Grant: Operating Grant

The health of our digestive system depends on the cells that line our intestines. These cells form a tight barrier that prevents the bacteria that live in our intestinal tract from leaking into our body and causing an immune response. These 'resident gut bacteria' do many good things, including competing with potentially dangerous 'invading' bacteria to prevent intestinal infections. The cells of our intestinal lining can sense bacteria, but they generally do not attack them. Instead, studies show that if our intestine becomes damaged, or in people who have Inflammatory Bowel Disease, our intestinal lining can undergo a slow healing process that occurs in response to bacteria. We wanted to find out why, and so asked (1) why don't our intestinal cells respond more strongly to bacteria, and (2) would higher responsiveness to bacteria improve healing of the intestine? We found that the cells lining the intestine make a protein called SIGIRR that suppresses the ability of cells to respond to bacteria. We obtained mice that were missing SIGIRR and then tested their response to a bacterium called Citrobacter that infects and damages the intestine. Without SIGIRR, the intestinal cells had a much stronger response and much better healing. At the same time, the intestinal cells also caused more inflammation and released many proteins that kill bacteria. Surprisingly, these proteins killed only the "good" resident bacteria, so that there was less competition with the invading Citrobacter bacteria, which left the intestine open to infection. Now we propose to test whether SIGIRR's actions are solely due its expression by intestinal cells, and define what immune signals are stronger when SIGIRR is absent. We also want to understand why only resident bacteria are killed in mice missing SIGIRR. These studies will clarify how SIGIRR promotes intestinal host defense, apparently sacrificing intestinal healing to enhance harmonious/protective interactions with resident bacteria.