The PRognostic Effect of Environmental Factors in Crohn's and Colitis

Background Inflammatory bowel disease (IBD) is a common cause of chronic ill-health among young people in the UK (prevalence estimated at 1 in 200 for adults and 1 in 2000 for children, with a peak incidence in the second and third decades of life)1-2. The major forms of IBD, namely Crohn's disease (CD) and ulcerative colitis (UC), all too often confer a lifetime of unpleasant, intrusive and potentially dangerous burden of intestinal inflammation on individuals. Typical symptoms include abdominal pain, diarrhoea, weight loss, and lethargy. These adversely affect schooling, work attainment, psycho-social well-being and sexual health 3-4. IBD costs the NHS £720 million per year, based on an average per patient cost of £3,000; of which half of the costs are directly attributable to relapsing patients 5. Healthcare expenditure focus in IBD is shifting from hospitalisation and surgery to medical therapy 6. However, existing treatment modalities remain limited by lack of efficacy, unacceptable toxicity and poor patient acceptability. Major surgical intervention is frequently required (\>50% in CD; \~20% in UC), with a high risk of disease recurrence, and there is an increased risk of cancer (in CD), with the highest incidence of colon cancer observed in those patients with poorly controlled disease 7. Nevertheless, there is a wide spectrum of disease severity. Around one third of patients will follow a relatively quiescent disease course 8. Understanding who gets severe, progressive disease and why, is an urgent research priority. Accurate prediction of these patients will enable precise, tailored intervention early in the disease course. This should reduce the substantial morbidity and costs associated with IBD. Genetics, Environment and the Microbiota and Disease Natural History. Genetic factors play a modest role in defining disease location and extent but not disease behaviour 9-12. There is very limited evidence about the gut microbiota in disease progression, although emerging data support a potential role in treatment response. We cannot alter our genes and, despite intense interest in modifying the gut microbiota (e.g. faecal transplantation) there is only limited clinically data to support this 13-14. However, it is within our control to change what we eat and to therefore potentially modify our gut microbiota to a more favourable phenotype. Patients suspect this should be part of the answer: one of the commonest questions in the clinic is, "What should I eat?" Established clinical strategies include the use of exclusive enteral nutrition (EEN) to induce remission in CD, and a low fibre diet to alleviate obstructive symptoms in stricturing disease 15. However, beyond this there is presently very limited data to support any on-going specific dietary strategy for the vast majority of patients with IBD 16. Multiple lines of emerging evidence in animal models suggest that diets high in natural plant fibres favour an anti-inflammatory gut milieu, via alterations in the gut microbiota, measurable by short-chain fatty acid (SCFA) concentrations in stool 17. Dietary fibre may protect against the development of IBD, through several mechanisms, through its conversion to acetate, butyrate and propionate (the major SCFAs). Firstly, butyrate is the main energy source for colonocytes and is associated with the maintenance of the intestinal epithelium 18. Secondly, SCFAs have immunomodulatory roles including inhibition of the transcription factor NF-KB and are the only known ligands of G-protein-coupled receptor, GPR43, which limits the inflammatory response 19-20. Interestingly, the fermentation of fibre is dependent on gut microbiota, such as Bacteroidetes species, which are deficient in patients with IBD 21. The individual source of fibre may also be important. In the US Nurses' Health Study of 170,776 women with 3,317,425 person-years of follow-up over 26 years there were 269 incident cases of Crohn's disease diagnosed and 338 cases of ulcerative colitis 22. For the latter illness, there were no associations with either total dietary fibre intake or fibre from any specific food groups. However, for Crohn's disease the highest quintile of energy-adjusted cumulative average dietary fibre intake, namely 24.3 g/day, was associated with a 41% reduction in risk compared with the lowest quintile (hazard ratio (HR) =0.59, 95% confidence interval (CI=)=0.39-0.90). This reduction was associated with the fibre content from fruits (highest vs. lowest quintile HR=0.57, 95% CI=0.38-0.85) with no associations detected between fibre from vegetables, cereals or legumes. These are important issues; the lack of data means patients may resort to untested and potentially harmful 'fad' diets 16. More pressingly, this is potentially a novel therapeutic approach to both induce and maintain prolonged remission. Interventional studies in cases and controls will be necessary, but first further data are required from observational epidemiological studies to inform which 'interventions' are indicated and/or justified. Rationale for the Study It is presently very hard to predict which IBD patients in remission will flare and when. Scant data are available to advise patients on any substantial lifestyle measure they can adopt to help prevent or retard future disease from flaring. Potential areas of direct relevance to patients are aspects of habitual diet, regular exercise, sleep and stress, including that from major life events. It is hypothesised that there are multiple factors in habitual diet that are associated with increased risk of disease flare, including reduced levels of dietary fibre, high levels of n-6 PUFAs, low levels of n-3 PUFAs and dietary emulsifiers. High levels of regular physical activity are also hypothesised to reduce the rates of disease flare. These dietary aspects and facets in concert with other lifestyle factors may contribute in part to the intestinal dysbiosis associated with flare, where the investigators anticipate seeing a reduction in microbial diversity. The major aim of this study is to identify the environmental and gut microbiota factors that predispose to disease flare and influence disease outcomes in IBD. Further, the investigators aim to build intelligent predictive models of disease behaviour and prognosis combining phenotypic, environmental and biological data inputs of direct clinical utility.

Bury St Edmunds, United Kingdom

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