to: Chemical Institute of Canada,

The W. A. E. McBryde Medal is presented to a young scientist working in Canada who has made a significant achievement in pure or applied analytical chemistry. We are so pleased that Dr. Philip Britz-McKibbin is the 2023 recipient. 

Britz-McKibbin’s research program focuses on developing new analytical methods for untargeted metabolite profiling and biomarker discovery using multiplexed capillary electrophoresis-mass spectrometry technology. His group has contributed new approaches for high throughput screening to identify novel small molecules of biological significance in complex samples with stringent quality control. His methods enable new discoveries in clinical medicine, exposure science and nutritional epidemiology with emphasis on early detection, disease prevention and population health.

Inhibitor for Breast Cancer and Melanoma

Dr. Borchers from McGill University coauthored Inhibition of the MNK1/2-eIF4E Axis Augments Palbociclib-Mediated Antitumor Activity in Melanoma and Breast Cancer. A significant discovery is that MNK1/2 inhibitors are promising medications for enhancing palbociclib’s antitumor effects and overcoming therapy-resistant illness.

The MNK1/2-eIF4E axis represents a convergence point for various signaling pathways that are typically activated continuously in melanoma.

Analytical Strategy for Clinical Applications’ Throughput

One of the widely accepted methods for metabolomics analysis is Liquid Chromatography Mass Spectrometry (LC-MS), which is not only useful for biomarker development but also for clinical diagnostics. Therefore, improving the efficiency of LC-MS is essential for advancing the field of metabolomics.

The chromatographic gradient lengths constrain these clinical applications’ throughput, making it challenging to analyze complex metabolomics samples in less than three minutes per sample. Dr. Ian Lewis’s group at the University of Calgary introduced an analytical strategy called SQUID (sequential quantification using isotope dilution), which combines serial sample injections into a continuous isocratic mobile phase to improve this throughput. Additional information can be found in this paper, Rapid LC–MS assay for targeted metabolite quantification by serial injection into isocratic gradients.

Schematic overview of SQUID
Source: Anal Bioanal Chem . 2023 Jan;415(2):269-276. doi: 10.1007/s00216-022-04384-x

Metabolomics Assays Development

Dr. Christoph Borchers’ Node at McGill University offers the Development and implementation of the custom targeted clinical LC-MS assays for drugs, hormones and metabolites. The assay development includes:

  • Streamline LC-MS assay development and optimization
  • Quantitative analyte determination using isotopically labeled internal standards
  • Assay validation according to CLSI guidelines
  • Multiplex analyses of panels of substances
  • Multiple analyte classes (drugs, hormones, vitamins, metabolites, etc.)
  • Multiple specimen types (blood, plasma, urine, saliva, tissue biopsies)

Dr. Borchers’ Node also provides a comprehensive identification of drug metabolites (MetID – metabolites identification). His lab is interested in multi-omics work (combining proteomics and metabolomics), and provides an integration of machine learning to data analysis. Contact us if you want to connect to our McGill Node and Dr. Christoph Borchers.

Dr. Britz-McKibbin Node also offers the following targeted and untargeted metabolomics services:

  • Targeted Analysis of Polar Metabolites utilizing a multi-segment injection (MSI) capillary electrophoresis TOF MS. This is a high sample throughput assay for the identification and quantification of a wide range of polar metabolites ideal for large scale studies, ionic metabolites and low volume samples (<5 uL or < 5 mg dried weight). Depending on the sample type, it allows profiling of 50-200 metabolites.
  • Targeted Analysis of Fatty Acids using nonaqueous capillary electrophoresis TOF MS (NACE- MS). This service allows measurement of free (nonesterified) fatty acids with in a high sample throughput format (24 metabolites with absolute quantification).
  • Targeted Analysis of Major Electrolytes/(In)organic Ions with CE-UV or CE-iUV (indirect UV). The assay offers measurement of 20 major electrolytes, including those with low ionization energy.
  • Targeted Analysis of Drugs of Abuse and Cannabinoid Metabolites using multi-segment injection (MSI) capillary electrophoresis TOF MS. This service allows identification and quantification of over 70 illicit and prescribed drugs (and their metabolites) in urine in < 3 min/sample.
  • High Throughput Global Metabolomics by MSI-CE-MS For Large Scale Epidemiological and Clinical Studies. This service aims at providing high throughput yet nontargeted metabolomic analyses that is optimal for large-scale epidemiological and clinical studies (n > 1000) with stringent quality control. It allows to profile 60-300 authentic metabolites, lipids or drugs.

Summarized by Juan Darius

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