title: Tryptophan catabolism restricts IFN-γ-expressing neutrophils and Clostridium difficile immunopathology.
abstract: The interplay between Clostridium difficile and the host's metabolome is believed to influence the severity of infection. However, the mechanism for this phenomenon remains unclear. In this study, we model one of these metabolic pathways by focusing on tryptophan metabolism in the host. We found that inhibition of tryptophan catabolism in IDO1-knockout mice led to increased mucosal destruction, cecal hemorrhage, and increased production of IFN-γ in response to C. difficile infection, but no significant change in mucosal effector or regulatory T cell numbers or IL-10 mRNA expression. The increased immunopathology in infected IDO1-knockout mice was associated with a lower C. difficile burden and an increased percentage of IFN-γ-expressing neutrophils. We further demonstrated the ability of kynurenine to induce apoptosis in bone marrow-derived neutrophils, whereas the presence of tryptophan reversed this effect, providing a possible mechanism for the increased neutrophil accumulation in IDO1(-/-) mice. We conclude that C. difficile induces tryptophan catabolism in cecal lamina propria cells, which restricts C. difficile-associated immunopathology and the accumulation of IFN-γ-expressing neutrophils. This might represent a self-regulatory mechanism for neutrophils, via the IFN-γ-IDO1 pathway, to restrict their own accumulation during infection. These findings have important clinical implications because IDO inhibitors are used to treat cancer in clinical trials (in patients particularly susceptible to getting C. difficile infection), and treatment with IDO1 inhibitors may exacerbate the severity of C. difficile colitis.
authors.affiliation: Department of Internal Medicine-Gastroenterology, University of Michigan, Ann Arbor, MI 48109; mohamade@med.umich.edu jykao@med.umich.edu.
authors.forename: Mohamad
authors.initials: M
authors.lastname: El-Zaatari
authors.affiliation: Department of Internal Medicine-Gastroenterology, University of Michigan, Ann Arbor, MI 48109;
authors.forename: Yu-Ming
authors.initials: YM
authors.lastname: Chang
authors.affiliation: Department of Internal Medicine-Gastroenterology, University of Michigan, Ann Arbor, MI 48109;
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Internal Medicine-Gastroenterology, University of Michigan, Ann Arbor, MI 48109;
authors.forename: Matthew
authors.initials: M
authors.lastname: Franz
authors.affiliation: Department of Internal Medicine-Gastroenterology, University of Michigan, Ann Arbor, MI 48109;
authors.forename: Andrew
authors.initials: A
authors.lastname: Shreiner
authors.affiliation: Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109;
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: McDermott
authors.affiliation: Laboratory of Experimental Intensive Care and Anesthesiology, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands; Department of Respiratory Medicine, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands; and.
authors.forename: Koenraad F
authors.initials: KF
authors.lastname: van der Sluijs
authors.affiliation: Department of Respiratory Medicine, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands; and Department of Experimental Immunology, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands.
authors.forename: René
authors.initials: R
authors.lastname: Lutter
authors.affiliation: Department of Internal Medicine-Gastroenterology, University of Michigan, Ann Arbor, MI 48109;
authors.forename: Helmut
authors.initials: H
authors.lastname: Grasberger
authors.affiliation: Department of Internal Medicine-Gastroenterology, University of Michigan, Ann Arbor, MI 48109;
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Kamada
authors.affiliation: Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109;
authors.forename: Vincent B
authors.initials: VB
authors.lastname: Young
authors.affiliation: Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109;
authors.forename: Gary B
authors.initials: GB
authors.lastname: Huffnagle
authors.affiliation: Department of Internal Medicine-Gastroenterology, University of Michigan, Ann Arbor, MI 48109; mohamade@med.umich.edu jykao@med.umich.edu.
authors.forename: John Y
authors.initials: JY
authors.lastname: Kao
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000276:immunology / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D039481:CD11b Antigen / Q000276:immunology / Q000378:metabolism; D002432:Cecum / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D016360:Clostridioides difficile / Q000276:immunology* / Q000502:physiology; D004761:Enterocolitis, Pseudomembranous / Q000235:genetics / Q000276:immunology* / Q000382:microbiology; D005434:Flow Cytometry; D054884:Host-Pathogen Interactions / Q000276:immunology; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology* / Q000378:metabolism; D007737:Kynurenine / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D018448:Models, Immunological; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism; D014364:Tryptophan / Q000276:immunology* / Q000378:metabolism
chemical_list: D000950:Antigens, Ly; D039481:CD11b Antigen; C583637:IDO1 protein, mouse; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; C480309:Ly6G antigen, mouse; D007737:Kynurenine; D007371:Interferon-gamma; D014364:Tryptophan