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Comparative Study
. 2010 Jan;16(1):105-11.
doi: 10.1002/ibd.21035.

Increased serum levels of L-arginine in ulcerative colitis and correlation with disease severity

Shih-Kuang S Hong  1 , Brad E Maltz, Lori A Coburn, James C Slaughter, Rupesh Chaturvedi, David A Schwartz, Keith T Wilson
Affiliations
Comparative Study

Increased serum levels of L-arginine in ulcerative colitis and correlation with disease severity

Shih-Kuang S Hong et al. Inflamm Bowel Dis. 2010 Jan.

Abstract

Background: L-arginine (L-Arg) is a semi-essential amino acid that is the substrate for both nitric oxide and polyamine synthesis. Cellular uptake of L-Arg is an active transport process that is subject to competitive inhibition by L-ornithine (L-Orn) and L-lysine (L-Lys). We investigated L-Arg utilization in patients with ulcerative colitis (UC).

Methods: Serum was collected from 14 normal controls and 22 UC patients with pancolitis of moderate or severe activity by histopathology score. The Mayo Disease Activity Index (DAI) and endoscopy subscore were assessed. Serum amino acid levels were measured by high-performance liquid chromatography. Arginine availability index (AAI) was defined as [L-Arg]/([L-Orn] + [L-Lys]).

Results: Serum L-Arg levels were significantly associated with histopathologic grade (P = 0.001). L-Arg levels were increased in subjects with severe colitis when compared to those with moderate colitis or normal mucosa. L-Orn + L-Lys levels were also increased in severe colitis, so that AAI was not significantly increased. L-Arg levels were also strongly associated with the endoscopy subscore (P < 0.001). There was a strong correlation between DAI and L-Arg levels (r = 0.656, P < 0.001).

Conclusions: Serum L-Arg levels correlate with UC disease severity but availability is not increased due to competitive inhibition by L-Orn and L-Lys. Our findings suggest that L-Arg uptake by cells in the inflamed colon is defective, which may contribute to the pathogenesis of UC. Studies delineating the mechanism of uptake inhibition could enhance our understanding of UC or lead to novel treatment options.

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Figures

Figure 1
Figure 1
Serum concentrations of L-Arg in human subjects with normal mucosa and UC. Individual values for different patients are shown. For each group, the heavy solid line represents the mean and the error bars are the SEM. Serum L-Arg concentration was significantly increased in subjects with severe colitis when compared to those with moderate colitis (P = 0.006) or normal mucosa (P = 0.001).
Figure 2
Figure 2
Serum concentrations of L-Orn + L-Lys in human subjects with normal mucosa and UC. Individual values for different patients are shown. For each group, the heavy solid line represents the mean and the error bars are the SEM. Serum [L-Orn+L-Lys] was increased in subjects with severe colitis when compared to those with moderate colitis (P = 0.03).
Figure 3
Figure 3
Serum L-Arg levels plotted versus endoscopy score. For each group, the heavy solid line represents the mean and the error bars are the SEM. Levels were higher in the severe group when compared to either the normal, mild, or moderate endoscopy score groups (P < 0.001 for each comparison).
Figure 4
Figure 4
Spline graph of L-Arg concentration versus Disease Activity Index (DAI). [L-Arg] was strongly correlated with DAI, which was assessed by Pearson’s correlation test (r = 0.656, P < 0.001). The association was almost linear.
Figure 5
Figure 5
Pathways for utilization of L-Arg and potential biological effects relevant to colonic homeostasis. Solid lines represent known biochemical processes, and dotted lines indicate potential effects. L-Arg is imported into cells by the transport proteins CAT1 and CAT2. This process is competitively inhibited by L-Orn and L-Lys. Once inside cells, L-Arg can be utilized by two competing pathways. 1. The arginase pathway generates L-Orn, which is the substrate for ornithine decarboxylase (ODC) that produces the polyamines putrescine, spermidine, and spermine. Polyamines have been shown to play a role in wound repair and are potential regulators of immune response, apoptosis and phagocytosis. 2. The inducible nitric oxide synthase (iNOS) pathway produces high levels of nitric oxide, which can have a wide variety of effects in the innate immune response. L-Arg may also have important roles in modulating the additional cellular functions indicated.
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