P0008The role and preliminary mechanism of erythritol in acute DSS-induced colitis and depressive behaviors in mice

Background Studies demonstrate ultra-processed food (UPF) links to higher risk of inflammatory bowel disease (IBD). Erythritol (ERY), a widely used non-nutritive sweetener (NNS) and key component of UPF, has an incompletely elucidated impact on colitis. This study investigated NNS intake in IBD patients and ERY’s role/mechanism in DSS-induced colitis and anxiety-depressive behaviors in mice. Methods IBD patients and healthy controls completed a food frequency questionnaire. Differences in UPF weight, energy, energy ratio, NNS-containing UPF types, total UPF types, and NNS-containing UPF type ratio were analyzed across groups. Five-week-old male C57BL/6 mice were randomly divided into 4 groups (Control, ERY, DSS, ERY+DSS) and fed for 4 weeks. On week 4, DSS and ERY+DSS groups received 2.5% DSS solution for 7 days to induce acute colitis. On days 5-7 of DSS induction, elevated plus maze, open field test, and tail suspension test were conducted respectively. 16S rRNA sequencing analyzed cecal microbiota composition; untargeted metabolomics detected colonic fecal metabolite changes; transcriptome sequencing analyzed intestinal mucosal gene expression. Results A total of 35 UC patients, 50 CD patients, and 99 healthy controls with valid questionnaires were included. UPF weight and energy showed a trend of CD > UC > healthy controls. NNS-containing UPF type ratio was higher in IBD patients than healthy controls, with a significant increase in UC patients (P < 0.05). Active IBD patients had higher NNS-containing UPF type ratio than those in remission (P = 0.05). ERY exacerbated DSS-induced acute colitis in mice, evidenced by more severe weight loss and higher DAI scores. 16S rRNA sequencing showed significantly increased abundances of Adlercreutzia muris and Alistipes sp. CHKCI003 in ERY+DSS vs. DSS group. Metabolomics indicated significant downregulation of tryptophan metabolism in ERY+DSS vs. DSS group. ERY+DSS mice had longer immobility time in tail suspension test vs. DSS group (P < 0.05), suggesting worsened depressive behaviors. Correlation analysis showed 5 differential metabolites (significantly downregulated in tryptophan pathway) had a negative trend with tail suspension test immobility time and a significant negative correlation with increased Alistipes sp. CHKCI003 (P < 0.05). Transcriptome analysis revealed significant upregulation of ferroptosis pathway and Atf4/Chac1 gene expression in ERY+DSS vs. DSS group. ERY may promote ferroptosis via ATF4/CHAC1 pathway, exacerbating acute DSS-induced colitis. Conclusion IBD patients may consume more NNS-containing UPF in China. ERY exacerbates colitis and depressive behaviors in mice by upregulating ferroptosis pathway, altering intestinal microbiota, and downregulating tryptophan metabolism. Conflict of interest: Dr. Liu, Yingying: No conflict of interest Ling, Liu: No conflict of interest Tian, He: No conflict of interest Wei, Lv: No conflict of interest Wenle, Liu: No conflict of interest Linglong, Ji: No conflict of interest