The Power of Microbiota: Drivers of the Brain-Gut Axis in Psychiatry

 Professor Ted Dinan 

Professor Ted Dinan 

Author: Anna Shajee Edited by: Ruchi Maniar

Professor Ted Dinan is currently a professor of Psychiatry at University College Cork and a Fellow of both the Royal Colleges of Physicians and Psychiatrists and of the American College of Physicians. SIU recently hosted him at our SIUKatowice event 'The power of poop'. Read the related article here. 

Professor Dinan has made significant contributions to the literature on the regulation of the hypothalamic-pituitary-adrenal axis in situations of stress and was awarded the Melvin Ramsey Prize for this research into the biology of stress in 1995. He has also authored numerous publications and books on the pharmacology and neurobiology of affective disorders. 

Here we interview him to learn more about his field of expertise- the role of microbiota in the gut-brain axis. 

1. What is the focus of your primary research which you are currently working on?

In humans, there are two endocrine systems. One enables us to deal with very acute stress and that is called the sympathoadrenal medullary system. When it comes to more chronic stress, it is the hypothalamic-pituitary adrenal axis, which is the core stress axis. When we are chronically stressed, cortisol is the end hormone produced by the adrenal cortex, and can be associated with certain stages of diseases. For example, in psychiatry, cortisol is heightened in depression and observed in very severely depressed patients. In endocrinology, one sees very significant heightening in Cushing’s disease.

My initial research started just after I left medical school, having spent many years doing single cell electrophysiology recording neurones in rat brains, such as neurones of the locus coeruleus and the hippocampus. Then, I switched, and for a number of years I worked in neuroendocrinology on the hypothalamic-pituitary adrenal axis. However, over the last fifteen years, my primary focus for research has been on gut microbes and how they influence a human’s brain function.

 2. What led to the discovery of a possible connection that our gut microbes could contribute to neurological disease?

My background is in pharmacology and most definitely is not in microbiology. Nonetheless, being at Cork, where microbiology is extremely strong, I came across some scientists that had been working with bacteria which they felt were probiotic or micro-positive. So, I decided to see if these bacteria had any behavioural impact in both animals and in humans. I mean, most of the bacteria that were put into animals did not involve positive or negative outcomes. But I worked with one or two bacteria fourteen or fifteen years ago, that really displayed anti-stress effects in animals. My research since then has really followed that on, looking at microbes and primarily the microbiota itself.

3. What are the techniques used in order to study the microbiota-gut-brain axis?

First thing you need is good sequencing in order to really determine which bacteria are present. There are two levels of sequencing: the 16S gives you an indication of what bacteria are present - although, you can do far more in depth sequencing with shotgun sequencing. Also, and I suppose optimally, you need a good understanding and good techniques for looking at brain biology. In rodents, the techniques used are different from those used for humans. You also need good neurobiology knowledge, and I imagine one also needs to be able to explore the links that connect the microbiota with the brain. So, things like the vagus nerve would be important there,or being able to look at various immune factors such as cytokines and being able to measure low levels of cytokines and altered levels of cytokines in the plasma.

4. Which potential pathway(s) in our body allow the gut-brain axis to communicate?

There is not one route of communication that dominates. We know the vagus nerve is important because it allows the signals from the brain to go into the gut and it enables signals from the microbiota to go to the brain. We have shown in animals that certain microbes, if you block the vagus nerve, cannot communicate. So the vagus nerve needs to be intact. But, personally, I am very interested in how short chain fatty acids are produced by bacteria. These short chain fatty acids,when they enter the bloodstream, travel to the brain via the bloodstream and can influence the brain directly. But cytokines which are inflammatory molecules can also influence the brain. An example would be tryptophan (very important for serotonin production), which is produced by these microbes and can travel to the brain as well via the bloodstream.

5. Would you say there is a discernable difference when comparing microbiota from a healthy person to an individual suffering from depressive illness? Does the diversity of present microbes influence one’s predisposition to a neurological disease?

Yes, there is. We need to get a much more sophisticated understanding of the differences that are present. Unquestionably, in those who are severely depressed, their microbiotas are less diverse. We also know that healthy aging is associated with maintaining diversity in our microbiota. If elderly people lose diversity, they tend to become frail rather rapidly afterwards. Therefore, maintaining diversity is extremely important.

6. Can you tell us about your work on biomarkers of response in treatment refractory depression?

I have worked on different biomarkers over the years and we still have not been able to find a wonderful biomarker for diagnosing depression. Having said that, that is true in a lot of areas of medicine. For example, with cancers, we do not have terribly accurate biomarkers either. If you look at let’s say prostate specific antigen (PSA) and prostate cancer, it is not a very good test. As another example, smear testing in cytology is not 100% accurate either. So over the years, I have worked on different biomarkers, from easy biomarkers like the dexamethasone suppression tests or CRH testing, to looking at other aspects of the hypothalamus-pituitary adrenal axis. But most recently, I suppose much of my research has been focused on inflammatory markers in depression because most patients who are severely depressed do have a poor inflammatory state. Cytokines like IL-1, IL-6, tumor necrosis factor alpha are elevated in those conditions.

 7. How do you see new therapies such as faecal transplant and psychobiotics influencing the future of depression and other similar conditions?

I think right now the only solid potential for faecal transplantation would be for the treatment of intractable C. difficile infection. Canada is the cutting-edge country in terms of that, although many centres including Cork have now started working on it. People are exploring the possibilities of including this for the treatment of autism, depression, Parkinson’s disease, and a raft of conditions. The real evidence is still not there for those conditions, but at the moment there is only evidence for C. difficile infection.

In relation to psychobiotics, I think there is accumulating evidence that there are several strains of bacteria out there that healthy individuals can ingest to help them become more resistant to stress. So I think within a short period of time, you will be able to see psychobiotics or probiotic bacteria being available for treating milder forms of depression and milder forms of anxiety.

8. What would be some valuable advice you would like to give to medical students aspiring to enter fields of medicine such as neurology, psychiatry and/or endocrinology?

My advice would be to train with somebody who is as good in the field as you possibly can. This does not necessarily mean working or training in the best university. You can be in a medical school that is well known, but it is pointless if there are no people there who are exceedingly good in the field of medicine you want to train in. The important thing is to be more focused on individuals rather than on institutions, because institutions may have big names but in a particular field they may not be good. My advice to medical students overall would be to have fun. Enjoy yourselves during medical school because life is too short.