Dr John Louis-Auguste
2014 - Guts UK /Nutritional Research Foundation Fellow
Title: Effects of multiple micronutrient and amino acid supplementation on intestinal function and microbiome-host interactions in environmental enteropathy: a study in Zambian adults
Project Start Date: 1 September 2014
Completion Date: 31 August 2016
Stunting affects one third of children in the developing world, equivalent to over 150 million children. This has lifelong detrimental effects on health and productivity – these children do not just grow into short adults. Compared to their unaffected peers, they are more likely to die, develop more slowly, achieve less in school, and earn less as adults. Stunting is therefore a major global health priority.
Unfortunately, efforts to improve stunting by increasing food intake or by reducing infectious disease burden have not been very effective. There is therefore now great interest within the global health community in a condition known as environmental enteropathy, which is thought could underlie all of these observations.
Environmental enteropathy is a symptomless disorder which is extremely common in stunted populations. It is thought to result from living in unsanitary conditions and being continually exposed to bacteria and other microbes. It is characterised by numerous abnormalities of small bowel structure and function, which predisposes to poor absorption of nutrients and allows gut microbes to enter the blood stream. This results in persistent low levels of inflammation, which puts excessive demands on the body’s immune system and takes resources away from growing and developing.
Environmental enteropathy is still poorly understood, and there are no established treatments for it. This study aims to examine some of the processes underlying this intriguing condition in more detail, and to see if there is any benefit from giving a dietary supplement of amino acids (the fundamental ‘building blocks’ of proteins) and / or micronutrients (minerals and vitamins).
Professor Paul Kelly, my supervisor, is Professor of Tropical Gastroenterology at Barts and the London School of Medicine. He has been conducting research into environmental enteropathy in Zambia for over 20 years. I will be conducting the field work at his unit at the University of Zambia School of Medicine, based at the University Teaching Hospital in Lusaka. The gastroenterology unit there is equipped with advanced high definition endoscopes (flexible cameras for examining the stomach and intestines internally), as well as a highly specialist research endoscope (see below). During the time I will be conducting the field work, I will also be conducting some of the lab work in his fully equipped laboratories.
I will be doing much of the lab work in the Blizard Institute based at Barts and the London School of Medicine, in collaboration with Dr Jim Lees, and will be analysing small bowel tissue samples under the supervision of Professor Stephen Greenwald, who is also based at Barts and the London.
Part of the project involves examining urine samples for by-products of metabolism by the gut and its microbes. This work will be supervised by Dr Jonathan Swann in the Department of Nutrition at the University of Reading, who is particularly interested in how changes in the gut’s bugs result in changes in these by-products. He is already collaborating with us on a separate enteropathy study.
We will be examining the effects of an amino acid and / or micronutrient supplement on environmental enteropathy. Approximately 80 healthy Zambian adults with environmental enteropathy will be divided into four treatment groups: placebo; daily amino acid supplement; daily micronutrient supplement; or both. We will include healthy HIV positive and negative volunteers. HIV is known to have a significant effect on the gut immune system, even in people who are otherwise well and don’t have any symptoms. We therefore suspect that this will affect how their gut responds to the conditions that are thought to result in environmental enteropathy. The supplements will be given for four months.
The study participants will provide blood, urine and stool samples. We will examine the first part of their small bowel in microscopic detail using an exciting and novel endoscopy technique, known as confocal laser endomicroscopy. The blood, urine, stool, endoscopy pictures and small bowel tissue samples will be taken before and after the supplementation period, and analysed for markers of gut inflammation, ‘leakiness’, and human-microbe interactions. We will look for (1) effects before and after supplementation; (2) differences between people who have had micronutrients and / or amino acids to people who haven’t; and (3) differences between HIV positive and negative individuals.
The clinical trial element and collection of samples will take place over a period of six to nine months, and the whole project will take 2-3 years. The project is due to begin in September 2014 and a final report will be completed by September 2017.
We expect to discover interesting and novel insights not only into the mechanisms of environmental enteropathy, but also into how nutrition influences the gut immune response and gut inflammation. This will allow us and others to develop further research ideas and clinical trials, both into environmental enteropathy and other conditions characterised by an abnormal gut immune response.
I hope that this study will also provide evidence for a simple nutritional intervention for this globally important condition, which can then be taken forward to large scale phase III clinical trials.
We expect this project to result in several publications in academic journals, and the data will also be presented at national and international scientific meetings and conferences.
During my clinical gastroenterology training, I have become increasingly interested in the influence of nutrition on gut inflammation, which is now an area of intense research but is still at an early stage. I wanted to combine this interest with my interest in global health. Environmental enteropathy is a perfect subject area which combines these interests, as it involves the study of abnormal gut immunity and nutrition in the developing world.
I am also very excited about the research techniques I will be using. These include both established and cutting edge methods such as the confocal laser endomicroscopy system, some of which have never been used to study this sort of problem before.
My main area of clinical interest is nutrition. This project will allow me to develop a deep understanding of some of the fundamental scientific principles of human nutrition, and how this influences (and is influenced by) gut inflammation. I am also having to learn a great deal about clinical aspects of human nutrition. This advanced knowledge will be invaluable in allowing me to treat patients at the bedside and in the clinic with nutritional problems that may or may not be related to bowel inflammation.
In the next 5-10 years I hope we will be able to provide an easily implementable nutritional intervention for environmental enteropathy that will give significant benefits to adults and children throughout the developing world. Furthermore, although the work is based in Zambia, we think that the results will improve our understanding of how nutrition can modify gut inflammation and immunity. This is an area of great current interest, and is relevant not just for environmental enteropathy, but also for diseases including inflammatory bowel disease, obesity, fatty liver disease and cirrhosis.
I am approaching the end of my clinical training, which I will complete after finishing my research degree. I would then like to pursue a career which would allow me to combine my research and clinical interests in nutrition. I enjoy both aspects and I think I would find it difficult to concentrate on one at the expense of the other.
From a research perspective, I would like to continue exploring the link between nutrition and intestinal inflammation in conditions such as inflammatory bowel disease, as well as continuing my work in environmental enteropathy. In particular, I would like to extend this current project to explore nutritional interventions for environmental enteropathy in the ‘first 1000 days’ (from conception to toddlerhood), for mothers-to-be and their babies. This is the most crucial period of a child’s physical and brain development, and intervening during this time is therefore likely to reap the greatest benefit in terms of lifelong improvements in health, wellbeing and productivity.
Thanks to CORE's support, I've been able to undertake a clinical trial into environmental enteropathy, a neglected bowel disorder affecting vast numbers of people in the developing world. This has been an brilliant experience for me as a clinician and as a scientist. I have been fortunate to collaborate with and learn from experts in the UK and Zambia. We've collected a large amount of samples and data which is still being analysed, and which will keep our team busy for at least another year. Our findings are providing promising insights into the abnormal gut function that characterises the disorder and how nutrients can influence it.Dr John Louis-Auguste