Bacteria and Bacterial rRNA Genes Associated with the Development of Colitis in IL-10-/-Mice

Microorganisms appear to play important yet ill-defined roles in the etiologies of Crohn's disease (CD) and ulcerative colitis (UC).1–3 CD and UC occur in regions of the intestine where enteric bacteria are found in the highest concentrations.4 Contact with intestinal contents triggers mucosal inflammation in CD,5 while diversion of the fecal stream promotes intestinal healing.6 The most direct evidence for the importance of microorganisms in disease etiology comes from investigations with animals. In numerous rodent models, colitis is absent when the animals are kept in a “germ-free” state, but it rapidly develops when standard intestinal microorganisms are introduced.7 Evidence also indicates that disease etiology involves specific bacteria, and or an aberrant immunological response to specific intestinal microorganisms. In animal studies, monoassociation experiments have shown that the type of colitis is dependent on the bacterial species.8,9 In addition, various antibiotics, possessing different taxonomic targets, have been shown to exhibit varying abilities to prevent and treat colitis in HLA-B27 rats10 and IL-10–/– mice.11 In human studies, evidence for the involvement of specific bacteria includes the differing abilities of various antibiotic therapies to induce disease remission.12–14 Evidence that the immunological responses to these bacteria are involved in disease etiology include the ability of CBir1-selective T cells to cause colitis when transferred to immunodeficient mice15 and the ability to utilize seroreactivity to specific microbial antigens for disease stratification.16 Prior investigations in our laboratories have demonstrated the utility of population-based approaches for identifying microorganisms involved in specific in situ processes such as plant-pathogen suppression in soil.17,18 The first step in this approach is to create or identify a series of samples/subjects with various levels of a specific functional parameter/phenotype. Extensive microbial community analyses are then performed on these samples or subjects. Finally, analyses are performed to identify associations between the abundance of specific taxa and the levels of the functional parameter/phenotype. In this study we used this experimental approach to identify bacteria and bacterial rRNA genes associated with the development of colitis in IL-10–/– mice. Various levels of colitis were examined by monitoring bacterial populations in 2 different environments, where the disease progression rates were different, and over a 6-month period, throughout the development of colitis. Bacteria and bacterial rRNA genes with both positive and negative associations with colitis were identified. Although such trends can be interpreted in several ways, we suggest that negative associations may represent particularly important trends in inflammatory bowel disease (IBD), because they may facilitate the identification of resident microbiota that are being targeted by aberrant immunological responses.