A NOVEL ORALLY ACTIVE METABOLITE REVERSES CROHN'S DISEASE-ASSOCIATED INTESTINAL FIBROSIS

Intestinal fibrosis is a debilitating complication of Crohn’s disease (CD) patients. Our groups and others discovered that intestinal metabolites are associated with fibrosis. We selected the most relevant determined their anti-fibrogenic efficacies in three mouse models compared metabolite profiles between non-IBD, stricturing CD, non-stricturing CD patients inflammatory bowel (IBD) multi-omics database to identify stricture-related metabolites. fecal trinitrobenzene sulfonic acid (TNBS)-treated mice without drug CSA13 treatment fibrosis-related Compared non-IBD patients, had reduced levels hydrocinnamate (H), inosine (I), taurine (T), tauroursodeoxycholate (TUDCA), sphingosine (S). Oral increased (I) (S) TNBS-treated mice. Overall activity (ODA) comprehensive assessment histology scores mRNA expression inflammation markers. Sphingosine (10mg/kg/day for 7-14 days via oral gavages) showed best effects against spontaneous ileal 42-week-old SAMP1/YitFc (11% ODA), cecal Salmonella-infected (10% colonic (9% ODA). The other four were ineffective reversing (10 microM), but not metabolites, directly inhibited collagen human CCD-18Co fibroblasts primary from (CD-HIF). RNA-seq proteomics identified low MAPK3 high ZEB1 intestines activated ERK1/2 phosphorylation TGF-b1-induced fibroblasts. sphingosine-mediated inhibition synthesis was reversed by inhibitor PD98059 overexpression. effect TNBS model Zeb1 Stricturing have higher circulating granulocyte-colony stimulating factor (G-CSF) than Csf3 promoted CD-HIF, while diminished G-CSF secretion peripheral blood mononuclear cells (PBMCs). also exerts potent modulating ERK1/2, ZEB1, expression.