Integrated Multi-Omics Analysis Reveals the Mechanisms of Intestinal Cell Injury Under Different Levels of Heat Stress

Given the escalating global temperatures and the consequent exacerbation of heat stress, dietary interventions have emerged as a promising therapeutic strategy. The gastrointestinal tract, being exquisitely sensitive to thermal challenges, revealing the underlying mechanisms of intestinal cell injury under high temperature, is essential for developing strategies to prevent heat stress. Here, we integrated metabolomic and transcriptomic analyses to investigate the metabolic and genetic changes in murine intestinal cells in response to different levels of heat stress. The results identified the PI3k-Akt-FoxO pathway as the major heat stress regulatory pathway Kin MODE-K cells. The possible regulatory mechanism is to reduce the expression of the <i>FoxO</i> gene through the downstream phosphorylation of PI3K under the stimulation of growth factors such as INS, IGF1 and TGF-β. Then, through acetylation modification, it regulates the expression of the <i>Gadd45</i> gene, promotes the expression of <i>p19</i> and <i>BNIP3</i> genes, and inhibits the expression of the <i>ATG8</i> gene, thus inducing apoptosis to remove cells that cannot be repaired. It also promotes <i>cyclinB</i>, <i>PLK</i>, and Bcl-6 gene expression in cells surrounding apoptotic cells to inhibit apoptosis. It promotes the expression of RAG1/2 to enhance cellular immunity and regulates the <i>G6pc</i> gene to maintain the homeostasis of glycogen metabolism and glucose under heat stress. Our findings provide a basis for the regulation of intestinal cell damage due to heat stress through dietary interventions.