Tryptophan metabolism and AhR activation are associated with fecal water-induced DNA damage in patients with inflammatory bowel disease

Inflammatory bowel disease (IBD) is associated with alterations in the intestinal luminal environment that may modify the composition of fecal water (FW) and its capacity to induce DNA damage. The aim of this study was to identify FW metabolites associated with DNA damage and aryl hydrocarbon receptor (AhR) activity and to investigate whether shared metabolic pathways may link these responses in patients with IBD. FW samples from 80 IBD patients and 20 healthy controls were analyzed. DNA damage in Caco-2 cells following FW exposure was assessed using the comet assay, AhR activity using the ethoxyresorufin-O-deethylase (EROD) assay, and FW metabolites by using liquid chromatography-mass spectrometry. Metabolite signatures associated with DNA damage and AhR activity were identified separately, and subsequent pathway analysis revealed overlapping metabolic pathways, prompting further investigation of AhR-associated tryptophan metabolites. Kynurenine was inversely associated with AhR activity but positively associated with DNA damage in IBD, whereas serotonin was positively related to AhR activity and was protective against FW-induced DNA damage. Indoles did not significantly contribute to FW-induced DNA damage. These findings suggest that inflammation-associated alterations in tryptophan metabolism are associated with altered AhR signaling and epithelial DNA damage in IBD.