How Advances in Metabolomics Are Driving Disease Research
Explore some of the latest developments and emerging applications in the metabolomics field.
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Obesity has almost tripled since 1975. More than 340 million children and adolescents aged between 5 and 19 were overweight or obese in 2016, while 39 million kids under 5 were by 2020, according to the World Health Organization.
“Overweight and obesity is a huge problem in our society,” said Professor Lynn Vanhaecke, a bioscientist at Ghent University, Belgium. She is determined to address the problem in her research and recently received five years of funding from the European Research Council to investigate gut molecules in children – a metabolomics study – and links to obesity.
Metabolomics is the analysis of small molecules such as lipids, amino acids and organic acids. For some, this is the logical step on from DNA sequencing. Genetics can tell you about basic makeup – what’s in their genes and flavors of proteins they make – but it doesn’t give a window into what’s going on in a person’s life or what a strain of bacteria is churning out.
This is where metabolomics steps in. For example, when someone radically changes their diet, the community of trillions of bacteria living in their gut will slowly begin to alter, over weeks or months. A metabolomics study, however, will reveal instant changes from day one, as the body and its microbes begin to live off a different sort of food. There are thousands of different molecules known to be produced in our gut, some by us, some by microbes.
Metabolomics concerns molecules below a specific size (1,500 Daltons) and excludes the larger proteins and nucleic acids. These molecules can serve as molecular footprints of problems in the body and there is now huge interest in identifying metabolites that can help to diagnose and monitor conditions ranging from cancer to Alzheimer’s disease.
Metabolomics is particularly suited to chronic, long-term health conditions explained Associate Professor Serge Rudaz, leader of the biomedical and metabolomics analysis group at the University of Geneva. “For example, chronic kidney disease is perfect because it slowly evolves and you can see changes in the concentrations of some metabolites in a small amount of blood,” he said.
Making sense of gargantuan amounts of metabolomic data becoming available, however, remains a key challenge for the field.
Obesity studies
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In her study, Vanhaecke will collect saliva or stool samples from 1,500 children: some healthy, some overweight, some obese. She will then try various lifestyle and diet interventions and watch how their metabolome changes. “We want to see if we can shift their metabolism towards a healthier state, because you see all sorts of disturbances in children who are overweight,” said Vanhaecke.
Vanhaecke’s ambitious goal is to investigate thousands of gut molecules. If some nutrients or microbes seem to be important in obesity, these will be fed to rodents and their metabolites will be studied to see if the mice behave differently or their health shifts.
Another scientist interested in studying how diet impacts our metabolism is Professor Pieter Dorrestein, a chemist at the University of California San Diego (UCSD). The pace of discovery here has been red hot. “We’re up to identifying 20,000 different bile acids now. If you spoke to me one year ago, maybe 700 were known,” said Dorrestein.
Bile acids help with the digestion of oils and fats, but also tweak how permeable the gut wall is and fine-tune types of white blood cells being made. Dorrestein suspects they also act as communication molecules from the gut to many organs, including the brain.
He points to studies suggesting that time of eating changes our molecular profile and, after a high-fat diet, a healthier bile acid profile was restored by time-restricted feeding in mice.
He is also interested in evidence from people who switched between an American or a Mediterranean diet, with different quantities of meat. A preprint study suggests that components of a Mediterranean diet may reduce inflammation and reverse some metabolic disturbances linked with Alzheimer’s disease.
“When you go from an American to a Mediterranean diet, most of the molecules that we think of as stress related were altered,” said Dorrestein. “They tend to decrease when you switch from American to Mediterranean, but we were surprised that meat didn’t influence these molecules significantly.” Something else in the diet must ramp up production of these stress-related molecules.
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Today, metabolomic studies may look at thousands of small biomolecules in discovery research, where scientists ask questions and try to identify unknown molecules.
The go-to analytical chemistry technique is called liquid chromatography-mass spectrometry, or LC-MS. “LC-MS is the most sensitive technique, and it can measure the lowest concentrations of most molecules,” explained Vanhaecke.
She recently used LC-MS to study the gut of children with allergies to dairy milk. Her studies convinced her that they had experienced a disturbance in their gut microbiome, with the number and abundance of microbes lower in children with allergies.
“We could relate specific changes that we see in the gut, which reflect how the children deal with those milk proteins and the digestive processes that are disturbed,” Vanhaecke explained. Metabolomic changes in a mouse study spotlighted a role for metabolism of starch, sucrose and tryptophan (an amino acid). Vanhaecke views the most likely culprit as a gut microbiome disruption early in life, such as antibiotics.
Meanwhile, Dorrestein developed a technique to image molecules from microbes in a lab using MS. This can reveal how two microbes might be exchanging molecules, beneficial or harmful. Given how easy it is to get skin samples, he decided to study the skin.
In one case, the lab took samples from a woman who had more Staphylococcus aureus on her neck than on her face or body. “It turned out she put lotion on her neck and face in the morning, but only washed her face at night,” recalled Dorrestein.
“We could see lots of personal care product molecules there [on her neck], wherever we saw that we had an increase in Staph.” This bacterium is an opportunist, and if someone were to cut themselves, they are more likely to get an infection with more S. aureus around.
In a later study, Dorrestein teamed up with Katherine Lemon at Baylor College of Medicine and Michael Fischback at Stanford University who discovered that Cutibacterium acnes – a bacteria that lives harmlessly on skin – could produce an antibiotic, cutimycin. This dampened the growth of Staph in hair follicles, but some C. acnes bacteria cannot make it.
“If you’re one of the unlucky people with C. acnes that doesn’t make that small molecule, then you are highly susceptible to acne infections. That’s because now S. aureus can colonize the follicles, causing pimples,” said Dorrestein. He hopes that commensals can be leveraged to develop skin therapies for atopic dermatitis, in a collaboration with Dr. Richard Gallo, a dermatologist at UCSD.
One way to figure out what microbes are doing is to carry out an all-encompassing metabolomics study. Once it used to take many hours and large machines to generate the contents of a metabolome, but now it takes considerably less time.
Vanhaecke has developed a rapid evaporative ionization MS method so that she can run at least 500 samples a day, rather than the usual 50, using a special adsorptive membrane that sieves out and stabilizes the important molecules from a biofluid sample.
Treasure troves
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A big issue in metabolomics is the quantity of data that can be generated, including unknown molecules. In an “untargeted metabolomics experiment” in 2016, Dorrestein said his group could annotate 1.8% of the molecules, while 98% were not annotated. Worse still, data was not being shared publicly. If you wanted to go back to the same patients, “you would have to collect samples from those same patients and re-run the metabolomics analysis,” explained Dorrestein.
One huge shift is the rise of three public data repositories. Metabolomics Workbench accepts data for studies on cells, tissues and organisms and is funded by the National Institutes of Health in the United States. It accepts data from untargeted and targeted studies and provides tools for analysis and visualization of data. This facility – housed at UCSD – contains over 164,000 discrete structures.
Second up is MetaboLights run by the European Bioinformatics Institute in the UK, which is part of the European Molecular Biology Laboratory. MetaboLights is a global database for metabolomics including the raw data and associated metadata. There were 8,544 studies in MetaboLights in September 2023, up from 1,432 studies in January 2020, as noted in a 2024 article looking at the database.
A third database is Global Natural Products Social Molecular Networking (GNPS), which Dorrestein was instrumental in setting up. It consists of tens of thousands of molecular entities but also hundreds of millions of molecular fingerprints. This is in the form of LC-MS that includes “fragmentation data,” which are the patterns formed when molecules are smashed into pieces in an MS machine. Those pieces are weighed by the MS machine, creating a barcode representing the original molecules.
GNPS is “solely designed for untargeted LC-MS data where you have fragmentation spectra,” said Dorrestein, who recently published an article on this open-access database in Nature Communications.
He credits the three repositories as revolutionizing possibilities in metabolomics, allowing the field to escape from a chicken-or-egg conundrum. “Do you get the data first, or do you develop the tools to mine the data first, because traditionally those tools did not exist,” said Dorrestein.
Other improvements followed. “There were about 40 different vendor formats for metabolomic data. If you didn’t have the right software, you could not look at it,” Dorrestein recalls. Now, it is possible to convert to an open text format, so that data harmonization is increasingly feasible.
Unearthing patient benefits
Scientists are reaping rewards. In 2020, Dorrestein and colleagues discovered three bile acids made by microbes, using GNPS. They searched databases for close matches and for patterns in animal or human studies linked to diet or illness, with the help of a search engine for public databases.
“We found this whole panel of microbial metabolites that increased in irritable bowel syndrome (IBS) and specifically in Crohn’s disease,” said Dorrestein. “We get all this information for free, because we searched thousands of studies at once,” Dorrestein enthused.
He is now chasing down molecules linked to inflammatory bowel disease (IBD). This may show how to manipulate the microbiome or its molecules with diet, thereby ameliorating disease, or it could highlight some key molecules such as bile acids that could be targeted for activation or inhibition. Finally, the UCSD group may uncover diagnostic markers that might separate out different forms of IBD. This could benefit tens of thousands of patients.
Dorrestein views the databases and the tools his group and others are developing to mine and ask questions of them as a huge advance. In his first paper using the techniques, his group discovered 800 new human-derived molecules.
“It creates a new branch of metabolomics science where you can now leverage the information that’s available in the public domain,” he explained. “It is becoming a big data science now, for the first time, and we are going to discover thousands of new molecules.”
About the interviewees:
Lynn Vanhaecke leads the Lab of Integrative Metabolomics at the University of Ghent in Belgium. She focuses on how human health can be influenced by diet, the microbes that live in our gut and the small molecules that they make. She recently received a prestigious funding award from the European Research Council to analyzse metabolomics to advance personalized medicine in children.
Pieter Dorrestein is co-director of the Institute for Metabolomics Medicine and director of the Collaborative Mass Spectrometry Innovation Center at the University of California, San Diego. An acknowledged leader in the field of metabolomics, this Dutch scientist aims to develop new mass spectrometry-based methods to understand the chemistry of microbes and the human microbiome, with the ultimate goal being the development of new medicines.
This article includes research findings that are yet to be peer-reviewed. Results are therefore regarded as preliminary and should be interpreted as such. Find out about the role of the peer review process in research here. For further information, please contact the cited source.
