Strain-specific colitis susceptibility in IL10-deficient mice depends on complex gut microbiota-host interactions

Background: Colitis susceptibility in Il10-/- mice depends on genetic background and microbiota composition. A major genetic locus mediating colitis susceptibility, Cdcs1, was transferred from susceptible C3Bir-Il10-/- to resistant B6-Il10-/- mice, resulting in susceptible congenic BC-R3-Il10-/- mice. The aim of this study was to determine the impact of microbiota on this differential colitis susceptibility using a Helicobacter hepaticus infection model. Methods: Parental C3Bir-Il10-/-, B6-Il10-/-, and congenic BC-R3-Il10-/- mice were inoculated with H. hepaticus and analyzed for inflammation. In parental Il10-/- mice, microbiota composition was determined by terminal restriction fragment length polymorphism (T-RFLP) and quantitative polymerase chain reaction (qPCR). Results: Most severe inflammation was observed in C3Bir-Il10-/- in the cecum, in BC-R3-Il10-/- in cecum and colon, and, unexpectedly, in B6-Il10-/- in the colon. C3Bir-Il10-/- and BC-R3-Il10-/- secreted significantly more interferon-gamma (IFN?) and interleukin (IL)17 than B6-Il10-/-. T-RFLP analyses in C3Bir-Il10-/- and B6-Il10-/- mice revealed 1) a significant impact of H. hepaticus infection on species richness and diversity, and 2) strain differences in microbiota composition only after H. hepaticus infection. qPCR revealed higher numbers of Clostridia leptum and Bacteroides spp. in the cecum of infected C3Bir-Il10-/- mice, and Lactobacillus spp. in B6-Il10-/- mice. Conclusions: Cdcs1 modifies the response to H. hepaticus infection. However, this infection alone does not reflect the original response to a complex colitogenic biota. H. hepaticus-induced inflammation altered intestinal microbiota in a mouse strain-specific manner. Bacteroides spp. became more abundant in susceptible C3Bir-Il10-/-, lactobacilli in B6-Il10-/- mice. Therefore, both host immune response and differential compositional changes of microbiota play a role in strain-specific colitis susceptibility in Il10-/- mice. (Inflamm Bowel Dis 2012;)