Intestinal transcriptome profiles of ND and WD-fed Tas1r3−/− and Wild Type mice using RNA-seq analysis

ABSTRACT: Purpose: Excessive intake of a western diet (WD), characterized by high fat and sugary drinks, is hypothesized to contribute to the development of inflammatory bowel disease (IBD). Despite the identified clinical association, the molecular mechanisms through which dietary changes lead to IBD development remain unknown. Here, we generated a murine model of severe intestinal inflammation triggered by long-term WD consumption, which exhibited markedly elevated taste receptor TAS1R3 expression in inflamed bowel tissues. Thus, we hypothesized that nutrient-induced TAS1R3 modulation is central to regulating intestinal inflammation. We tested our hypothesis by analyzing changes in gene expression profiles and inflammatory cell infiltration in the inflamed bowel tissues of WD-fed Tas1r3-deficient mice. Methods: We carried out RNA-Seq of ileum tissue of wild-type (WT) and taste receptor Tas1r3 knockout (Tas1r3−/−) mice fed a normal diet (ND) or western diet (WD) for 10 weeks using Ion Proton System. Raw RNA-seq reads were split into individual samples based on barcodes and quality controlled using the FASTQC tool. The reads were analyzed with Partek Flow software (Partek, St. Louis, MI, USA) (http://www.partek.com/partekgs). The sequence reads that passed quality filters were analyzed at the transcript isoform level. Results: We confirmed that Tas1r3-deficient mice are protected from WD-induced intestinal inflammation. Consistent with little or no phenotypic change in the ND group, the gene expression profiles from the ND-fed Tas1r3−/− and WT mice were similar, whereas the ileal transcriptome profiles from the WD-fed Tas1r3−/− mice were readily distinguishable from those of WD-fed WT mice. Inflammatory cytokines such as Tnfα and Il1b were highly expressed in WD-fed WT mice, whereas Pparg, Tjp3, and Defa27 were highly expressed in WD-fed Tas1r3−/− mice. Importantly, we confirmed that the absence of TAS1R3 caused a significant reduction in the inflammatory response-related signaling pathway; GSEA plots also revealed that the mTOR signaling pathway was greatly suppressed. Most notably, the PPAR signaling pathway was significantly affected by TAS1R3 absence. GSEA confirmed that genes associated with the PPAR signaling pathway were significantly enriched in the set of DEGs between Tas1r3−/− and WT mice in the WD groups. Conclusion: Our data suggest that, due to its suppressive action on mTOR, TAS1R3 might function as an important regulator of the PPAR-γ signaling pathway in the intestinal tract.

ORGANISM(S): Mus musculus

PROVIDER: GSE190059 | GEO | 2023/04/19

REPOSITORIES: GEO