Arginase impedes the resolution of colitis by altering the microbiome and metabolome
Julia Baier, Maximilian Gänsbauer, Claudia Giessler, Harald Arnold, Mercedes Muske, Ulrike Schleicher, Sören Lukassen, Arif Ekici, Manfred Rauh, Christoph Daniel, Arndt Hartmann, Benjamin Schmid, Philipp Tripal, Katja Dettmer, Peter J. Oefner, Raja Atreya, Stefan Wirtz, Christian Bogdan, Jochen Mattner
Julia Baier, Maximilian Gänsbauer, Claudia Giessler, Harald Arnold, Mercedes Muske, Ulrike Schleicher, Sören Lukassen, Arif Ekici, Manfred Rauh, Christoph Daniel, Arndt Hartmann, Benjamin Schmid, Philipp Tripal, Katja Dettmer, Peter J. Oefner, Raja Atreya, Stefan Wirtz, Christian Bogdan, Jochen Mattner
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Research Article Gastroenterology Immunology

Arginase impedes the resolution of colitis by altering the microbiome and metabolome

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 colitis than Arg1-expressing (Arg1fl/fl) 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 proresolving 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 WT recipients ameliorated intestinal inflammation, while transfers from WT 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 accounts for the accelerated resolution from colitis in the absence of Arg1. Consequently, l-arginine metabolism may serve as a target for clinical intervention in IBD patients.

Authors

Julia Baier, Maximilian Gänsbauer, Claudia Giessler, Harald Arnold, Mercedes Muske, Ulrike Schleicher, Sören Lukassen, Arif Ekici, Manfred Rauh, Christoph Daniel, Arndt Hartmann, Benjamin Schmid, Philipp Tripal, Katja Dettmer, Peter J. Oefner, Raja Atreya, Stefan Wirtz, Christian Bogdan, Jochen Mattner

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Figure 1

Expression of Arg1 in human IBD and mouse DSS-induced colitis.

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Expression of Arg1 in human IBD and mouse DSS-induced colitis. (A–C) Usi...
(A–C) Using qPCR, Arg1 expression was evaluated in intestinal tissue biopsies from CD and UC patients (A), sigmoid tissue biopsies from UC patients (B), or in IECs or myeloid cells purified from WT mice before and after DSS application (C). The ratio of Arg1 mRNA copies relative to Hprt copies was calculated in the indicated cells and tissues of 14–16 CD and UC patients (A), 4–10 UC patients (B) for each score and 10–16 individual female mice (C). The relative increase in Arg1 copy numbers in tissues of patients for each score and of naive versus DSS-treated WT mice is displayed. Depending on the number of groups and the distribution of data, data were analyzed using 1-way ANOVA followed by Bonferroni’s post hoc test for pairwise comparisons if the former was significant, or for multiple comparisons, the Mann-Whitney U test or the Kruskal-Wallis test followed by Dunn’s post hoc test was used if the former was significant. *P ≤ 0.05; **P < 0.01; ***P < 0.001. Error bars indicate SD of the mean. (D–F) Using confocal laser microscopy, Arg1 expression was determined in mLNs (D) and in total colonic tissue of naive and DSS-treated SPF B6 mice (E and F). Serial sections from mLNs (D) or colonic lesions (E and F) were stained for Arg1 (green), NOS2 (white), CD11b (red), or CD31 (red). Nuclei were stained with DAPI (blue). Scale bars: 100 μm. Original magnification, ×100.