Microbiota-driven arginase 1 expression impedes the resolution of intestinal inflammation

Arginase 1 (Arg1), which converts L-arginine into ornithine and urea, exerts pleiotropic immunoregulatory effects. Patients with inflammatory bowel disease (IBD) show an enhanced expression and activity of Arg1 in the intestinal (sub-)mucosa, but the function of Arg1 in IBD remains poorly characterized. Here, we found that Arg1 expression correlates with the degree of inflammation in colitic tissues of IBD patients. In mice with - experimental colitis 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 littermates. This correlated with decreased vessel density, compositional changes in the intestinal microbiota, diminished infiltration by myeloid cellsand an accumulation of intraluminal polyamines that are associated with epithelial healing. Dietary L-arginine restriction abolished the protective effect of Arg1-deletion, suggesting that protection is related to an increased availability of L-arginine. Fecal microbiota transfers from Tie2-Cre+/-Arg1fl/fl mice into wildtype recipients restored the protective, anti-inflammatory phenotype while transfers from wildtype littermates into Arg1-deficient mice prevented the accelerated recovery from colitis. Thus, altered intestinal microbiota and metabolic products in Tie2-Cre+/-Arg1fl/fl mice account for the accelerated resolution from colitis in the absence of Arg1. Subsequently, L-arginine serves as novel therapeutic and diagnostic target for clinical intervention in IBD patients. Overall design: Total RNA from 8 mice (4 conditional Arg1-ko and 4 wildtype littermates) was analyzed by RNA-Seq to identify differences in gene expression between the two groups.