L-arginine metabolism as pivotal interface of mutual host-microbe interactions in the gut

Abstract

L-arginine (L-arg) is a versatile amino acid and a central intestinal metabolite in mammalian and microbial organisms. Thus, L-arg participates as precursor of multiple metabolic pathways in the regulation of cell division and growth. It also serves as a source of carbon, nitrogen, and energy or as a substrate for protein synthesis. Consequently, L-arg can simultaneously modify mammalian immune functions, intraluminal metabolism, intestinal microbiota, and microbial pathogenesis. While dietary intake, protein turnover or de novo synthesis usually supply L-arg in sufficient amounts, the expression of several key enzymes of L-arg metabolism can change rapidly and dramatically following inflammation, sepsis, or injury. Consequently, the availability of L-arg can be restricted due to increased catabolism, transforming L-arg into an essential amino acid. Here, we review the enzymatic pathways of L-arg metabolism in microbial and mammalian cells and their role in immune function, intraluminal metabolism, colonization resistance, and microbial pathogenesis in the gut.

Keywords: L-arginine (L-arg); colonization resistance; dietary L-arg supplementation; host–microbe interaction; intestinal microbiota; microbial pathogenesis; mucosal immune function; mutual metabolic pathways; virulence factor.

Figure 1.

Anabolic and catabolic pathways of L-arg metabolism in mammalian cells. The key enzymatic pathways for the degradation of L-arg in mammals are Arg1 and Nos2. Both are cytosolic enzymes that utilize L-arg as substrate. While Nos2 catalyzes the formation of NO and citrulline from L-arg, Arg1 converts L-arg into ornithine and urea. Once transported into mitochondria, the ornithine transcarbamylase (Otc) converts ornithine into citrulline. The ornithine aminotransferase (Oat), another mitochondrial enzyme, can build ornithine from glutamate and proline in the gut, whereas in other tissues, conversely, glutamate and proline are the products of this enzymatic reaction. Conversely, the combined action of the cytosolic enzymes argininosuccinate synthetase (Ass) and argininosuccinate lyase (Asl) convert citrulline again into L-arg.

Figure 2.

Anabolic and catabolic pathways of L-arg metabolism in microbial cells.

Figure 3.

Mutual interactions of L-arg with host tissues, intestinal microbiota and pathogens and their consequences for the outcome of infection.

Figure 4.

Effects of L-arg on microbial pathogenesis.

Figure 5.

Effects of L-arg on commensal microbiota, the intestinal epithelium and mucosal immune homeostasis.