Epithelial IDO1 Modulates AHR and Notch Signaling to Increase Differentiation of Secretory Cells and Alter Mucus-Associated Microbiota.
Gastroenterology. 2019 Jul 13;:
Authors: Alvarado DM, Chen B, Iticovici M, Thaker AI, Dai N, VanDussen KL, Shaikh N, Lim CK, Guillemin GJ, Tarr PI, Ciorba MA
BACKGROUND & AIMS: Inflammation, injury, and infection upregulate expression of the tryptophan metabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) in the intestinal epithelium. We studied the effects of cell-specific IDO1 expression in the epithelium at baseline and during intestinal inflammation in mice.
METHODS: We generated transgenic mice that overexpress fluorescence-tagged IDO1 in the intestinal epithelium under control of the villin promoter (IDO1-TG). We generated intestinal epithelial spheroids from mice with full-length Ido1 (controls), disruption of Ido1 (KO mice), and IDO1-TG and analyzed them for stem cell and differentiation markers by real-time PCR, immunoblotting, and immunofluorescence. Some mice were gavaged with enteropathogenic Escherichia coli (E2348/69) to induce infectious ileitis, and ileum contents were quantified by PCR. Separate sets of mice were given dextran sodium sulfate or 2,4,6-trinitrobenzenesulfonic acid to induce colitis; intestinal tissues were analyzed by histology. We utilized published datasets GSE75214 and GDS2642 of RNA expression data from ilea of healthy individuals undergoing screening colonoscopies (controls) and patients with Crohn’s disease.
RESULTS: Histologic analysis of small intestine tissues from IDO1-TG mice revealed increases in secretory cells. Enteroids derived from IDO1-TG intestine had increased markers of stem, goblet, Paneth, enteroendocrine, and tuft cells, compared with control enteroids, with a concomitant decrease in markers of absorptive cells. IDO1 interacted non-enzymatically with the aryl hydrocarbon receptor (AHR) to inhibit activation of Notch1. Intestinal mucus layers from IDO1-TG mice were 2-fold thicker than mucus layers from control mice, with increased proportions of Akkermansia muciniphila and Mucispirillum schaedleri. Compared to controls, IDO1-TG mice demonstrated an 85% reduction in ileal bacteria (P=0.03) when challenged with enteropathogenic Escherichia coli, and were protected from immune infiltration, crypt drop-out, and ulcers following administration of dextran sodium sulfate or 2,4,6-trinitrobenzenesulfonic acid. In ilea of Crohn’s disease patients, increased expression of IDO1 correlated with increased levels of MUC2, LYZ1 and AHR but reduced levels of SLC2A5.
CONCLUSIONS: In mice, expression of IDO1 in the intestinal epithelial promotes secretory cell differentiation and mucus production; levels of IDO1 are positively correlated with secretory cell markers in ilea of healthy individuals and Crohn’s disease patients. We propose that IDO1 contributes to intestinal homeostasis.
PMID: 31325428 [PubMed – as supplied by publisher]