TY - JOUR
T1 - Epithelial Indoleamine 2,3-Dioxygenase 1 Modulates Aryl Hydrocarbon Receptor and Notch Signaling to Increase Differentiation of Secretory Cells and Alter Mucus-Associated Microbiota
AU - Alvarado, David M.
AU - Chen, Baosheng
AU - Iticovici, Micah
AU - Thaker, Ameet I.
AU - Dai, Nattalie
AU - VanDussen, Kelli L.
AU - Shaikh, Nurmohammad
AU - Lim, Chai K.
AU - Guillemin, Gilles J.
AU - Tarr, Phillip I.
AU - Ciorba, Matthew A.
N1 - Funding Information:
Funding This study was supported by grants DK077653 (PIT and DMA), DK109384 (MAC), DK109081 (KLV), Mucosal Immunology Studies Team Young Investigator Award (MAC), Crohn's and Colitis Foundation Daniel H Present Senior Research Award (ref 370763 to MAC), and philanthropic support from the Givin’ it all for Guts Foundation ( https://givinitallforguts.org/ , MAC) and the Lawrence C. Pakula MD IBD Research, Innovation, and Education Fund (MAC and DMA). Histology services were provided by the Washington University Digestive Disease Research Core Center and supported by grant P30DK052574 . Slide imaging was supported by Shared Instrumentation Grant NCRR 1S10RR027552 .
Funding Information:
Funding This study was supported by grants DK077653 (PIT and DMA), DK109384 (MAC), DK109081 (KLV), Mucosal Immunology Studies Team Young Investigator Award (MAC), Crohn's and Colitis Foundation Daniel H Present Senior Research Award (ref 370763 to MAC), and philanthropic support from the Givin? it all for Guts Foundation (https://givinitallforguts.org/, MAC) and the Lawrence C. Pakula MD IBD Research, Innovation, and Education Fund (MAC and DMA). Histology services were provided by the Washington University Digestive Disease Research Core Center and supported by grant P30DK052574. Slide imaging was supported by Shared Instrumentation Grant NCRR 1S10RR027552. Conflicts of interest These authors disclose the following: Phillip I. Tarr 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. Matthew A. Ciorba received investigator-initiated research funding from Incyte Corporation, maker of Epacadostat, an IDO1 inhibitor in clinical trials. The remaining authors disclose no conflicts.
Funding Information:
Conflicts of interest These authors disclose the following: Phillip I. Tarr 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. Matthew A. Ciorba received investigator-initiated research funding from Incyte Corporation, maker of Epacadostat, an IDO1 inhibitor in clinical trials. The remaining authors disclose no conflicts.
Publisher Copyright:
© 2019 AGA Institute
PY - 2019/10
Y1 - 2019/10
N2 - 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.
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.
KW - Kynurenine
KW - Metabolism
KW - Microbiome
KW - Organoids
KW - Ulcerative Colitis
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U2 - 10.1053/j.gastro.2019.07.013
DO - 10.1053/j.gastro.2019.07.013
M3 - Article
C2 - 31325428
AN - SCOPUS:85072546855
SN - 0016-5085
VL - 157
SP - 1093-1108.e11
JO - Gastroenterology
JF - Gastroenterology
IS - 4
ER -