Lay Summary

Proposal No. IBD-0215R
Principal Investigator:  Jeremy D. Sanderson, M.D.
Applicant Organization:  King's College London (United Kingdom)
Project Title:  The persistence of bacteria in lamina propria macrophages in Crohn's disease: role in pathogenesis
Period of Award:  November 1, 2007 – December 31, 2009

Whilst the exact cause of IBD remains unknown, most research points to an interaction between inherited susceptibility and environmental factors. More specifically, it is likely that chronic inflammation in the gut stems from an abnormal immune response directed at some of the bacterial flora normally resident on the surface of the intestine.

We and others have previously shown that species of the bacteria, E. coli, gain access to the lining of the gut in patients with IBD, particularly Crohn’s disease. This observation fits with other studies showing that patients with IBD frequently show immune responses in the blood (antibodies) to components of E. coli. However, there are many types of E. coli, varying from the completely harmless (often found in the normal gut flora) to extremely harmful (such as the well-known 0157 strain). The strains found in the gut wall in IBD are not entirely innocent (typing suggests they can cause infections such as urinary infections) but evidence suggests they have largely got into the wall of the gut as a result of a damaged lining.  Once inside the gut lining, the bacteria are taken up in the usual way by macrophages, the immune cells responsible for clearing bacteria and other material from the gut wall. However, in IBD, the macrophages then appear unable to kill and digest the bacteria. As a consequence, these moderately pathogenic bacteria remain viable and orchestrate an immune response (attempting to get rid of them) which only serves to increase the inflammation in the gut wall. Our hypothesis is that there is a pre-existing defect in macrophages in patients with IBD, which leads to persistence of bacteria within these cells. In the proposed research, using biopsy samples taken at routine colonoscopy, we aim to isolate individual macrophages containing bacteria from the wall of the gut and measure various markers of macrophage function. We will then compare this to macrophages not “infected” with bacteria and to macrophages from people with a healthy intestine. In a separate part of the study, we will also examine the behavior of macrophages isolated from blood samples from patients with IBD and from healthy individuals when exposed to E. coli bacteria, measuring the same markers of macrophage function as in tissue macrophages. Finally, we will look at known markers of genetic predisposition to IBD (including the well-known NOD2 or CARD15 gene) and how they might influence the interaction between macrophage and bacteria.

We hope that the results of these studies will lead not only to a greater understanding of how IBD develops, but also to new approaches to treating IBD.