DR MARK WILLIAMS
PROJECT TITLE: Reconstructing the human intestinal mucosa to study the role of acetylcholine in innate immunity: implications for health and inflammatory bowel disease
PROJECT TIMESCALE: 1 October 2015 – 30 September 2018
PHD STUDENT: Nicolas Palaez-Llaneza
NOVEMBER 2015 – A ‘NEXT GENERATION’ HUMAN INTESTINAL TISSUE CULTURE SYSTEM TO STUDY GUT HEALTH AND DISEASE
(taken from Winter 2015 newsletter)
The human intestine is the site of debilitating, prevalent and life threatening conditions such as inflammatory bowel disease (IBD) and colorectal cancer. In the UK, there are over 400,000 people suffering from IBD, and annually there are more than 40,000 new cases of colorectal cancer, of whom only half will live for more than 5 years. There is thus a dire need for new and improved therapies, but progress has been hampered by the lack of pertinent in vitro culture models of native human intestinal tissue.
The gut is a complex organ consisting of numerous different tissue types including, muscle cells, immune cells, nerve cells (which act as the gut’s very own brain!) and the inner most barrier layer called the epithelium, all of which are bound together by connective tissue and perfused by blood vessels. In a reductionist approach, some success in developing novel culture systems has been achieved by initially separating these different tissue types comprising the human gut. For example, on the basis that the epithelial barrier is the site of colon cancer and is also disrupted in IBD, the Williams laboratory at UEA developed an ex vivo3D culture model of the epithelial lining of the human gut (Reynolds et al., Gut, 2014; funded by the Humane Research Trust), thereby permitting investigation of what maintains the integrity of this vital barrier to the hostile contents of the bowel. However, it is clear that ‘next generation’ native tissue culture models are now required to investigate the multitude of interactions that occur between the different tissue types comprising the human gut … and its resident guests.
The gut lumen is home to 100 trillion micro organisms. ‘Good’ bacteria fulfil important physiological roles such as digesting dietary fibre and they help to maintain the integrity of the epithelial barrier in the presence of ‘bad’ bacteria. There is intense interest in understanding the mechanisms by which the gut epithelial lining senses the presence of bacteria and keeps them at bay, as it is thought that when these mechanisms fail it can lead to the onset of inflammation and disease. Intriguingly, it appears that there is a convergence of the mechanisms by which bacteria and human gut nerves maintain the integrity of the intestinal barrier.
Nicolas Palaez-Llaneza has just started a Trust-funded PhD research programme in the Williams laboratory to investigate the interactions between the gut brain, the epithelial barrier and gut bacteria. ‘Nico’ will establish a ‘next generation’ co-culture system between human gut nerves, gut bacteria and the intestinal epithelium. It appears that nerves in the gut brain interact with stem cells in the gut epithelium to promote barrier integrity by releasing a chemical called acetylcholine. Somewhat surprisingly, acetylcholine is also synthesized by bacteria and the gut epithelium itself! Nico will unravel the relative influence of these sources of acetylcholine on maintaining gut health and determine if probiotics exert their positive influence via acetylcholine secretion.
Nicolas commented, “I come from Vigo in the northwest of Spain and developed my undergraduate studies in biology at the University of Santiago de Compostela, Spain. I later moved to the Netherlands to carry out my master’s degree on Molecular Life Sciences at Wageningen University. During my time there I had the opportunity of joining a research project on liver stem cells and stem cell therapies at Utrecht University as part of my master’s thesis. This experience helped me to realise that doing research was what really interested me and I also became aware of how important the role of a scientist is in helping to understand the cellular and molecular basis for human health and how can we use this knowledge to prevent and treat diseases. These thoughts persuaded me to continue my career in science. When looking for a similar project, I found the work Dr Williams had carried out at the University of East Anglia very interesting and I quickly understood the importance of his research. After our first meeting, I was introduced to Dr. Williams’ research ethos. The idea of contributing to the understanding of how our intestine functions in the healthy state and how all this changes when we suffer from conditions such as IBD or colorectal cancer fascinated me. That is the reason I approached him to express my desire to join his team. I am extremely grateful for having been accepted at his lab, but also for having been funded by the Humane Research Trust whose policies and ideas I truly share and admire”