Moving metabolomics up a gear: Enhanced international collaboration enabled by NMR

To gain statistical significance from metabolomic studies of human diseases, you need a large cohort of patients willing and able to take part in medical studies – and an instrument that’s able to handle small volumes of samples and provide quantitative and reproducible analyte concentrations. Dr. Christoph Trautwein at the University of Tübingen, Germany, has been able to address both issues, thanks to the power of nuclear magnetic resonance (NMR). We talk to him about his work.

The research of Dr. Christoph Trautwein spans both preclinical and clinical studies and covers a wide range of medical conditions – from neurodegenerative disorders such as Parkinson’s Disease and Alzheimer’s Disease, to breast cancer, hepatocellular carcinoma, glioma, stroke and inflammatory diseases.

Identifying metabolites and lipoproteins associated with Covid-19

But since the Covid-19 pandemic started in early 2020, his research focus has grown: “We simply wanted to contribute something to the research into Covid-19”, he says. Initially, this work involved colleagues in the Medical Genetics department at the University of Tübingen, where we investigated immune cells implicated in the ‘cytokine storm’ that is a major cause of mortality from Covid-19¹.

“The first part was some fundamental research into the metabolites,” says Dr. Trautwein. “Using NMR, we found that actively infected patients had distinct metabolic profiles, in line with existing research.” Then, with the help of a software package supplied by Bruker, they started on some quantitative work: “We found that there were several metabolites in blood plasma that were present at higher levels, which was interesting because these are typically associated with insulin resistance, cardiovascular disease and inflammation,” he adds.

Work in progress: Uncovering insights into Long Covid

This finding may be significant for research into Long Covid, says Dr. Trautwein: “Because of my previous research in neurology², I was very interested in investigating the effects that Covid-19 has on the brain. Perhaps amongst these metabolites we have found, there could be one that would tell us why some people with Long Covid have headaches, or problems with memory and concentration.”

In fact, Dr. Trautwein has started a new collaboration into exactly this topic with Heidelberg University, Germany, which will use serum and urine samples from a cohort of almost 350 people that suffered from an acute SARS-CoV-2 infection with some of them developing Long Covid. “It’s ongoing work,” he says, “but we have the metadata for the participants already, and we’re looking forward to finding out some interesting insights.”

Convenient, sensitive analysis with NMR

But along with opportunities, some challenges arise, he adds – and in this case it’s the difficulty in seeing exactly what’s going on inside the brain. He says that magnetic resonance imaging (MRI) is a good tool in this respect, but it’s expensive and shows only major brain damages: “You can’t do it every week!” But NMR-based metabolomics is cheaper and easier: “So long as you have the hardware installed, you could measure a sample every day, in principle.” That opens up the possibility of using NMR data as a more convenient way of studying Covid-19 patients with neurological symptoms, by first correlating the data with MRI scans.

The Bruker 600 MHz NMR Avance-IVDr instrument at Tübingen has played a central role in much of his research, says Dr. Trautwein, because it’s tailored to quantitative high-throughput biofluid screening. “Having a system with high reproducibility and sensitivity was vital for detecting the small quantities of metabolites in our samples and because it could accommodate 3 mm tubes rather than the regular 5 mm type, we were able to use volumes of just 100 µL from precious patient samples.”

There is also a unique practical benefit of running experiments on the Avance-IVDr, Dr. Trautwein says: “A useful aspect of all Avance-IVDr systems is that they use the same hardware, software and standard operating procedures, meaning that data acquired in different laboratories can be immediately compared.”

Comparable data for improving collaboration

The upshot of this cross-comparability is particularly relevant to Covid-19 studies, Dr. Trautwein explains: “One challenge with Covid-19 is that a relatively small proportion of patients are willing or able to put themselves forward for research projects, which means that many studies struggle to achieve statistical significance.”

But the comparability of datasets from the Avance-IVDr NMR systems means that Dr. Trautwein and his collaborators can pool datasets: “So we’ve studied samples from Australia, Spain, Germany, UK and Italy side-by-side, enabling us to filter out confounding factors, and better understand the effects of Covid-19 both in the acute phase and in the long-term.”

So, thanks to the capabilities offered by Bruker’s NMR instruments, he says, metabolomics has moved up a gear: “When you’re tackling complex diseases – whether Covid-19, cancer, neurodegenerative diseases, or metabolic diseases – sharing data and expertise with experts around the world allows us to make more progress, more quickly. This is how science should really work!”

References

1. Y. Singh, C. Trautwein et al., SARS-CoV-2 infection paralyzes cytotoxic and metabolic functions of the immune cells, Heliyon, 2021 7(6):e07147, https://doi.org/10.1016/j.heliyon.2021.e07147
2. C. Trautwein et al., Tissue metabolites in diffuse glioma and their modulations by IDH1 mutation, histology and treatment, JCI Insight, 2021, https://doi.org/10.1172/jci.insight.153526
3. Lucia Laugwitz, Laimdota Zizmare, Vidiyaah Santhanakumaran, Claire Cannet, Judith Böhringer, Jürgen G. Okun, Manfred Spraul, Ingeborg Krägeloh-Mann, Samuel Groeschel, Christoph Trautwein, Identification of neurodegeneration indicators and disease progression in metachromatic leukodystrophy using quantitative NMR-based urinary metabolomics, JIMD reports, 2022, https://onlinelibrary.wiley.com/doi/10.1002/jmd2.12273

Dr. Christoph Trautwein studied Environmental Engineering at the University of Stuttgart, Germany, before starting in 2007 a second career in Molecular Medicine at the University of Freiburg, where he also completed his PhD. After a postdoc at the Karlsruhe Institute of Technology, in 2017 he joined the Werner Siemens Imaging Center at the University of Tübingen, where he currently leads the research group for Metabolomics & Systems Medicine.

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