GEM study to launch in UK Sept 2014 in search of cause(s) of Crohn’s disease

The incidence of Crohn’s disease continues to rise in Scotland and across the United Kingdom. There is almost a doubling in the number of new cases presenting in young people each decade. Why? Our best understanding at present is that environmental factors trigger this devastating chronic inflammatory bowel disease (IBD) in genetically susceptible individuals. Having a family member affected with IBD is the strongest known risk factor for developing Crohn’s disease. Yet, the vast majority of such individuals will never develop IBD. We have made tremendous progress in recent years identifying nearly 200 genes that predispose to the development of disease. These genetic variants confer a very small risk, and are presently no use for predicting who will get Crohn’s disease. Indeed the vast majority of individuals with even the highest genetic risk will remain healthy. But genetics has, as we had originally hoped, taught us a lot about disease biology. All the data suggest that a central feature is the defective handling of the gut microbiota by the mucosal immune system in the intestine.

The microbiome – our ‘other genome’ – varies from individual to individual, over time, and in response to environmental stimuli.  The gut microbiota contains 10 times more cells than the entire human body, and 100 times the number of genes than our genome. It is critical for many normal functions, including immune homeostasis, metabolic and cardiovascular health and is implicated in a wide range of diseases from diabetes to obesity. The huge challenge presented to the intestinal immune system is to live in balance with these billions of ‘healthy’ bacteria, while remaining on guard to fight off potentially dangerous pathogens (for example, salmonella or campylobacter induced gastroenteritis).  Patients with inflammatory bowel disease have reduced microbial diversity in the gut microbiota. But we do not know if this is the cause of disease or a secondary effect of active gut inflammation. And to do date, multiple studies have failed to identify a single microbial factor that ‘causes’ Crohn’s disease. In reality it is likely to be far more complicated that one single bacterial trigger. Dietary factors are known to directly impact on the gut microbiota. Recent studies have shown that switching from an animal protein based diet to a plant based diet (and vice versa) causes dramatic shifts in microbial diversity within just 48 hours.

Our diets have shifted dramatically in the past 40-50 years – foods are increasingly processed, containing highly refined flours, sugars and preservatives. Refrigeration is a relatively new invention. Convenience foods dominate the diets of most young people in the Western world. This is a world apart from the diets of our ancestors, who ate a mostly plant-based diet supplemented by occasional intake of meat following a successful hunt. Moreover, we are exposed to multiple other environmental stimuli that are known to alter our gut microbiota – for example antibiotics, non-steroidal anti-inflammatories, infections.

Recent trends in the ‘developing’ world offer additional fascinating insight. As these countries have adopted an increasingly Westernised lifestyle, the incidence of IBD has exploded. My recent trips to China have offered a clear window on this (Korea, India and Japan all provide further excellent examples). You see the juxtaposition of ‘old’ and ‘new’ habits on every street corner: traditional vendors battle for space and customers outside a multitude of fast-food stores. Visit the local hospitals and you witness huge clinics of new and complex cases of Crohn’s disease and colitis. The sheer size of these populations means that IBD will increasingly be a major global health and economic burden.

Putting all of this together, it seems mostly likely that genetic, environmental and microbiota factors underpin both the causes and the consequences of Crohn’s disease. The GEM study aims to address the first part of this. To avoid potential bias and get around the ‘cause and effect’ question we need to recruit individuals before they develop disease. With this in mind we are looking for healthy individuals aged between 6 and 34 years of age who have a first-degree relative who has Crohn’s disease. At a baseline visit we will take a blood sample for genetic analysis, a stool sample to assess the gut microbiota and provide a series of questionnaires to address environmental exposures and dietary habits. All subjects will be followed for a minimum of 3 years. Ultimately the baseline characteristics of those who develop Crohn’s disease during the course of the study will be compared with those who do not.

The GEM study originated in Toronto, Canada and is now expanding to ensure recruitment targets are met. 5000 individuals are required to give the study sufficient ‘power’ to detect meaningful differences in baseline environmental factors in those that develop Crohn’s disease versus those that do not. $20m has been invested in the study through the Helmsley Foundation and the Crohn’s and Colitis Foundation of Canada.  A substantial portion of this money is now enabling the launch of GEM in the UK. From our central co-ordinating centre in Edinburgh (with the Edinburgh Clinical Trials Unit) we will be opening up to recruitment in approximately 15 adult and paediatric gastroenterology units across England, Scotland and Wales from 1st September 2014. Further details on how to participate will be posted in due course (here and through Crohn’s and Colitis UK).

In parallel we are in the advanced planning stages for the PREdiCCt study (the prognostic effect of environmental stimuli in Crohn’s and colitis). In PREdiCCt we will examine the effect of the gut microbiota and diet on disease outcomes in a large cohort of individuals with established Crohn’s disease and ulcerative colitis. Individuals recruited during periods of clinical remission (to avoid the effect of active inflammation on the gut microbiota) will be followed over time using a series of innovate e-health tools in development for this study. These tools will translate directly to routine clinical practice. Indeed, the smartphone app, funded by Crohn’s and Colitis UK, has already been successfully trialled in NHS Highland. Specific components of the diet (plant fibre; animal protein intake) and gut microbiota collected at baseline will be compared in those individuals whose disease flares during the study versus those who remain in remission.

We hope that this study will enable us to better advise patients on suitable dietary and lifestyle measures to prevent a disease flare. We anticipate that it will yield targeted interventional studies in this population. Moreover the factors that predict flare may yield additional clues as to the primary triggers for the development of IBD. Finally, the vast dataset collected for this study will enable us to develop intelligent prognostic algorithms. These will allow us to identify individuals at ‘high-risk’ of an aggressive disease course in whom early targeted intervention may be beneficial. A co-funding arrangement for PREdiCCt, is being pursued with Cure Crohn’s and Colitis, 3Cs and the Scottish Government.