Arginase expression impedes the resolution of intestinal inflammation by altering the fecal microbiome and the metabolome

Baier J, Gänsbauer M, Giessler C, Arnold H, Muske M, Schleicher U, Lukassen S, Ekici AB, Rauh M, Daniel C, Hartmann A, Schmid B, Tripal P, Dettmer K, Oefner PJ, Atreya R, Wirtz S, Bogdan C, Mattner J (2020)

Publication Type: Journal article

Publication year: 2020

Journal

Journal of Clinical Investigation American Society for Clinical Investigation

DOI: 10.1172/JCI126923

Abstract

Arginase 1 (Arg1), which converts L-arginine into ornithine and urea, exerts pleiotropic immunoregulatory effects. However, the function of Arg1 in inflammatory bowel disease (IBD) remains poorly characterized. Here, we found that Arg1 expression correlated with the degree of inflammation in intestinal tissues from IBD patients. In mice, Arg1 was upregulated in an IL-4-/IL-13- and intestinal microbiota-dependent manner. Tie2-Cre+/-Arg1fl/fl mice lacking Arg1 in hematopoietic and endothelial cells recovered faster from experimental colitis than Arg1-expressing littermates. This correlated with decreased vessel density, compositional changes in intestinal microbiota, diminished infiltration by myeloid cells and an accumulation of intraluminal polyamines that promote epithelial healing. The pro-resolving effect of Arg1-deletion was reduced by an L-arginine-free diet, but rescued by simultaneous deletion of other L-arginine-metabolizing enzymes such as Arg2 or Nos2, demonstrating that protection from colitis requires L-arginine. Fecal microbiota transfers from Tie2-Cre+/-Arg1fl/fl mice into wild-type recipients ameliorated intestinal inflammation while transfers from wild-type littermates into Arg1-deficient mice prevented an advanced recovery from colitis. Thus, an increased availability of L-arginine as well as altered intestinal microbiota and metabolic products account for the accelerated resolution from colitis in the absence of Arg1. Consequently, the metabolism of L-arginine may serve as target for clinical intervention in IBD patients.

Authors with CRIS profile

Julia Baier Professur für Medizinische Mikrobiologie und Infektionsimmunologie Maximilian Gänsbauer Institute of Microbiology – Clinical Microbiology, Immunology and Hygiene Mercedes Muske Institute of Microbiology – Clinical Microbiology, Immunology and Hygiene Ulrike Schleicher Institute of Microbiology – Clinical Microbiology, Immunology and Hygiene Sören Lukassen Professur für Humangenetik Arif Bülent Ekici Institute of Human Genetics Manfred Rauh Department of Paediatrics and Adolescent Medicine Christoph Daniel Department of Nephropathology Arndt Hartmann Lehrstuhl für Allgemeine Pathologie und Pathologische Anatomie Benjamin Schmid Optical Imaging Center Erlangen (OICE) Philipp Tripal Optical Imaging Center Erlangen (OICE) Raja Atreya Professur für Translationale Immunforschung bei chronisch entzündlichen Darmerkrankungen (Heisenberg-Professur) Stefan Wirtz Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Christian Bogdan Lehrstuhl für Mikrobiologie und Infektionsimmunologie Jochen Mattner Professur für Medizinische Mikrobiologie und Infektionsimmunologie

Involved external institutions

Universität Regensburg DE Germany (DE)

How to cite

APA:

Baier, J., Gänsbauer, M., Giessler, C., Arnold, H., Muske, M., Schleicher, U.,... Mattner, J. (2020). Arginase expression impedes the resolution of intestinal inflammation by altering the fecal microbiome and the metabolome. Journal of Clinical Investigation. https://dx.doi.org/10.1172/JCI126923

MLA:

Baier, Julia, et al. "Arginase expression impedes the resolution of intestinal inflammation by altering the fecal microbiome and the metabolome." Journal of Clinical Investigation (2020).

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