How the bugs in your gut control your emotions: The emerging science of the microbiome

Humans like to think of themselves as individuals. In reality, all of us are an ecosystem: most of the cells that inhabit our body are not human. If we take a genetic perspective, it is even more shocking. You can find 500 genes belonging to the bacterial, archaea, fungal and viral genomes living within us. A final humbling fact: our microbiome weighs roughly the same as our brain. This powerful image serves as a metaphor for the stimulating argument put forward by Prof. Cryan: our brains are no more than mere puppets controlled by the whims of our microbes’ cilia and flagella.

In a very entertaining seminar, we were taken on a journey through the speakers’ career, which neatly illustrates a recent shift in the thinking about the biological basis of animal behaviour. Starting out as a molecular pharmacologist studying the role of different signalling pathways in the pathogenesis of neuropsychiatric diseases, he mostly used rodent models, working as a sort of mouse psychotherapist using behaviour analysis as a substitute for the couch. After joining the APC Microbiome Institute in 2005, he became fascinated with the cross-talk between the brain and the gut, in particular the gut microbiome. He never looked back, and both as a pioneer and a cheerleader, has had a major influence on how the field has exploded in the last few years.

Several studies, in both humans and animal models, show that the microbiome composition is extremely sensitive to changes in the external environment. This is both in the physical sense, such as the food we eat, but it is also sensitive to changes in our emotional state, like stressful situations, an aspect that Prof. Cryan’s group has studied extensively. Increasingly, it has become clear that changes in the microbiome can have a profound impact on our health. For example, taking antibiotics dramatically affects the microbiome, and these changes have been linked to reduced function of the immune system and development of allergies, while many other suspected effects remain to be fully explored (Dudek-Wicher et al., 2018). The question arises: how do we move from correlation to causation?

One important way involves raising mice within germ-free isolators. They have no microbiome. Germ-free mice develop a large number of abnormalities in practically all aspects of their physiology. Importantly, many deficits can be improved by artificial colonization of the gut (reviewed in Luczynski et al., 2016). For example, germ-free mice have increased sensitivity to pain, and this phenotype can be corrected by gut colonization (Luczynski et al., 2017). In a landmark series of studies, Prof Cryan’s group revealed surprisingly specific changes that could be directly linked to the absence of our friends inside. These include increases in adult neurogenesis, increased myelinisation in the prefrontal cortex (Hoban et al., 2016) and increased splicing in the amygdala in response to social interaction (Stilling et al., 2018).

An important message from Cryan’s research is the hope for a relatively rapid translation of research findings into clinical practice. He stressed the plasticity of the microbiome, in contrast to the challenges associated with changing the genome. By far the easiest way to affect gut microbes is our diet. Not surprisingly, processed foods and refined carbohydrates reduce the health of our microbiome, while green vegetables that are rich in fibre, wholegrains and fermented foods are all beneficial. In a recent book published in collaboration with Scott Anderson and Dr. Ted Dinan titled “The psychobiotic revolution”, the authors coined the term psychobiotic to describe any intervention that improves our brain function by supporting the growth of beneficial gut bacteria.

A more drastic way to modify the microbiome is through faecal transplants, a life-saving procedure that boasts 92% success rate in curing Clostridium difficile infection (Quraishi et al., 2017). This is exactly what it says on the tin - the “seeding” of a patients’ gut using the microbes present in a donor sample (or poo!). This is a very exciting and extremely active area of research that is showing a lot of promise in the treatment of several diseases (obesity for example) which has had immense media exposure. However, despite remaining optimistic regarding the future of the field, a healthy dose of scepticism was provided, reminding us all of how young the field is, and how important rigorous scientific studies will be in realising its potential impact in the future of medicine.

References

• Dudek-Wicher, R.K., Junka, A., and Bartoszewicz, M. (2018). The influence of antibiotics and dietary components on gut microbiota. Prz Gastroenterol 13, 85-92.
• Hoban, A.E., Stilling, R.M., Ryan, F.J., Shanahan, F., Dinan, T.G., Claesson, M.J., Clarke, G., and Cryan, J.F. (2016). Regulation of prefrontal cortex myelination by the microbiota. Transl Psychiatry 6, e774.
• Luczynski, P., McVey Neufeld, K.A., Oriach, C.S., Clarke, G., Dinan, T.G., and Cryan, J.F. (2016). Growing up in a Bubble: Using Germ-Free Animals to Assess the Influence of the Gut Microbiota on Brain and Behavior. Int J Neuropsychopharmacol 19.
• Luczynski, P., Tramullas, M., Viola, M., Shanahan, F., Clarke, G., O'Mahony, S., Dinan, T.G., and Cryan, J.F. (2017). Microbiota regulates visceral pain in the mouse. Elife 6.
• Quraishi, M.N., Widlak, M., Bhala, N., Moore, D., Price, M., Sharma, N., and Iqbal, T.H. (2017). Systematic review with meta-analysis: the efficacy of faecal microbiota transplantation for the treatment of recurrent and refractory Clostridium difficile infection. Aliment Pharmacol Ther 46, 479-493.
• Stilling, R.M., Moloney, G.M., Ryan, F.J., Hoban, A.E., Bastiaanssen, T.F., Shanahan, F., Clarke, G., Claesson, M.J., Dinan, T.G., and Cryan, J.F. (2018). Social interaction-induced activation of RNA splicing in the amygdala of microbiome-deficient mice. Elife 7.

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