Ultra-processed foods sourced 7-ketositosterol aggravates colitis through gut dysbiosis induced-PDLIM3 activation

Excessive ultra-processed foods (UPFs) consumption has been reported to increase the risk of inflammatory bowel disease (IBD). However, the specific mechanisms involved remain unclear. As an important ingredient of UPFs, 7-ketositosterol (KS) is synthesized mainly from high-temperature heated oils. We found that KS intake is higher in IBD patients and is related to disease activity. KS exacerbates colitis in a gut microbiota-dependent manner in mice, altering the gut microbiota composition and increasing the abundance of potential pathogenic bacteria, especially <i>Staphylococcus lentus</i> (SL). Moreover, SL aggravates DSS-induced colitis. Mechanically, KS upregulates the expression of PDZ and LIM domain 3 (PDLIM3). SL-derived lysin motif peptidoglycan-binding domain-containing protein (LPDP) interacts with PDLIM3 and activates the p38MAPK/NF-κB signaling pathway. Furthermore, tubuloside B, which is selected by high-throughput screening, blocks the interaction of PDLIM3 and LPDP, and ameliorates SL-aggravated colitis. Our study reveals that KS exposure promotes colitis via the gut microbiota and PDLIM3 interaction, providing evidence of IBD pathogenesis and a potential therapeutic strategy for IBD treatment.