Feature: A delicate balance – investigating intestinal inflammation

Professor Fiona PowrieThere are more immune cells in the intestine than anywhere else in the human body. Their job is to identify and destroy invaders such as viruses, bacteria or parasites that could make us ill; however, unlike in other parts of the body, where any unfamiliar cell is likely to be potentially harmful, our guts play host to hundreds of species of bacteria.

Professor Fiona Powrie

Most of these bacteria are harmless or even help us – by aiding digestion, for example. The intestinal immune system, therefore, has to be more discriminating in its response to foreign bodies, which might explain why it needs so many immune cells.

When the immune system detects an invader, its response usually involves inflammation. This is caused by an influx of specialist cells and molecules that are equipped to deal with an intruder by neutralising, killing or consuming it – sometimes all three.

Inflammation can damage the body, but usually the short-term pain and swelling are worth it to snuff out the danger of serious disease. However, if the immune system triggers inappropriate inflammation in the gut, this can drive chronic, often devastating conditions called inflammatory bowel diseases, which include ulcerative colitis and Crohn’s disease.

Controlling the body’s response to the harmless bacteria in the gut while keeping it alert to dangerous microbes is a difficult balancing trick. In most of us, our immune systems pull it off, so what makes some people’s immune systems overreact? That question is at the heart of research led by Professor Fiona Powrie, a Wellcome Trust Senior Investigator at the University of Oxford.

Fiona probes the workings of the intestinal immune system and the inflammatory response, teasing out the molecular signalling pathways that determine how our bodies respond to the bacteria in our gut. We often talk about the immune system as if it were the same throughout the body, a consistent defence mechanism against invasion. Fiona explains that this is not quite true.

E. coli

The immune system’s cells and signals do different things according to where they are. The immune system in a specific tissue – such as the gut – does not behave in the same way as it does in the blood, which is where it has most commonly been studied.

Escherichia coli on the surface of intestinal cells. E. coli are part of the normal environment of the gut; however, some strains are pathogenic and produce toxins that can cause toxins, so E. coli is often associated with food poisoning. Credit: Dr Paul Dean, Newcastle University, Wellcome Images.

Pathway to success

Fiona has been studying the intestinal immune system since her days as a postgraduate student in Oxford, when she made her first discovery about how the balance between our immune system and bacteria is maintained in the gut. Even in healthy people, there is a constant low level of intestinal inflammation that is kept in check by a group of immune cells called ‘regulatory T cells’. Fiona and her mentor Don Mason were among the first to describe the role of regulatory T cells in suppressing inflammation.

“I did my PhD in Don Mason’s lab in the William Dunn School of Pathology,” says Fiona. “There were only four of us in the team – you wouldn’t find many labs like that now.” The discovery that regulatory T cells had a suppressive role ran against the tide of thought in immunology at the time.

“Suppression had been floated as an idea before but then fell out of favour,” she explains. “New technology allowed us to identify a controlling mechanism for regulatory T cells and to demonstrate that negative regulation was important in the immune system.”

It meant that, rather than being switched off until it was needed, the immune response was always ticking over in a carefully controlled way. This might make it quicker to respond when genuine threats arise, at which point the regulatory T cells take off the shackles until the inflammatory response has removed the danger.

Fiona left Oxford to do more work on regulatory T cells with Bob Coffman at the DNAX Research Institute in California. There, she found that modifying regulatory T cells in mice led to intestinal inflammation similar to that seen in human inflammatory bowel diseases. Mice with these specific modifications could be used as research models to understand the human disease better.

“It was very exciting,” she says. “These were among the first models of inflammatory bowel disease to be developed. It opened up my eyes to the clinical importance of the area and led me to focus my work on intestinal immunology.”

Her research focus set, Fiona returned to Oxford with a succession of Wellcome Trust Senior Fellowships from 1996 to 2009. Then, she accepted the inaugural Sidney Truelove chair in Gastroenterology along with roles as Head of both the Experimental Medicine Division and a new Translational Gastroenterology Unit at Oxford’s John Radcliffe Hospital.

In 2011, she was among the first cadre of researchers to receive Wellcome Trust Investigator Awards. The new funding model provides a firm footing for research alongside her administrative roles: “The Senior Investigator Award is perfect for me in this setting,” says Fiona. “The length and flexibility of the award is very important as the programme of research moves forward. We’re able to expand our horizons from mouse models to understanding the pathways at work in humans, to understanding human disease.”

Location, location, location

The Translational Gastroenterology Unit is the ideal place for this research. Basic researchers work alongside clinical researchers, who are also doctors in the hospital treating the patients suffering from inflammatory bowel diseases.

Fiona says such collaboration brings much added value: “How we think about the animal models is influenced by thinking about patients and talking with clinicians about the challenges they face.

“The clinicians come to meetings where we are talking about research into the drugs and agents they are actually giving to their patients. It is inspiring, and there is huge benefit in having postdoc scientists with a better awareness of the interactions between these different disciplines.”

The aim is to apply that scientific understanding and develop new treatments for inflammatory bowel diseases. There are some promising candidates in development, and Fiona and her team have been working with pharmaceutical companies to run proof-of-principle trials in their patients.

It is equally important to develop better ways of diagnosing inflammatory diseases. As well as knowing which specific condition a patient has, their care could be improved if doctors knew accurately how far the disease had progressed and even how likely the patient was to respond to a particular treatment. Eventually, it may be possible to categorise groups of patients by their genes – genetics undoubtedly has an important role in determining our likelihood of getting inflammatory bowel disease.

“It’s a very exciting time in this area,” says Fiona. “We’re part of a global effort, revealing regulatory pathways from human genetics and mouse models, which leads to understanding the operation of these pathways in humans. In turn, that leads to an understanding of what goes wrong in the specific set of patients with inflammatory bowel disease.”

Top image: Professor Fiona Powrie. Credit: Wellcome Library, London.