Our interview with Dr Daniel March
Dr Daniel March is a Research Associate at the University of Leicester where he plays a key role in running clinical trials that aim to reduce cardiovascular risk and improve outcomes for renal patients, such as the NIHR funded CYCLE-HD trial and an upcoming trial using L. casei Shirota. We caught up with him to find out more about his career and research.
1. Can you tell us about your career path, and how you got to your current position as Research Associate at the University of Leicester?
I completed my undergraduate degree in 2007, at Aberystwyth University in Sport and Exercise Science. Following my undergrad I undertook a two-year master’s degree in Exercise Science at the University of Dayton, in the United States, before returning to the Sport and Exercise department at Aberystwyth University to study for a research masters in Exercise Physiology, between 2010-2011.
In 2011 I was lucky enough to begin my PhD studies in exercise immunology, looking at the effect of exercise on cellular damage in the intestine and also on intestinal permeability, which lasted three and a half years. Following the completion of my PhD in January 2015, I was appointed as a Clinical Trial Facilitator at the University of Leicester to run the CYCLE-HD trial, which investigates the effect of exercise during dialysis treatment in those who have end-stage kidney disease. Since then I have been appointed as a Research Associate at the University of Leicester in January 2019, where I continue to work on the CYCLE-HD trial.
2. What led to your research interest in reducing the cardiovascular risk in renal patients, and also your personal research interest in the gut microbiota?
The link between my PhD work and my current role is very much the exercise component. In 2015 I was appointed to run the CYCLE-HD trial, a randomised-controlled trial looking at the effects of a six-month exercise programme on the cardiovascular health of dialysis patients, which is where my interest in cardiovascular health in renal patients came to the fore. The reasons for addressing cardiovascular health specifically in kidney patients with end-stage kidney disease is because they have an elevated risk of cardiovascular death. We are looking at developing new treatments that address the cardiovascular risk in these patients and ultimately improve their lives.
Although, my PhD didn’t directly investigate the gut microbiota, I read a lot of studies in this area. The novelty of the research, around 2011, and the large amount of associations between the changes in intestinal permeability and the gut microbiota is what initially sparked my interest.
3. Based on your PhD research looking at exercise induced intestinal permeability, can you tell us about the effects of exercise on the gut and immune system, and at what point does exercise stop benefiting the immune system?
Change in permeability is related to the immune system. During my PhD we found that getting healthy, active subjects to run for 20 minutes at 80% of their VO2 max resulted in increased markers for cellular damage and permeability. One of these markers was intestinal fatty acid binding protein, which increased after exercise compared to baseline, and the other was gut permeability, which we found also increased after the intense exercise that participants took part in.
We also looked at the effects of running for 60-minutes in the heat, where we found similar results to the 20 minute run but at greater levels.
Many changes to the intestinal cellular markers are likely to be caused by changes to blood flow during exercise. When the participants exercise, blood is re-distributed from their central areas, for example their guts, to their exercising muscles and their skin to help dissipate heat, which explains some of the physiological mechanisms.
Although we saw changes in the permeability of the gut and in cellular damage markers, increases in these markers doesn’t increase clinical markers such as gastrointestinal symptoms of participants. Therefore, this may just be a normal response to exercise.
The current state of evidence within infection risk is that if you do the recommended level of exercise by the government, 5x30 minutes of exercise per week, you will lower your risk of infection. It was thought that small amounts of exercise were beneficial but high workloads, such as those in marathon runners and tri-athletes, could increase your risk of infection, known as the ‘J-shape relationship’, however there isn’t really any evidence that elite athletes experience more infections than the general population. Some people are now suggesting that elite athletes may be better protected against infection. Overall, there is little evidence that high workloads of exercise are bad for the immune system especially in healthy individuals.
4. For your PhD you looked at the effects of ‘nutraceuticals’, specifically bovine colostrum & zinc carnosine, on intestinal permeability. What are ‘nutraceuticals’ and what is the current state of evidence within this field; is more rigorous testing of potential health benefits needed?
The word nutraceutical is a portmanteau of the words nutrition and pharmaceutical, and is briefly defined as a claim that suggests or implies that the role of a food category, a food or a constituent of a food, has a specific benefit beyond that normally maintained from the diet on the physiological functions of the body. I don’t really like this term and prefer to use the term ‘dietary supplement’. Most nutraceuticals are supplements which do not have enough scientific evidence behind them and many spurious claims are made around these foods, which is quite a concern especially when it comes to social media.
For most people, a healthy balanced diet is most likely to be sufficient in providing all the nutrients that are needed for health, however, there are exceptions for certain people where supplements may be needed. I would urge everyone to look at the literature and evidence behind whichever supplement they are considering taking.
Zinc carnosine, which is used in Japan to treat gut ulcers, is a supplement that needs to be better investigated in terms of how it interacts with the immune system.
Bovine colostrum, which is the milk produced by a mother cow in the 48-hours after giving birth, has also been shown to reduce the increased gut permeability of those taking non-steroidal anti-inflammatory medication. This is likely to be due to certain constituents, such as growth factors, contained within the bovine colostrum that may have direct effects on the gut and once they have been absorbed they could have some effects in the circulation on immune function.
My PhD was a RCT cross-over trial in eight participants, looking at the effect of zinc carnosine, bovine colostrum, a combination of both or placebo on the gut permeability of subjects, before and after running for 20 minutes at 80% of their VO2 max. We found that both zinc carnosine and colostrum on their own reduced the increase in exercise induced permeability after 14-days of treatment, but when they were combined there was an enhanced effect.
5. You’re currently running the CYCLE-HD study looking at ‘Improving cardiovascular health in dialysis patients using a structured programme of exercise’. Why is the cardiovascular health of dialysis patients a concern?
It is a concern because end-stage kidney patients receiving haemodialysis have the highest five year mortality, behind pancreatic and lung cancer, so they have really high mortality rates and most patients die of cardiovascular disease (CVD). Younger patients with end-stage renal disease have a 1000x greater risk for CVD than the general population, and this is not very well understood.
Most people within the healthy population who have CVD tend to die of myocardial infarction (heart attack) which is related to atherosclerosis.
The reasons for CVD in the healthy population compared to renal patients receiving dialysis are different. Treatment for CVD in a healthy population looks at targeting traditional risk factors such as diabetes, high blood pressure and high BMI. Unfortunately targeting these risk factors in dialysis patients is not nearly as effective. The excessive rates of CVD in renal patients is multifactorial and includes what we call non-traditional risk factors such as inflammation, anaemia, oxidative stress and renal bone disease.
Another important non-traditional risk factor is left ventricular hypertrophy, simply an increase in size of the left side of the heart. Dialysis patients get increased scarring in the heart (known as fibrosis) which results in an enlarging of the heart. The primary aim of the CYCLE-HD trial was to try and reduce this hypertrophy (or enlargement of the heart).
6. How does improving the cardiovascular health of a healthy individual with an exercise programme differ from an individual receiving dialysis? What are some of the challenges of creating an exercise programme for a dialysis patient with cardiovascular disease?
Exercise is important as it is associated with being protective of CVD and reduced levels of exercise can lead to increased mortality, at least in the general population. Some studies have shown that exercise can improve traditional risk factors as well as some non-traditional risk factors, therefore we believe this is why it is important to get dialysis patients to exercise.
Dialysis patients are highly sedentary and not physically active, and we think the reasons for this are multi-factorial, but we do know that many renal patients have co-morbidities such as muscle wasting and anaemia. A large factor to their sedentary lifestyles is the fact that they receive dialysis treatment three times a week which takes up the majority of a patients day, automatically causing three sedentary days a week. Something else you have to consider is that many patients will report that they are tired on their non-dialysis days and do not feel like exercising.
The CYCLE-HD trial had to take into account all of these factors, so we got dialysis patients to cycle for 30-minutes at a moderate intensity during each of their dialysis treatments.
7. You will soon be starting a clinical trial amongst dialysis patients using L. casei Shirota. Can you tell us a bit more about what this study aims to investigate?
Inflammation is a non-traditional risk factor, there is increase in certain cytokines in dialysis patients that are associated with increased cardiovascular risk and also mortality. There is evidence that the outer cell wall of gram-negative bacteria ‘endotoxin’, that are normally confined to the gut, can enter the circulation when gut permeability changes and can contribute towards the inflammation that is common in dialysis patients. There have been studies in dialysis patients to show that increases in endotoxin within the blood is associated with mortality. There are also some studies to show that probiotics may reduce the permeability of the gut wall, and therefore if we could reduce the permeability of the gut wall we may be able to reduce these levels of endotoxin in the blood.
We will soon be conducting a placebo-controlled, randomised-study supplementing with L. casei Shirota or a matched placebo for six-months, and we will be measuring circulating levels of endotoxin as the primary outcome.
8. What does a typical working day look like for you?
This varies; if a trial is running then my day may consist of going to the human dialysis unit to recruit patients, contacting patients to arrange a time to collect samples (blood, saliva, urine), and supplying patients with product as well as obtaining outcome measures before dialysis. There is also an academic aspect to my job, so I try to continue writing grants, different research papers and supervising students. After a trial is completed my days consist of collecting data and writing reports and papers. When a trial isn’t running there is much more time to do the more traditional academic roles.
9. What do you enjoy the most about your job?
My role is quite varied, which I enjoy. During my PhD I worked with healthy patients, whereas I now work with patients with kidney disease, and I like the hands-on aspect of working with those patients, it can be very rewarding.
In the last few years I have increasingly enjoyed writing and it has become an aspect of my job that I particularly like. As a scientist being able to write in a clear and concise manner is very important.
10. Do you have one tip you would give to a student who is thinking about pursuing a future career in research?
I think there is something for everyone in research, as the careers can be quite broad and there are multiple areas of research you can go into, such as: lab, clinical, qualitative, medical statistician and many others. The nice thing about research is that you can try different things especially in your career.
I would say finding an area of research that interests you is important and if you think research is something you might like and you have skills that are well suited to research I would definitely recommend it. Finally, I would also try to find people you like working with, something I have been fortunate with.