20 December 2012
By Alan Walker
In this study, we used a mouse model of ulcerative colitis that resembles many aspects of the human disease. These mice lack an important regulator of immune responses, a transcription factor called T-Bet, and subsequently develop colitis.
Previous studies from the United States had indicated that colitis could be transmitted to previously healthy mice. This heightened interest in this mouse model and raised the intriguing possibility that inflammatory bowel disease might be caused by potentially novel colitis-triggering intestinal microbes.
However, when our London-based collaborators reared their own mice lacking T-bet, they found that, in contrast to the earlier studies, these mice did not develop colitis. It was clear from this that disease required the presence of a specific, but unidentified, microbial trigger.
To try and identify the cause of disease, our team at the Sanger Institute therefore compared the bacteria that were present in the intestines of mice that developed colitis to those that did not.
Our results showed that only mice with colitis were infected with Helicobacter typhlonius, a pathogenic organism that had previously been shown to cause gut inflammation in mice.
When our collaborators then infected healthy T-bet deficient mice with H. typhlonius these mice also subsequently developed colitis. These results suggest that disease was not caused by novel transmissible agents from within the host’s intestinal bacterial communities, but by a known pathogen.
In a series of elegant experiments, our collaborators then used this H. typhlonius infection model to demonstrate the key role that T-bet plays in simultaneously regulating multiple components of host innate immune responses. They were then able to show that they could reduce colitis symptoms by specifically treating many of the immune factors that were altered in the H. typhlonius-infected mice lacking T-bet. In the presence of specific deleterious microbial triggers, this single transcription factor can therefore profoundly impact the balance between maintenance and loss of intestinal health.
This study therefore generated novel insights into the complex interactions that drive development of colitis in T-bet deficient mice, which may also have relevance for human inflammatory bowel disease.
Nick Powell, Alan W. Walker, Emilie Stolarczyk, James B. Canavan, M. Refik Gökmen, Ellen Marks, Ian Jackson, Ahmed Hashim, Michael A. Curtis, Richard G. Jenner, Jane K. Howard, Julian Parkhill, Thomas T. MacDonald and Graham M. Lord. (2012) The Transcription Factor T-bet Regulates Intestinal Inflammation Mediated by Interleukin-7 Receptor Innate Lymphoid Cells. Immunity, Volume 37, Issue 4, 19 October 2012, Pages 674-684, ISSN 1074-7613, 10.1016/j.immuni.2012.09.008.