Is Metabolomics the Rosetta Stone for Understanding the Microbiome?
by Kirk Beebe
There’s been a lot of interest recently in the microbiome and the “bugs” (bacteria) that live on and within us. Their breadth of influence on our health is astonishing – certainly in metabolic diseases such as diabetes, but also in disorders that aren’t so obvious, such as autism, chronic fatigue syndrome and depression.
Bacteria can dictate how drugs or metabolites interact with our brain, make us susceptible to infectious diseases, and affect a host of conditions including cardiovascular disease and cancer. Since they have co-habitated with humans throughout evolution, it’s not surprising that they play such an important role. For better or worse, we’re in this together.
While many recent publications associate different bacteria to certain diseases, they have often been criticized for failing to clarify how the microbiome functionally influences disease. In fact, the discussion sections of many of publications from the past few years reveal a need to move beyond “description” and into “function or mechanism.”
It’s all about functon
Function is where metabolites come in. The language and currency of microbial communities throughout nature are small molecules – metabolites. This is not lost on microbiome researchers. Many studies conduct some form of metabolite profiling, which often provides a key element to bringing more functional insight to the research. However, most microbiome studies have focused primarily on determining the type of microbes present and sometimes the collection of genes they contribute.
Now, there is a shift among many key opinion leaders who have started promoting metabolomics as a way forward in assigning function more directly to the microbiota. For a good example of this, see “Specialized Metabolites from the Microbiome in Health and Disease,” Cell Metabolism, 2014.
Small molecules reveal more about host-microbiota interaction
Metabolomics can take on many forms, each providing different levels of insight. The type of information you get from a technology that profiles 40 metabolites, such as NMR, is distinct from the information you get from a technology that measures 1,000 or more metabolites, such as LC/MS.
We believe that to effectively address the complexity of the microbiome’s influence on human health, you must employ a technology that is capable of surveying host metabolism, xenobiotics, dietary metabolites and novel metabolites produced by the microbiota. This is what Metabolon’s platform does. It offers a very precise, systematic surveillance of the metabolome, which may include novel, bacterially-produced compounds.
Combining metabolomics with traditional microbiome genetic research tools has resulted in some exciting findings in gut microbiome research.
- Sarkis Mazmanian’s group at Caltech discovered that 4-ethylphenylsulfate was altered with behavior in a mouse model of autism. They developed a probiotic strategy that led to the reduction of 4-EPS and a reduction in the behavioral phenotype.1
- Epidemiologic studies have revealed a number of environmental exposures associated with asthma that could account for its escalation over the past 30 years. Many of these exposures could be the result of microbiota changes. Recent experimental evidence suggests a “critical window” early in life where gut microbial changes (dysbiosis) may lead to asthma. To explore this hypothesis and determine if these changes precede the development of asthma, microbiota and metabolomics analysis was performed on subjects enrolled in the Canadian Healthy Infant Longitudinal Development (CHILD) Study. Infants at risk of asthma exhibited transient gut microbial dysbiosis and metabolome changes (e.g., urobilinogen) during the first three months of life. These metabolites or microbiome differences may aid in the design of pre- or probiotics or serve as prognostic biomarkers. 2
- Much of the body’s serotonin is produced by the gastrointestinal (GI) tract, but the mechanism for this production was unknown. Given the expanding connection of the gut microbiota to many aspects of physiology, investigators sought to determine if the microbiota played a role. Using an array of methods including metabolomics, they showed that the microbiota regulates GI-serotonin biosynthesis from colonic enterochromaffin cells (ECs), and that fecal metabolites likely provide the signals for production, since elevating their luminal concentrations increase colonic and blood serotonin in germ-free mice. The results are yet another example of the how microbiota are intimately connected to our physiology and that this connection is frequently modulated by metabolites. 3
- The ultimate prize for combining metabolomics and microbiome research is human health. We are excited to contribute to work that dovetails genomic, microbiome analysis with metabolomics data at Craig Venter’s Human Longevity, Inc. and Health Nucleus and Lee Hood’s Arivale.
We share many more examples of this research in our eBook. Download it here.
Making sense out of skin microbiota
Metabolomics can be applied to another dimension of the human microbiome - the skin. Like the gut, our skin contains an entire ecosystem of microorganisms that are not just important in dermatological conditions such as acne, psoriasis and rosacea, but also in immune function. The skin is a major barrier to infection, and the microbes that live upon it are a front line of defense.
Microbiome research in the skin field is at an earlier stage compared to the gut. The first waves of basic characterization of the microbes that colonize the skin are completed, but studies probing associations with various conditions and diseases are few, relative to gut microbiome research.
By using metabolomic technology as a first-line tool, skin researchers can bypass the challenges that arose for gut microbiome researchers with assigning function to the myriad of associations they uncovered. Examples of the small molecule-metabolite connection are beginning to trickle out in dermatology research, such as that by D. Kang et al. showing how B vitamin metabolism is mechanistically linked to acne. 4
Realizing the importance of metabolomics in understanding skin biology, Metabolon has invested a tremendous effort in methods and tools for skin research. In addition to our metabolomics platform and accompanying methods for skin biopsies and tape strips, we have a stratum corneum panel directed at lipids, a metabolite class of high importance in skin biology.
We envision that these tools will not only promote better understanding of the basic principles governing skin biology, but also become a frontline approach for understanding the complex interaction between the host and microbiota that govern skin health.
Cracking the functional code
Much as the Rosetta Stone was vital to deciphering a previously untranslated ancient language, metabolomics may hold the key to unlocking the secrets of the microbiome. Microbiome research has outlined an important landscape for human health, and combining metabolomics with existing research tools will help populate this landscape with functional detail.
To learn more about metabolomics in microbiome research, download our free eBook.
- Hsiao, E.Y. et al. Microbiota Modulate Behavioral and Physiological Abnormalities Associated with Neurodevelopmental Disorders. Cell 155, 1451-1463 (2013).
- M. C. Arrieta et al., Science Translational Medicine 7, 307ra152 (2015).
- J. M. Yano et al., Cell 161, 264 (2015).
- D. Kang, B. Shi, M. C. Erfe, N. Craft, H. Li, Science Translational Medicine 7, 293ra103 (2015).