Alterations in biopterin metabolism and the effects of tetrahydrobiopterin supplementation in a rat model of short bowel syndrome.

PURPOSE: Maintaining microcirculation via NOS function is critical for intestinal adaptation for short bowel syndrome (SBS). We investigated the dynamics of tetrahydrobiopterin (BH4), a key NOS cofactor, and the therapeutic potential of BH4 in our experimental SBS model. METHODS: Rats were divided into Sham (n = 18), SBS (n = 22), SBS+BH4 (n = 6), and Control (n = 4) groups. The BH4 related metabolites, NOS mRNA expression, histological parameters with hematoxylin and eosin staining, and immunohistochemistry staining with nitrotyrosine and Ki67 were analyzed in the remnant jejunum and ileum. RESULTS: The SBS group exhibited significant BH4 dysregulation, marked by increased biopterin oxidation and decreased BH4/BH2 ratios, particularly in the jejunum on day 3. SBS also induced a significant upregulation of iNOS and eNOS mRNA and increased nitrotyrosine expression. The SBS+BH4 group showed a significantly preserved villus height and absorptive area in the jejunum, along with enhanced crypt cell proliferation in both the jejunum and ileum. The SBS+BH4 group effectively modulated the NOS expression and significantly reduced the nitrotyrosine levels to Sham levels. CONCLUSION: This study, using an SBS rat model, showed that BH4 dysregulation leads to nitrosative stress and impairs intestinal adaptation. BH4 administration can help to modulate the NOS-related pathways and maintain intestinal homeostasis.