Mike Milburn Ph.D. Chief Scientific Officer Metabolon
Kirk Beebe Ph.D. Director of Application Science Metabolon

Researchers Need to Look at the Metabolome to Understand the Dynamic Relationship between the Microbiome and the Human Body

In the past 15 years, scientists have begun to characterize what they consider to be a newly discovered endocrine organ. So far, they have found that it is critical for protecting you against infection and regulating your metabolism, and that it can even affect your behavior. It can be damaged by antibiotics, and it can be restored by swallowing capsules filled with dehydrated fecal matter. What is this unusual yet versatile organ? It is the human microbiome.

The human microbiome is large and complex. It is thought that there are as many indigenous microbes in your body as there are other cells, comprising about 160 species and present throughout your body—including in your mouth, on your skin, and in your intestines. Samples from only 124 European individuals collected by the European MetaHIT consortium contained more than 1,000 different bacterial species with 3.3 million unique genes—150 times more genes than in the human gene complement. Altogether, scientists treat the human microbiome as its own organ with its own unique, but necessary, functions.

To make sense of this vast and diverse population of microbial cells, scientists have revisited an approach that they exploited 20 years ago to understand human cells—genetic sequencing. In fact, the study of the microbiome’s genome, the metagenome, has allowed scientists to characterize and catalog the entire microbiome and gain a general understanding of how it supports human health.

Genomics, however, does not give us all the information we need to understand the link between microbes and health. Approaches like 16S RNA (rRNA) sequencing and metagenomics can, at best, reveal the identity of an individual’s microbiota and give scientists an estimation of microbial activity in the body. But genomic data alone is unable to give scientists a direct peek into how the human microbiome dynamically interacts with its surroundings.

The only way to understand how the microbiome’s presence affects the body at any given time is through studying the comprehensive or global metabolome—the collection of metabolites that the microbiome and host produces and interacts with. Metabolites are the microbiome’s language. By studying them, in addition to the microbes they come from, scientists will reveal an invariably fuller picture of the ever-changing relationship between the microbiome and the human body. For metabolomics to be most effective, many different classes of metabolites, including xenobiotics, bacterial, and host, need to be measured simultaneously. In short, trying to resolve the link between the microbiome and human health without looking at the metabolome is like trying to predict a married couple’s compatibility without observing how they communicate with each other.

Recently, studying this metabolomic “chatter” has led to discoveries in all areas of disease research that could not be achieved by characterizing the metagenome itself:

• While studying the microbiome and metabolome of infants at risk for asthma and allergy, scientists discovered distinct predictive biomarkers for these conditions. Researchers recently compared the microbiomes and metabolomes of infants with varying levels of susceptibility to asthma and allergy; and among the most susceptible infants, they found deficiencies of several native bacterial species in the gut. Interestingly, this cohort also displayed high concentrations of pro-inflammatory T-cells and relatively low concentrations of T cells that protect against asthma and allergy. These immunological differences suggest that, in conjunction with the gut microbiome, an infant’s metabolome can be used as a biomarker to predict one’s susceptibility to allergy and asthma.

• Metabolites have also been found to link the microbiome to psychiatric disorders such as autism. In one study, a mouse model for autism showed an elevation in the concentration of two bacterial species in the gut, and a subsequent metabolomic analysis revealed elevated levels of several metabolites. Shockingly, injecting healthy mice with one of these metabolites caused autistic-like behaviors to arise, proving the causal link between the microbiome and autistic symptomatology.

• Metabolomics may also be the key to preventing lethal C. difficile infections. Ironically, one of the largest risk factors for C. difficile infection is antibiotic treatment. Antibiotics wipe out a wide variety of indigenous bacteria, creating an environment that is more suitable for C. difficile growth. Due to the nonspecific nature of antibiotics, however, it is difficult to determine which extinction of an indigenous bacterial species was responsible for promoting C. difficile growth.

But a metabolomic analysis found that while antibiotics kill many bacterial species, they only cause a change in the concentrations of a few metabolites, potentially simplifying the path to the development of treatments that do not promote C. difficile growth. These data show that, in addition to cataloguing how antibiotics alter the gut microbiome, identifying how they affect the metabolome is critical for understanding the relationship between health and disease.

• Metabolomics research can even yield an understanding of serotonin synthesis in the gut, where 90% of the body’s serotonin is produced. Gut serotonin has been implicated in several disorders, including cardiovascular disease, irritable bowel syndrome, and osteoporosis. Until recently, it was not understood how serotonin production in the gut is regulated. A metabolomics study revealed that it is regulated by metabolites released by indigenous spore-forming bacteria, further confirming the importance of the gut microbiome to human health.

Metabolomics has elucidated the link between the microbiome and many other conditions ranging from periodontal disease to obesity, and its relevance is only bound to increase as we learn more about the role of our indigenous microbes in disease.

Now that we have the ability to profile our full metabolome in conjunction with our microbiome, we believe it is time for the biomedical research community to concentrate not only on the genetic makeup of the microbiome but also the metabolites they produce. Since a metabolomics approach allows scientists to examine all the small molecules in our body, including hormones, amino acids, co-factors, neurotransmitters, and other compounds, it gives us a shot at understanding every step of disease etiology, from gene to phenotype.

Cataloguing the human microbiome has advanced biomedical research by revealing the importance of the microbiome in human health. Now, we must take the next step and use the metabolome to bring us the rest of the way. Since it accounts for all the small molecules in the body, metabolomics is the most comprehensive approach to studying how the microbiome can be used to detect and treat disease. Given its versatility and impact, we cannot afford to overlook the metabolome anymore.

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