Instrumental Drift in Untargeted Metabolomics: Optimizing Data Quality with Intrastudy QC Samples

The metabolism of an organism is the entity of all chemical processes needed to sustain its life. It integrates information from genetic and regulatory processes, as well as environmental factors such as diet and lifestyle and is, therefore, very close to the actual phenotype. Thus, studying the metabolism can lead to valuable insights for understanding health and disease. A promising approach to study the metabolism is called untargeted metabolomics, which is the measurement of all detectable small molecules within a sample. However, the employed analytical techniques suffer from inevitable instrumental variation, in particular in large clinical studies. Hence, it is crucial to consider these variations during data processing to ensure high-quality data. The instrumental variation can be modeled, using intrastudy quality control samples, which are generated by mixing all biological samples within a specific study. A lot of methods exist, utilizing these intrastudy quality control samples to reduce the instrumental variation in the data. In this review, the authors evaluate methods of different complexity, using multiple precision metrics and machine-learning based approaches to recommend the reader an optimal data processing workflow. This workflow will generate high-quality data that are suitable for further downstream processing, leading to more accurate and meaningful insights into the underlying biological processes.

Original publication:

Märtens A, Holle J, Mollenhauer B, Wegner A, Kirwan J, Hiller K. Instrumental Drift in Untargeted Metabolomics: Optimizing Data Quality with Intrastudy QC Samples. Metabolites. 2023; 13(5):665.

Effective against an overactive immune system

Excerpt from the TU-BS magazine:

A team of scientists led by Professor Karsten Hiller from the Braunschweig Centre for Systems Biology BRICS has discovered an endogenous, anti-inflammatory substance: mesaconic acid. This molecule could be a drug candidate that can be further developed to treat shock resulting from blood poisoning and autoimmune diseases such as psoriasis and inflammatory bowel disease (IBD) – without the known side effects of anti-inflammatory drugs currently in use.

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Original publication:

He, W., & Hiller, K. (2022). Mesaconate is synthesized from itaconate and exerts immunomodulatory effects in macrophages, Nature Metabolism, DOI: 10.1038/s42255-022-00565-1

Plasma lactate acts as a metabolic buffer after food intake

The human body is constantly trying to keep nutrient levels in balance, inside the cells but also in the blood stream. When we consume food, large amounts of nutrients enter the system, challenge homeostasis and force metabolism to react. Following an interdisciplinary approach, an international team of scientists at the Technische Universität Braunschweig, Germany and the Unilever Foods Innovation Centre, Wageningen, The Netherlands has now been able to quantify metabolic flux adaptations taken by the human body to keep nutrient levels in a physiological range after food intake. The results have been published in the special issue “Nutrition and Metabolism” of the journal "Frontiers in Nutrition".

Food intake causes a major challenge for the human organism to keep all nutrients (e.g. sugars, amino acids, lipids, vitamins etc.) in a range that can be tolerated by the human body. This state after food consumption, i.e. the postprandial phase, is characterized by rapidly changing metabolite concentrations and metabolic flux adaptations. The quantification of metabolic fluxes in the highly dynamic postprandial phase represents a major experimental challenge.

Interdisciplinary approach – key for this investigation

An international team of researchers with different areas of expertise was needed to tackle this research question. Scientists from the Unilever Foods Innovation Centre designed the nutritional intervention study that involved twelve human subjects, in vivo stable isotope labeling and time-resolved blood collection. Two food products with different carbohydrate sources were investigated, a glucose solution and a wheat flour based porridge. The plasma samples were analyzed by scientists from the TU Braunschweig using a specialized analytical approach to obtain absolute concentrations of several central carbon metabolites. The generated data were used as input for a mathematical metabolic network model resembling the metabolic situation in the postprandial phase. This combined approach enabled the generation of quantitative metabolic fluxes in this highly dynamic metabolic state.

Plasma lactate pool enables metabolic flexibility

The researchers found that, depending on the consumed food product, the metabolic adaptations were vastly different. After intake of the nutritionally more complex wheat porridge, flux alterations were stronger as in the less complex glucose solution. The researchers showed that the net direction of several fluxes changed during the course of the postprandial phase and demonstrated that systemic lactate and to a lesser extent, pyruvate and alanine, serve as metabolic buffers in the postprandial phase: When excessive amounts of nutrients are available, the nutrients are converted into lactate and channeled into the systemic lactate pool, however, when nutrient availability is reduced, systemic lactate is mobilized to serve as substrate for other metabolic processes. Further investigations on metabolic flux alterations as accurate biomarkers in the context of metabolic diseases are warranted.

Original publication:

Schlicker L, Zhao G, Dudek C-A, Boers HM, Meyer-Hermann M, Jacobs DM and Hiller K (2022) Systemic Lactate Acts as a Metabolic Buffer in Humans and Prevents Nutrient Overflow in the Postprandial Phase. Front. Nutr. 9:785999. doi: 10.3389/fnut.2022.785999

Mitochondrial metabolism in macrophages

The authors (Mohamed Zakaria Nassef, Jasmin E. Hanke, and Karsten Hiller) of this review paper have worked together to produce a comprehensive review of the latest advances in mitochondrial metabolism in macrophages.

Mitochondria are considered to be the powerhouse of the cell. Normal functioning of the mitochondria is not only essential for cellular energy production but also for several immunomodulatory processes. Macrophages operate in metabolic niches and rely on rapid adaptation to specific metabolic conditions such as hypoxia, nutrient limitations, or reactive oxygen species to neutralize pathogens. In this regard, the fast reprogramming of mitochondrial metabolism is indispensable to provide the cells with the necessary energy and intermediates to efficiently mount the inflammatory response. Moreover, mitochondria act as a physical scaffold for several proteins involved in immune signaling cascades and their dysfunction is immediately associated with a dampened immune response. In this review, we put special focus on mitochondrial function in macrophages and highlight how mitochondrial metabolism is involved in macrophage activation.”

The review paper has been published in volume 321, issue 6, December 2021, pages C1070-C1081 of the American Journal of Physiology-Cell Physiology, a Journal of the American Physiological Society. This paper is part of a series of reviews on the theme of “Mitochondrial Biology in Health, Ageing and Disease”, to mark the 60th anniversary of key discoveries on mitochondrial structure and function through the publication of Peter Michell's chemi-osmotic hypothesis (Nature (1961), 191:144-8).

Original publication:

Nassef, Mohamed Zakaria, Jasmin E. Hanke, and Karsten Hiller. 2021. “Mitochondrial Metabolism in Macrophages.”

Toxische Wirkung von Parkinson-Medikament auf Gehirnzellen untersucht

Auszug aus dem TU-Braunschweig Magazin:

Levodopa gilt als eines der wichtigsten Medikamente zur Behandlung von Parkinson. In der Vergangenheit wurde oft berichtet, dass die Behandlung mit der Substanz schädlich für die Neuronen sein könnte, weil diese verstärkt zur Bildung von Sauerstoffradikalen führt. Ein Team von Wissenschaftlerinnen und Wissenschaftlern an der Technischen Universität Braunschweig in Kooperation mit dem Labor von Prof. Marcel Leist an der Universität Konstanz konnte jetzt zeigen, dass es sich in fast allen dieser Studien um Artefakte durch zu viel Sauerstoff in den Zellkultur-Experimenten handelte. Vielmehr konnte der Einfluss von Levodopa erstmalig ohne störende Sauerstoffradikale untersucht und auch Effekt des Medikaments auf den Stoffwechsel der Neurone und deren Mitochondrien bestimmt werden. Es sieht so aus, als wenn Levodopa die Energieversorgung der Neurone stört und dies auch die Ursache für Levodopa-Nebenwirkungen sein könnte.

Hier weiterlesen.