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Gut feeling about drug metabolism during depression

After many years studying the gastrointestinal tract, pharmacologist and senior physiology lecturer Niall Hyland will use his Global Grant for Gut Health to examine how the microbiome influences the ability to metabolise anti-depressant or anti-psychotic drugs.

Credit: Tomas Tyne

Niall Hyland is a senior lecturer in the Department of Physiology, and a faculty member in APC Microbiome Ireland, at University College Cork. In his early career he took a PhD in pharmacology, spent time in Louisiana, and as a post-doc in Calgary before returning to Ireland in 2007 to join APC Microbiome Ireland. On returning to Cork, his primary research focus was on the gut-brain disorder Irritable Bowel Syndrome (IBS), providing him with a strong basis from which to study the influence of the gut microbiome on drug metabolism in psychiatric illnesses.

What inspired you to get involved in microbiome research?

It is only in the last 20 years or so that our gut microbiome has become the focus of many physiological studies. Scientists became aware that these microbes were likely both benefitting and adversely affecting our health in various ways. More recently, experts have begun to explore the microbiome’s interaction with medications. Individuals respond to drugs in different ways, and it appears that each person’s microbiome may play a significant role in how drugs are absorbed and metabolized by the body. I have followed new research in this area with great interest because of my background as a pharmacologist. These insights prompted my team to ask the question ‘If depression has a knock-on effect on the microbiome and can generate gut-related disorders, how might depression affect the ability to process anti-depressant or anti-psychotic drugs?’ It was round the same time that I spotted the Global Grants for Gut Health funding call.

What prompted you to apply for a Global Grant for Gut Health?

The application process was very straightforward, and I was pleased that the call was broad and flexible enough to allow us to put in a multi-disciplinary proposal. Essentially, it’s a brilliant proof-of-concept grant programme, giving researchers the chance to get started on a large-scale project and achieve viable results. Winning the grant means we can quickly gain traction on this important topic, and we will hire a researcher for a year to focus on the project with me, and our cross-disciplinary team: Gerard Clarke, lecturer in psychiatry and neurobehavioural science; Timothy Dinan, professor of psychiatry; and Brendan Griffin, a senior lecturer in pharmaceutics. Another bonus of the grant programme is that there are no restrictions on intellectual property and publishing of follow-up research; this means it is significantly less complicated in the long term.

What does your project propose to do?

Our project proposal takes a step-by-step approach to verify how the microbiome affects the ability of individuals to respond to anti-depressants or anti-psychotics. First, we need to confirm that there is a clear difference in microbiome make-up between our patients with depression and our control group, which we and others have previously observed. To do this, we will take faecal samples from every individual in each group and analyse them to determine the bacterial communities and enzymes present. Ideally, none of the participants will have been given any drugs prior to the samples being collected.

Once we have confirmed the microbial differences, we will then expose the enzyme fraction of each sample — the so-called fecalase — to one of four commonly prescribed drugs, two anti-depressants and two anti-psychotics, in the lab. We will monitor how the bacterial enzymes in the samples metabolize the drugs. Our hypothesis is that microbiome-derived enzymatic activity in certain individuals could alter the structure or activity of the drugs, rendering them ineffective or resulting in potential side-effects or problems.

The gut and the brain are separated anatomically but well-connected physiologically — with the microbiome mediating that connection.Credit: Catherine Buckley

How will you examine drug metabolism in the body?

It has been shown that if you take a faecal sample from a person with depression and transplant that sample into a healthy rat, the rat will begin o show signs of depressive illness. We plan to build on this and will transplant our human faecal samples into rats. After a couple of weeks, once a unique humanized gut microbiome is established inside each animal, we will administer a single dose of one of the drugs to each rat and monitor what happens to the drug inside the body. This will generate pharmacokinetic data for the different drugs during depressive illness which we will analyse alongside the enzymatic activity and microbiome profile of each donor sample.

How might insights from these data eventually help patients?

We will use all these data to begin to build a predictive computer model. It would be brilliant if scientists could one day input data from a patient’s faecal sample into a computer model, and it would predict how that patient might respond to specific drugs. Our initial model will incorporate details from people with depression, and look at anti-depressants, but could then be expanded to predict responses to other drugs for other conditions as well. This is an area I would be very keen to explore — presumably, if patients who are clinically depressed process anti-depressants differently from healthy people, then their ability to metabolize drugs for other conditions will also be affected. There is growing interest in this kind of research especially now as we begin to understand that particular bacteria, and possibly probiotics, may also inadvertently affect a person’s ability to metabolize drugs and therefore their response to them. It is a potentially enormous area of research and future exploration.

What do you do when you’re not in the lab?

When I’m not at work, you’d probably find me out running or taking part in adventure races. I find it so important to clear my head before or after a day at work. Many ideas spring to mind without other distractions.

Find out more about the Global Grants for Gut Health here.