IDDF2024-ABS-0193 Nobiletin attenuates ulcerative colitis via targeting HIF-1α to modulate gut microbiota and inhibit ferroptosis

<h3>Background</h3> Ulcerative colitis (UC) is a chronic inflammatory bowel disease that is closely linked to imbalances in gut microbiota and dysfunction of the intestinal mucosal barrier. Currently, there is no known cure for UC, both domestically and internationally. Nobiletin (NBT), a natural flavonoid found in citrus peels, is known for its antioxidant properties and potential anti-inflammatory and anti-cancer effects. However, its effects on UC have not been studied. <h3>Methods</h3> The DSS-induced mice model and LPS-induced IEC6 cell model were evaluated for the efficacy of NBT. In addition, metabolomics profiles and 16S rRNA analysis were used to explore the effective mechanisms of NBT. <h3>Results</h3> Experiments conducted in both laboratory settings and living organisms have shown that NBT can help alleviate ulcerative colitis by inhibiting a process called ferroptosis. Analysis of gene activity indicated that this inhibition of ferroptosis is linked to the regulation of glutathione metabolism. A test called cellular thermal shift assay confirmed that NBT targets a protein called HIF-1α to alleviate ulcerative colitis. Additionally, NBT was found to influence the composition of gut bacteria in mice, with non-targeted metabolomics revealing that it affects fatty acid metabolism, which is linked to the metabolism of gut bacteria. Specifically, the abundance of beneficial bacteria such as <i>Bifidobacterium</i> and <i>Lactobacillus</i> increased, while harmful bacteria like <i>Bacteroides</i> decreased after NBT treatment, leading to a more balanced gut microbiota. (IDDF2024-ABS-0193 Figure 1) <h3>Conclusion</h3> Our study initially verifies that NBT effectively combats UC by focusing on HIF-1α to regulate the gut microbiota, preventing ferroptosis in the colon and repairing the intestinal barrier.