PMID- 31325428 OWN - NLM STAT- MEDLINE DCOM- 20191022 LR - 20211108 IS - 1528-0012 (Electronic) IS - 0016-5085 (Print) IS - 0016-5085 (Linking) VI - 157 IP - 4 DP - 2019 Oct TI - Epithelial Indoleamine 2,3-Dioxygenase 1 Modulates Aryl Hydrocarbon Receptor and Notch Signaling to Increase Differentiation of Secretory Cells and Alter Mucus-Associated Microbiota. PG - 1093-1108.e11 LID - S0016-5085(19)41094-9 [pii] LID - 10.1053/j.gastro.2019.07.013 [doi] AB - BACKGROUND & AIMS: Inflammation, injury, and infection up-regulate 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 (knockout mice), and IDO1-TG and analyzed them for stem cell and differentiation markers by real-time polymerase chain reaction, immunoblotting, and immunofluorescence. Some mice were gavaged with enteropathogenic Escherichia coli (E2348/69) to induce infectious ileitis, and ileum contents were quantified by polymerase chain reaction. 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 data sets 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 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 = .03) when challenged with enteropathogenic E coli, and were protected from immune infiltration, crypt dropout, 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 aryl hydrocarbon receptor, 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. CI - Copyright (c) 2019 AGA Institute. Published by Elsevier Inc. All rights reserved. FAU - Alvarado, David M AU - Alvarado DM AD - Division of Gastroenterology, Washington University in St Louis School of Medicine, St Louis, Missouri. FAU - Chen, Baosheng AU - Chen B AD - Division of Gastroenterology, Washington University in St Louis School of Medicine, St Louis, Missouri. FAU - Iticovici, Micah AU - Iticovici M AD - Division of Gastroenterology, Washington University in St Louis School of Medicine, St Louis, Missouri. FAU - Thaker, Ameet I AU - Thaker AI AD - Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas. FAU - Dai, Nattalie AU - Dai N AD - Washington University in St Louis, St Louis, Missouri. FAU - VanDussen, Kelli L AU - VanDussen KL AD - Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, Missouri. FAU - Shaikh, Nurmohammad AU - Shaikh N AD - Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Washington University in St Louis School of Medicine, St Louis, Missouri. FAU - Lim, Chai K AU - Lim CK AD - Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Australia. FAU - Guillemin, Gilles J AU - Guillemin GJ AD - Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Australia. FAU - Tarr, Phillip I AU - Tarr PI AD - Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Washington University in St Louis School of Medicine, St Louis, Missouri. FAU - Ciorba, Matthew A AU - Ciorba MA AD - Division of Gastroenterology, Washington University in St Louis School of Medicine, St Louis, Missouri. Electronic address: mciorba@wustl.edu. LA - eng GR - T32 DK077653/DK/NIDDK NIH HHS/United States GR - S10 RR027552/RR/NCRR NIH HHS/United States GR - K01 DK109081/DK/NIDDK NIH HHS/United States GR - P30 DK052574/DK/NIDDK NIH HHS/United States GR - R01 DK109384/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20190717 PL - United States TA - Gastroenterology JT - Gastroenterology JID - 0374630 RN - 0 (AHR protein, human) RN - 0 (Ahr protein, mouse) RN - 0 (Basic Helix-Loop-Helix Transcription Factors) RN - 0 (IDO1 protein, human) RN - 0 (IDO1 protein, mouse) RN - 0 (Indoleamine-Pyrrole 2,3,-Dioxygenase) RN - 0 (Receptors, Aryl Hydrocarbon) RN - 0 (Receptors, Notch) SB - IM MH - Animals MH - Bacteria/*metabolism MH - Basic Helix-Loop-Helix Transcription Factors/genetics/*metabolism MH - Case-Control Studies MH - *Cell Differentiation MH - Cell Line MH - Cell Lineage MH - Disease Models, Animal MH - Epithelial Cells/enzymology/microbiology/pathology MH - *Gastrointestinal Microbiome MH - Genotype MH - Humans MH - Indoleamine-Pyrrole 2,3,-Dioxygenase/deficiency/genetics/*metabolism MH - Inflammatory Bowel Diseases/*enzymology/genetics/*microbiology/pathology MH - Intestinal Mucosa/*enzymology/*microbiology/pathology MH - Mice, Knockout MH - Phenotype MH - Receptors, Aryl Hydrocarbon/genetics/*metabolism MH - Receptors, Notch/genetics/*metabolism MH - Secretory Pathway MH - Signal Transduction MH - Stem Cells/enzymology/microbiology/pathology PMC - PMC6756966 MID - NIHMS1534609 OTO - NOTNLM OT - Kynurenine OT - Metabolism OT - Microbiome OT - Organoids OT - Ulcerative Colitis COIS- Conflict of Interest: DMA: No conflicts to disclose. BC: No conflicts to disclose. MI: No conflicts to disclose. AT: No conflicts to disclose. ND: No conflicts to disclose. KLV: No conflicts to disclose. NS, No conflicts to disclose. CKL: No conflicts to disclose. GJG: No conflicts to disclose. PIT: Serves as a consultant to, a member of the Scientific Advisory Board of, and a holder of equity in MediBeacon, a company that is developing technology to detect intestinal permeability and is the potential recipient of royalty payments from this technology. He is also a consultant to Takeda Pharmaceuticals. MAC: received investigator-initiated research funding from Incyte Corporation, maker of Epacadostat, an IDO1 inhibitor in clinical trials. EDAT- 2019/07/22 06:00 MHDA- 2019/10/23 06:00 PMCR- 2020/10/01 CRDT- 2019/07/21 06:00 PHST- 2018/08/17 00:00 [received] PHST- 2019/06/07 00:00 [revised] PHST- 2019/07/01 00:00 [accepted] PHST- 2019/07/22 06:00 [pubmed] PHST- 2019/10/23 06:00 [medline] PHST- 2019/07/21 06:00 [entrez] PHST- 2020/10/01 00:00 [pmc-release] AID - S0016-5085(19)41094-9 [pii] AID - 10.1053/j.gastro.2019.07.013 [doi] PST - ppublish SO - Gastroenterology. 2019 Oct;157(4):1093-1108.e11. doi: 10.1053/j.gastro.2019.07.013. Epub 2019 Jul 17.