Gut Microbiome May Play Role in Myelination Disorders Including Multiple Sclerosis Interview with:

Professor JF Cryan PhD Department of Anatomy and Neuroscience APC Microbiome Institute University College Cork Cork, Ireland

Prof. John Cryan

Professor JF Cryan PhD
Department of Anatomy and Neuroscience
APC Microbiome Institute
University College Cork
Cork, Ireland What is the background for this study? What are the main findings? 

Prof. Cryan: Over the past decade there has been an ever growing body of preclinical studies that highlight an essential role of the gut microbiota in many aspects of physiology including and perhps most surprtisingly the brain . Germ-free animals are one useful approach used to establish causality in gut microbiota-brain relationships. This model has been extremely useful in establishing that the microbiota is essential for appropriate stress responsibility, anxiety-like behaviours, neurogenesis, blood-brain barrier function and microglia activity. From these findings we can see that there is a clear cut role for the microbiota in CNS developmental processes.

Here we wanted to investigate using next generation sequencing, as we had done previously in the amygdala what impact life without microbes has on transcriptional regulation in the prefrontal cortex, a brain region essential in many aspects of emotional behaviour. What we uncovered from this was that there was a large number of dysregulated genes in germ-free animals that have a direct role in myelination. We found increased expression levels of genes that encode for structural proteins that are key in forming the myelin sheath. We followed up this finding with transmission electron microscopy to identify whether this marked increase in myelin related gene expression was functional at a structural level. What we found was germ-free myelinated axons in the prefrontal cortex were hypermyelinated (lower g-ratio), they had thicker myelin sheaths compared to conventionally raised mice. Additionally we also had germ-free colonized animals, animals that were born germ-free but have been colonized with a conventional microbiome early in life. These animals displayed no change in myelin related gene expression and appeared to be indistinguishable from the conventional animals. However, at the protein levels they appeared to have increased myelin protein like germ-free mice. This could be due to the fact that these mice were germ-free for at least 3 weeks of life and the hypermyelinated axons had already been established before colonization. Really this shows that we can still target the microbiota in later life that can have an impact of myelin gene regulation. What should clinicians and patients take away from your report? 

Prof. Cryan:  The concept of microbiota and disorders of demyelination have been around for the last couple of years with remarkable studies showing that germ-free mice had heightened resistance to or do not develop multiple sclerosis symptoms in a well utilized animal model for multiple sclerosis. The reasoning for this may appear to be due to the imbalanced immune system associated with germ-free animals, as foremost multiple sclerosis is an autoimmune disease. What our study shows is that developmental myelination at least in the prefrontal cortex is dependent on the presence of the host microbiome. What clinicians should potentially consider is that there may be other additional strategies for treating demyelinating disorders such as multiple sclerosis and that maybe the microbiota could be a missing piece in understanding myelination. Ultimately promoting myelination is a desirable therapeutic stagey for many disorders associated with demyelination. What we need to ask next is whether there is any potential to promote myelination through known mediators that affect gut microbial communities as we now know that a major disturbance to the microbiota-gut brain axis results in cortical hypermination in germ-free mice. What we hope this data at least does is open up clinicians to the idea that the gut bugs have a much larger role in host health, not only proper gut function but brain as well. We hope our data prompts others into investigating further the potential role the gut microbiota could have in CNS related disorders, especially disorders of myeln. What recommendations do you have for future research as a result of this study?

Prof. Cryan:  Again, now that we know that the presence of the microbiota is necessary for appropriate myelination in this model, we need to investigate further what bacterial communities seem to be putting the brakes on myelinations. Clearly absence of a microbiome results in increased myelination so one could ask whether there are certain bacterial strains that produce or secret some factors that can dampen down the activity of our myelinating cells. We know the microbiota is essential for microglial function and maybe there is a similar story that could be said of oligodendrocytes. We need to start looking into exactly what the bacteria are producing, how it’s signalling to the brain and what impact is it ultimately having. From our study we know that colonization of the entire microbiome has an effect, at least on myelin gene expression. What if we were to colonize with specific single bacterial strain, could this have an impact on myelin? If so this could help us design strategies to take out or introduce certain bacteria that could have an impact on myelin. Is there anything else you would like to add? 

Prof. Cryan: We never stop being surprised by the breadth of the microbiome’s influence especially regarding brain health.

Citation: Translational Psychiatry (2016) 6, e774; doi:10.1038/tp.2016.42
Published online 5 April 2016

Regulation of prefrontal cortex myelination by the microbiota
A E Hoban1,2, R M Stilling1,2, F J Ryan1,3, F Shanahan1, T G Dinan1,4, M J Claesson1,3, G Clarke1,4,5,6 and J F Cryan

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Professor JF Cryan (2016). Gut Microbiome May Play Role in Myelination Disorders Including Multiple Sclerosis