<p>Intestinal stem cell number or their regeneration ability is crucial for attaining mucosal healing. Deciphering the molecular mechanisms responsible for the impairment of intestinal stem cells in inflammatory bowel disease could yield innovative therapeutic insights. Altered bile acid metabolism is a hallmark feature of inflammatory bowel disease, typically characterized by elevated fecal levels of primary bile acids, such as glycocholic acid. However, the relationship between glycocholic acid and inflammatory bowel disease remains unclear. Here, we report that glycocholic acid accelerates inflammatory bowel disease progression through downregulating TRIB3 expression to disrupt intestinal stem cells self-renewal. TRIB3 is highly expressed in crypt cells and sustains intestinal epithelial stemness by preventing ID1 palmitoylation and AP3D1-mediated lysosomal degradation. Glycocholic acid is found to suppress TRIB3-ID1 axis, thereby compromising intestinal epithelium integrity. Notably, we identify Bergenin, a natural compound, as a potential therapeutic agent against inflammatory bowel disease via upregulating TRIB3. These findings highlight the TRIB3-ID1 axis as a promising therapeutic target for inflammatory bowel disease therapy.</p>