This is a summary of my talk at the ACTRIMS 2019 Forum, describing the current state of research using a technique called “metabolomics” in MS patients. The term refers to the measurement of levels of small molecules (for example glucose) in blood or spinal fluid (could be any body fluid). Most metabolomics studies utilize one of two platforms to measure metabolites:
- nuclear magnetic resonance (very specific but detects a small number of metabolites) and
- mass spectrometry (detects a very large number of metabolites but not all of these are easily identifiable).
Experiments can either measure as many metabolites as possible (global or untargeted) or measure a specific set of metabolites we are interested in (targeted). I find this method fascinating because the levels of metabolites in circulation depend not only on genetic makeup but also diet, gut bacteria, and other environmental exposures. This means that metabolomics can provide information about various aspects of MS disease risk, but also makes it more challenging to figure out the source of the changes that we identify.
Do MS patients have a different metabolic profile to healthy controls?
We have now performed multiple studies in our attempt to understand whether MS patients have changes in their metabolic profile compared to controls. We noted changes in oxidative stress-related metabolites, energy metabolites and xenobiotics (substances that are not naturally produced by the human body). Several of these findings were not unexpected, because increased oxidative stress has previously been demonstrated in MS brain tissue and is thought to be detrimental.
Several studies have demonstrated that amino acids are an important source of fuel for inflammatory immune cells and our findings of lower levels of amino acids in MS may be driven by inflammation. Interestingly, the metabolism of amino acids by gut bacteria can also affect their levels in the blood. In pediatric MS patients, our collaborators identified changes in tryptophan (an amino acid) metabolism driven by gut bacteria. This suggests that changes in gut bacteria, that are known to exist in MS patients, might exert effects through changes in circulating metabolites.
Does studying the metabolic profile help us understand how certain treatments affect MS patients?
We have used metabolomics to try to understand how interventions affect MS patients. In one of our initial studies, we compared changes in metabolites between MS patients and controls who had all received 5000 IU of vitamin D daily for 3 months. We found that MS patients showed a less robust response in the reduction of oxidative stress-related molecules compared to controls, suggesting that MS patients may not respond to vitamin D treatment in the same manner as a healthy person. This study suggests that we could potentially use metabolomics to identify whether an individual was responding appropriately to an intervention or potentially whether they would develop unwanted adverse effects.
Can the metabolic pathways that are affected be targeted to treat MS?
This is obviously the most interesting question that we are currently looking to answer. I do think that metabolomics might help us to identify pathways that could be potential targets for treatment, and I will talk about a couple in a little more detail.
The tryptophan pathway appears to be a potential target since there are excellent studies in animal models demonstrating that certain tryptophan metabolites can act on different types of brain cells like astrocytes and microglia in the brain and reduce inflammation. This, coupled with the existing data in humans, provides compelling reasons to try to target this pathway. We still need to understand in MS patients whether the source of abnormality is the abnormal gut bacteria or an individual’s own metabolism. This knowledge would help design studies to target this pathway in MS patients.
We recently noted that MS patients had lower levels of several bile acid molecules in the blood compared to healthy people. These metabolites help in absorbing fat in the gut, but once in the blood, they can affect various cells in the body including the brain. We found that receptors for these metabolites are present in MS lesions, especially on inflammatory cells and astrocytes. In an animal model, supplementing with a bile acid helped reduce inflammation in the brain and spinal cord. Based on our findings we are now testing the effects of supplementation with a bile acid in progressive MS patients to understand whether this could potentially correct the abnormalities we identified in this metabolic pathway.
We are at an early stage of understanding the importance of studying the metabolic profile of MS and larger studies will help identify additional pathways that are abnormal in the disease. These studies will also help us understand which pathways influence MS disease activity and would be potential targets for treatment. Studies integrating data from metabolomics and profiling of the gut bacteria could then identify the source of these metabolic abnormalities and design strategies to correct them.
By Pavan Bhargava
Dr. Pavan Bhargava is an Assistant Professor of Neurology at the Johns Hopkins University School of Medicine. Prior to his current appointment he completed a Neuroimmunology fellowship at the Johns Hopkins University supported by a Sylvia Lawry physician fellowship from the NMSS. His research interests include utilizing metabolomics to identify the metabolic alterations in MS, to help identify new diagnostic and prognostic biomarkers and to better understand the pathogenesis of MS. He is currently conducting a trial sponsored by the NMSS testing bile acid supplementation in progressive MS patients.
He has authored over 40 papers in journals such as Science, Brain, Neurology and the Annals of Neurology. His work is funded by multiple agencies including the National MS society, Race to Erase MS, American Academy of Neurology, Department of Defense, and the Conrad N Hilton foundation. He has received a John F. Kurtzke Clinician Scientist Development award from the American Academy of Neurology and the Marilyn Hilton Award for Innovation in MS. He is a reviewer for multiple journals and has reviewed grants for the Italian MS Society, the US-Israel Binational Science Foundation and the National MS Society.