Serum metabolome mapped in detail

Your blood contains information about almost everything that happens in your body.

What you eat, what your gut bacteria do, what medicine you take and what your body does all leave markers in the blood in the form of thousands of molecules called metabolites.

The plethora of metabolites that circulate in your blood is called the metabolome, and researchers have now completed one of the most comprehensive analyses of the serum component of blood to date regarding the origins of a number of annotated metabolites.

The researchers also created a reference data set of the human serum metabolome, and this probably contains information researchers can use to achieve future major breakthroughs in the health sciences.

“Metabolites in the blood can benefit health, be involved in disease and be biomarkers of disease. We must therefore assume that understanding the origins of metabolites better will enable us to better understand our health and reduce disease. These are the perspectives for such a large basic science research project like this,” explains a Danish contributor, Oluf Borbye Pedersen, Professor and Research Leader, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen.

The research has been published in Nature.

Metabolites can originate in four places

Metabolites in blood originate primarily from four sources.

· The body can produce them itself. For example, when the body has to send signals between tissues and organs, it sends molecules into the bloodstream. The body also produces metabolites in all possible situations: for example, during exercise, which changes the concentration of lactate and other metabolites in the blood.

· The food and drink we consume also contain many compounds that end up as metabolites. When the food we eat is digested in the gut, many of the resulting molecules can cross the intestinal barrier and enter the bloodstream. Vitamins, protein, carbohydrate and fat are examples of this type of blood metabolites. Some molecules retain their original structure as metabolites in the blood, while others are transformed into various intermediate products.

· Taking medicine also affects the blood metabolome, whether the medicine is injected into the bloodstream or is taken orally and then chemically modified by gut bacteria or the liver.

· Gut bacteria are an incredibly complex chemical factory that constantly function in interaction with the human host. The gut bacteria constantly produce a number of various metabolites, which are absorbed through the gut wall and become part of the blood metabolome.

“Individual blood metabolites rarely have one origin, usually several. Nevertheless, despite different sources of origin, blood contains a wide spectrum of compounds that affects cells in all body organs for example by influencing epigenetics. This is why novel insights about metabolites are so important for biological science aiming at optimizing public health,” says Oluf Borbye Pedersen.

Diet and gut bacteria mostly determine the blood metabolome

The researchers analysed serum samples from 491 individuals in Israel. They profiled the samples using various techniques to measure the concentrations of 1,251 metabolites. Most were known, but about one third were not.

The researchers used powerful computers and machine-learning algorithms to organize the vast data set and find specific associations that would be very difficult to find manually. These associations include determining the sources and interindividual variation of individual metabolites.

This groundbreaking part of the new study, therefore, is not that researchers mapped the human serum metabolome as such but rather that they likely found the sources of the 1,271 metabolites in the serum and what determines how the metabolome varies between people.

“One of the most exciting aspects is that the food we eat seems to determine about half of the variation in the metabolome between people. Gut bacteria comprise about one third of the variation between people, and genetics and biology determine relatively little. Further, some metabolites can only be explained by their origin from one of the four sources mentioned previously. For example, the microbiome data significantly predicted the levels of 34 metabolites,” explains Oluf Borbye Pedersen.

The accuracy of the findings was validated in 245 samples from people from northern Europe with type 2 diabetes from an IMI DIRECT cohort funded by the EU, with Oluf Borbye Pedersen leading the microbiome research.

Identifying the cause of many diseases

Oluf Borbye Pedersen says that the research output has major clinical perspectives despite being basic science.

An improved understanding of the serum metabolome enables researchers to explore both biomarkers and causes of diseases.

For example, researchers could determine that a cluster of specific metabolites is involved in developing cardiovascular disease, obesity or a cognitive disorder.

Determining the origin of the metabolites enables the researchers to backtrack and identify the source in, for example, the food or specific bacteria in the gut microbiome.

“These are the perspectives. Once we can determine the origin of the pathogenic metabolites, we can use this information in future intervention studies to try to influence them in cases in which the metabolites are directly involved in causing disease,” says Oluf Borbye Pedersen.

Investigating the metabolome of people with heart disease

Oluf Borbye Pedersen explains that his research team already used the reference data set for the human serum metabolome in a new study (submitted to Nature) examining both the composition of gut bacteria and the origins of the metabolites among several hundred people with various types of ischaemic cardiovascular disease.

“This presents interesting opportunities for understanding why these people developed cardiovascular disease, and we can use this knowledge in future clinical trials,” concludes Oluf Borbye Pedersen.