Impact of chronic intestinal inflammation on colonic immune responses to secondary challenge with Citrobacter rodentium
SEIDLER W. 1, SURENDER S. 1, GELMEZ E. 1, LEHR K. 3, EBEL J. 4, LINK A. 3, WESTENDORF A. 4, JERON A. 2, FRENTZEL S. 1, BRUDER D. 1
1 Otto-von-Guericke-University Magdeburg, Institute of Medical Microbiology and Hospital Hygiene, Magdeburg, Germany; 2 Helmholtz Centre for Infection Research, Research Group Immune Regulation, Braunschweig, Germany; 3 Otto-von-Guericke University Hospital, Department of Gastroenterology, Hepatology and Infectious Diseases, Magdeburg, Germany; 4 University Hospital Essen, University of Duisburg-Essen, Institute of Medical Microbiology, Essen, Germany
Inflammatory bowel diseases such as Crohn's disease and ulcerative colitis are chronic recurrent diseases of the gastrointestinal tract associated with damage of the intestinal epithelium and symptoms such as abdominal pain and diarrhea. Former characterization of mice with acute and chronic intestinal inflammation and the respective remission phases uncovered marked alterations in immune cell composition, a maladapted cytokine milieu in the colonic lamina propria and epigenetic changes in colonic epithelial cells. However, whether epigenetic modifications in epithelial cells evolve into an exaggerated pro-inflammatory response or immunological exhaustion upon infectious challenge remains unknown.
Here, we aim to characterize the immunological consequences of intestinal maladaptation induced during chronic colitis with respect to the epithelial response to intestinal bacterial infection against the enteric pathogen Citrobacter rodentium (CR).
We infected mice in the remission phase of chronic DSS colitis (day 39 after colitis induction) and healthy controls with CR. 10 days post infection, FACS analysis was performed to quantify major immune cell subsets in the colonic lamina propria. Furthermore, intestinal microbiota analysis was performed by DNA-sequencing. Currently, we perform ex vivo transcriptional profiling (RNA-seq) of colonic epithelial cells to identify the impact of chronic inflammation on their inflammatory response to the pathogen. Also, cytokine concentrations in blood plasma are currently quantified by cytometric bead array.
So far, we show that the disease severity following CR infection is markedly increased in the remission group compared to controls. The number of colonic B cells decreases during CR infection in both groups. In addition, the CD4+ and CD8+ T-cell populations show alterations between the different infection stages. CR infected mice in the remission phase display marked changes in the intestinal microbiota composition compared to CR infected healthy controls. Thus, we conclude that preceding colonic inflammation sustainably alters intestinal inflammatory response to secondary bacterial infection.