Exploring the landscape of preclinical mouse intestinal inflammation models through meta-analysis of transcriptomic data

Inflammatory bowel diseases (IBD) are a group of intestinal disorders that are diagnosed in millions of people every year. One of the most widely used model systems in IBD research is the mouse as it reflects many symptoms and features of human IBD. The strategies employed to induce intestinal inflammation can be classified according to the insult employed against the intestinal tissue, categorizing them in barrier damage, immune stimulation, and infection models. To this day, no study has performed comprehensive comparative analyses of these mouse models. In this thesis, the transcriptomes of 13 selected IBD models were sequenced and processed for analysis to characterize the specific and common expression changes observed in each model. For the transcriptomic analyses, this thesis describes the development of a pipeline for transcriptome processing and a web-based platform to explore the dataset of mouse intestinal inflammation models. Using different comparative statistical analyses, it was possible to establish similarities and differences between the different mouse models. The alterations observed in the tissue composition revealed common features related to the loss of epithelial cells, increments in the immune cell populations, and changes in minor cell types. Shared gene groups further revealed an up-regulated genetic signature composed of immune and inflammation-related processes and a down-regulated signature that included selected metabolic processes. More complex clustering techniques revealed co-expression modules covering multiple processes related to immune regulation, carboxylic acid metabolism, and angiogenesis, among other relevant ontologies. Selected processes related to inflammation correlated well between mouse intestinal inflammation models and human IBD cohorts. Translating the mouse model features into single-cell experiments revealed the cells responsible for particular changes in immune regulation, metabolic alterations, and other processes. In summary, this thesis explored common and exclusive features in the mouse models, revealing core processes relevant to intestinal inflammation. Therefore, the findings of this thesis support the current concept of IBD as a group of diseases with common clinical features and a multi-factorial origin.