Tremendous progress has been made in our understanding of the pathobiology of inflammatory bowel disease (IBD: Crohn’s disease (CD) and ulcerative colitis (UC)) through research on mouse models of gut inflammation, human population genetics studies and immunological research.1^–4 However, despite these important advances, many of the primary features of human IBD remain unexplained.

In this article we pose a series of 10 fundamental questions about the epidemiology and clinical course of IBD that remain unanswered to this day. In order to obtain “best guess” answers to these questions, we have interviewed experts who are leaders in the field of each question. This article is a distillation of their opinions which we hope will refocus future research onto these remaining mysteries (Box 1) which are essential for improving the clinical management of IBD.

WHAT EXPLAINS THE GEOGRAPHICAL AND HISTORICAL VARIATION IN THE INCIDENCE OF IBD?

The incidence of IBD has risen sharply in the last 50 years in the USA and western European countries; with the increase occurring in higher social classes before lower social classes.5 6 The increase in incidence is too rapid to be accounted for by genetic changes and strongly points to changes in environmental risk factors, especially changes in diet and intestinal microflora.7 In Japan, a correlation between incidence of IBD and fat and meat intake has been reported.8 Changes in diet and food preparation could influence intestinal microflora. Large variations in the range of bacterial lineages within the intestines of different individuals have been reported.9 However, the relationship between the microbial community structure within the gut and IBD is unknown. New concepts that intestinal microbiota exist in a finely balanced ecosystem in which changes to one microbial species influences other species suggest that ideas that IBD is caused by a single microbial species may be oversimplistic.10