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APC Microbiome Institute Scientists Show Surprising New Impact of Gut Bacteria on Gene Expression in the Brain

thinkingsmallaugust2017alanhobangerclarkejohncryan

Small things can sometimes make a big difference and this may be doubly true considering the crosstalk between the microbes in our gut (microbiome) and the brain. The extent, and the manner, of this dialogue is made clear in research published in the journal Microbiome, revealing a new level of communication between the gut microbiome and the brain.

This research demonstrates in animal models that the trillions of bacteria within the gastrointestinal tract can influence microRNAs (miRNAs) in areas of the brain, such as the amygdala and prefrontal cortex that are involved in anxiety and fear-related behaviours. These miRNAs, which can regulate gene expression, may then act ‘upstream’ of our gut microbes to fine tune physiological processes that are fundamental to the functioning of the central nervous system.

Dr Gerard Clarke and Professor John F. Cryan, along with their PhD student Alan Hoban, used mice and rats that have either no gut microbes at all or depleted gut microbes and demonstrated that the miRNA expression profile is dysregulated in the amygdala and prefrontal cortex brain regions. The amygdala is responsible for the emotional response to fear stimuli, while the prefrontal cortex is key to higher cognitive functions and in the expression of anxiety and social behaviours.

The team was able to show that some of the miRNA alterations seen could be rescued by adding back the gut microbiome later in life. However we also noted a number of miRNAs that remained altered following exposure to microbes, which supports the concept of critical neurodevelopmental windows during which the gut microbiota is essential in influencing brain development.

miRNAs are small nucleotide sequences and have recently emerged as a new class of gene-expression regulators because miRNA-expression levels are altered in patients suffering from depression and anxiety and in animal models of these disorders. The possibility of using miRNAs for the treatment of psychiatric disorders is thus under consideration. Research in this area has faced several challenges and the development of safe compounds that are able to cross the blood-brain barrier and target brain regions relevant to anxiety was considered paramount for the emergence of novel, efficacious miRNA-based therapies in the clinical arena.

To our knowledge, this is the first time that the gut microbiome has been so clearly implicated in miRNA expression in both the amygdala and the prefrontal cortex. This study gives a better understanding of the factors that control miRNA expression and suggests that some of the hurdles impeding the exploitation of their therapeutic potential could be cleared by instead targeting the gut microbiome. This tallies with an increasing body of the work over the past decade that highlights the influence of our gut bacteria on brain function and behaviour.

Altered expression of these miRNAs is implicated in the support of neuronal survival, growth and development, as well as neurogenesis, all important targets for the treatment of stress-related psychiatric disorders.  We can now add miRNAs to an expanding range of therapeutic targets in the brain that can potentially be controlled by manipulating the bacteria in our gastrointestinal tract. However that more work is needed before the full benefits of this exciting work can be moved into a clinical setting and that we need a more advanced understanding of the underlying mechanisms before such essential translational progress can be made.

The research is published in the high impact journal Microbiome and was supported by Science Foundation Ireland through a Research Centre grant to the APC Microbiome Institute and by the Brain and Behaviour Research Foundation.

Full reference:
Alan E. Hoban, Roman M Stilling, Gerard Moloney, Rachel D Moloney, Fergus Shanahan, Timothy G. Dinan, Gerard Clarke & John F. Cryan (2017) “Microbial Regulation of microRNA Expression in the Amygdala and Prefrontal Cortex” Microbiome 25 August 2017  https://microbiomejournal.biomedcentral.com/articles/10.1186/s40168-017-0321-3

Photo: (left to right): Dr Alan Hoban, Dr Gerard Clarke and Prof John Cryan, APC Microbiome Institute and Departments of Anatomy & Neuroscience and Psychiatry & Neurobehavioural Science, University College Cork