Dietary Arginine Regulates Severity of Experimental Colitis and Affects the Colonic Microbiome

Abstract

There is great interest in safe and effective alternative therapies that could benefit patients with inflammatory bowel diseases (IBD). L-arginine (Arg) is a semi-essential amino acid with a variety of physiological effects. In this context, our aim was to investigate the role of dietary Arg in experimental colitis. We used two models of colitis in C57BL/6 mice, the dextran sulfate sodium (DSS) model of injury and repair, and Citrobacter rodentium infection. Animals were given diets containing (1) no Arg (Arg 0 ), 6.4 g/kg (Arg NL ), or 24.6 g/kg Arg (Arg HIGH ); or (2) the amino acids downstream of Arg: 28 g/kg L-ornithine (Orn HIGH ) or 72 g/kg L-proline (Pro HIGH ). Mice with DSS colitis receiving the Arg HIGH diet had increased levels of Arg, Orn, and Pro in the colon and improved body weight loss, colon length shortening, and histological injury compared to Arg NL and Arg 0 diets. Histology was improved in the Arg NL vs. Arg 0 group. Orn HIGH or Pro HIGH diets did not provide protection. Reduction in colitis with Arg HIGH diet also occurred in C. rodentium -infected mice. Diversity of the intestinal microbiota was significantly enhanced in mice on the Arg HIGH diet compared to the Arg NL or Arg 0 diets, with increased abundance of Bacteroidetes and decreased Verrucomicrobia. In conclusion, dietary supplementation of Arg is protective in colitis models. This may occur by restoring overall microbial diversity and Bacteroidetes prevalence. Our data provide a rationale for Arg as an adjunctive therapy in IBD.

l -Arginine sensing regulates virulence gene expression and disease progression in enteric pathogens

“…Our studies investigated the role of dietary arginine in the peak of C. rodentium infection in a susceptible murine strain. However, a previous report suggested that supplementation of arginine in the diet decreased pathogen burden, in a less susceptible murine strain at a later time point, close to the resolution of the disease (30). Interestingly, in both our and the previous studies the levels of arginine in the colon remained the same regardless of its presence or concentration in the diet (SI Appendix, Fig.…”

“…Interestingly, in both our and the previous studies the levels of arginine in the colon remained the same regardless of its presence or concentration in the diet (SI Appendix, Fig. S7) (30). However, arginine dietary differences impacted the levels of this amino acid in the serum under homeostasis, and its levels were enhanced in both the colon and serum upon the onset of inflammation due to dextran sulfate sodium treatment (30).…”

“…S7) (30). However, arginine dietary differences impacted the levels of this amino acid in the serum under homeostasis, and its levels were enhanced in both the colon and serum upon the onset of inflammation due to dextran sulfate sodium treatment (30). The combination of these studies suggests that arginine orchestrate a complex interaction between pathogen and host responses, and arginine dietary supplementation to enhance gut health grants further research.…”

Transcriptional and Metabolomic Analysis of L-Arginine/Nitric Oxide Pathway in Inflammatory Bowel Disease and Its Association with Local Inflammatory and Angiogenic Response: Preliminary Findings

“…Correspondingly, its high intake has been linked with restored microbial diversity in the gut, specifically, with an increased prevalence of Bacteroidetes. Consequently, arginine supplementation has led to improved histology and reduced bowel shortening while supplementation with proline or ornithine, amino acids downstream of arginine, had no effect [57].…”

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

“…Enzymatic consumption of l-arginine promotes colitis. Recently, oral l-arginine supplementation of DSS-treated mice was found to improve the course of colitis (59,60) and to enhance intraluminal and systemic polyamine concentrations (61). Here, we tested to determine whether dietary l-arginine restriction reversed the improved outcome of DSS-induced colitis in Tie2-Cre Arg1 fl/fl mice.…”