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-13and intestinal microbiota-dependent manner. Tie2-Cre Arg1 fl/fl mice lacking Arg1 in hematopoietic and endothelial cells recovered faster from colitis than Arg1-expressing (Arg1 fl/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 Arg1 fl/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.

Citrulline supplementation attenuates the development of non-alcoholic steatohepatitis in female mice through mechanisms involving intestinal arginase

“…S4 ). Additionally, arginase activity, shown to be the opponent of inducible nitric oxide synthase (iNOS) but also in recent years discussed to be critical in the development of inflammatory bowel diseases [ 39 , 40 ], was significantly lower in proximal small intestine of FFC-fed mice when compared to FFC + L-Cit-fed animals ( Fig. 4 ).…”

“…Arginase has been shown before to be the counter regulator of nitric oxide synthases, including also iNOS, thereby also regulating the bioavailability of NO [ 61 ]. Also, in recent years, results obtained in humans with inflammatory bowel disease and of rodent models of inflammatory bowel diseases suggest that alterations of intestinal arginase and herein especially arginase 1 found in macrophages and endothelial cells [ 62 ], may be critical in the development of inflammatory alterations in these diseases [ 40 , 63 ]. In the present study, contrasting these findings of others, protein levels of arginase 1 were below the level of detection.…”

Associations of serum short-chain fatty acids with circulating immune cells and serum biomarkers in patients with multiple sclerosis

“…The communication is most likely bidirectional, whereby SCFAs affect not only immune processes but also, immune cells and their mediators regulate the gut microbiota. For example, it has recently been reported that arginase can alter the microbiome 50 . In addition, the gut microbiome can be considered a hub for integrating signals from the immune and other body systems 51 .…”

Control of T-Cell Activation and Signaling by Amino-Acid Catabolizing Enzymes

“…As an illustration of the importance of such metabolism, the levels of AHR ligands produced by the gut microbiota have been recently shown to be reduced in patients with celiac disease (Lamas et al, 2020). Conversely, the activity of host amino-acid catabolizing enzymes can influence the availability of amino acids to the microbiota, with consequences on local inflammation, as shown by the role of host Arg1 on the composition of microbiota and bacterial production of protective polyamines in a mouse model of inflammatory bowel disease (Baier et al, 2020). Thus, the microbiota participates in local immune homeostasis through its amino-acid catabolizing activity and alterations of such activity can lead to immunopathology.…”