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Summary
Inflammatory gut disorders, including inflammatory bowel disease (IBD), can be impacted by dietary, environmental and genetic factors. While the incidence of IBD is increasing worldwide, we still lack a complete understanding of the gene-by-environment interactions underlying inflammation and IBD. Here, we profiled the colon transcriptome of 52 BXD mouse strains fed with a chow or high-fat diet (HFD) and identified a subset of BXD strains that exhibit an IBD-like transcriptome signature on HFD, indicating that an interplay of genetics and diet can significantly affect intestinal inflammation. Using gene co-expression analyses, we identified modules that are enriched for IBD-dysregulated genes and found that these IBD-related modules share cis-regulatory elements that are responsive to the STAT2, SMAD3, and REL transcription factors. We used module quantitative trait locus (ModQTL) analyses to identify genetic loci associated with the expression of these modules. Through a prioritization scheme involving systems genetics in the mouse and integration with external human datasets, we identified Muc4 and Epha6 as the top candidates mediating differences in HFD-driven intestinal inflammation. This work provides insights into the contribution of genetics and diet to IBD risk and identifies two candidate genes, MUC4 and EPHA6, that may mediate IBD susceptibility in humans.
Experiment design
At 29 weeks of age, mice of 52 BXD strains including parental C57BL/6J and DBA/2J strains were fasted overday and then were sacrificed. Phenotyping were performed and multi-organ were flash-frozen and bio-banked for future use, the assoiacted datasets are mentioned in the paper. In this study, proximal colon samples were collected and immediately frozen in liquid nitrogen for RNA extraction and RNEasy cleanup. Each dietary and strain cohort consisted of ~5 animals which were prepared independently then pooled evenly by µg RNA before the Affymetrix arrays were run.
Contributors
Citation
- Li X, Morel JD, Benegiamo G, Poisson J et al. Genetic and dietary modulators of the inflammatory response in the gastrointestinal tract of the BXD mouse genetic reference population. Elife 2023 Oct 19;12. PMID: 37855835