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 remain unclarified. As an important ingredient of UPFs, 7-ketositosterol (KS) is mainly synthesized from high-temperature heating oils. We find that KS intake is higher in IBD patients and related to disease activity. KS exacerbats colitis in a gut microbiota-dependent manner in mice, altering the gut microbiota composition, increasing the abundance of potential pathogenic bacteria, especially Staphylococcus_lentus (SL). Morevoer, SL aggravates DSS-induced colitis. Mechanically, KS up-regulates the expression of PDZ and LIM Domain 3 (PDLIM3). SL-derived lysin motif peptidoglycan-binding domain-containing protein (LPDP) interacts with PDLIM3, and activates p38MAPK/NF-?B signaling pathway. Furthermore, tubuloside B, 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 gut microbiota and PDLIM3 interaction, providing evidence of IBD pathogenesis and potential therapeutic strategy for IBD treatment. Overall design: In KS aggravated DSS-induced colitis model, colonic tissue from mice in DSS group and DSS+KS group was collected, extracted and purified for RNA sequencing, and feces from mice in control group, KS group, DSS group and DSS+KS group was collected for 16s rRNA sequencing.