METABOLOMICS ANALYSIS IDENTIFIED AN ORALLY ACTIVE METABOLITE FOR TREATING CROHN’S DISEASE-ASSOCIATED INTESTINAL FIBROSIS

Abstract BACKGROUND Intestinal fibrosis is a debilitating complication of Crohn’s disease (CD) patients. Surgical resection used to treat intestinal strictures, but this approach may adversely affect the patients' quality life. Based on findings our groups and others, we hypothesize that metabolites are associated with fibrosis. We aimed discover novel anti-fibrogenic metabolites. METHODS compared metabolite profiles between non-IBD, stricturing CD, non-stricturing CD patients in an inflammatory bowel (IBD) multi-omics database identify stricture-related fecal trinitrobenzene sulfonic acid (TNBS)-treated mice without CSA13 treatment mouse fibrosis-related RESULTS Compared non-IBD patients, had reduced levels inosine. normal mice, TNBS-treated CSA13-exposed increased inosine levels. Oral administration (10 mg/kg/day for 14 days) effectively ileal fibrotic 40-week-old SAMP1/YitFc 96-100% reduction collagen mRNA expression 87% overall activity. Although did not directly inhibit primary human fibroblasts from (CD-HIF), it fresh tissues RNA-seq proteomics identified peroxiredoxin 2 (PRDX2) negatively strictures PRDX2 thiol-specific antioxidant gene reduces peroxides alcohols. Inosine secretion epithelial cells (HPEC). The inosine-mediated was inhibited by pretreatment adenosine 2A receptor (A2AR) inhibitor ZM241385. cell stress, induced stress-related protein (cyclooxygenase 2/COX-2), CD-HIF. Inhibition COX2 indomethacin reversed effect caused Lentiviral overexpression Prdx2 ameliorated mice. Fibrotic circulating free thiol, reflecting systemic oxidative stress. restored thiol CONCLUSIONS orally active promotes cells. newly protein, which reducing