Dose-dependent beneficial effects of citrulline supplementation in short bowel syndrome in rats

Supplementing diet with citrulline has proved an efficient means of preserving nitrogen balance and improving nutritional status after massive intestinal resection. The aim of this study was to model the action of citrulline in gut-resected rats using a dose-ranging study focused on skeletal muscle nitrogen homeostasis. Forty-six rats were randomly assigned to one of the following groups: citrulline 0.5 g·kg·d–1 (n = 9), citrulline 1 g·kg·d–1 (n = 7), citrulline 2.5 g·kg·d–1 (n = 8), citrulline 5 g·kg·d–1 (n = 8), control (n = 6), and sham (n = 8). The sham group underwent transection and the other groups underwent resection of 80% of the small intestine. All rats were then fed enteral nutrition (EN; all diets were isocaloric and isonitrogenous). After 10 d, the rats were sacrificed to measure and analyze animal weight; duodenum, jejunum, and ileum weight; and muscle trophicity. Protein fractional synthesis rate (FSR) and mammalian target of rapamycin complex (mTORC)1 activation were measured in the tibialis muscle. There was a significant dose-dependent association between rat weight and citrulline dose up to 2.5 g·kg·d–1 (P = 0.004). There was a significant improvement in tibialis weight correlated to plasma citrulline. Net protein FSR in the tibialis tended to be greater after resection and tended to return to baseline after citrulline supplementation. Citrulline supplementation significantly decreased the activated phosphorylated forms of S6 K1 (P = 0.003) and S6 RP (P = 0.003), with a significant positive association between myofibrillar FSR and activation of S6 K1 (r = 0.614; P = 0.02) and S6 RP (r = 0.601; P = 0.023). Jejunum weight was significantly positively correlated with plasma citrulline (r = 0.319; P = 0.0345). Citrulline promotes body weight gain, preserves muscle trophicity, and enhances intestinal adaptation in a dose-dependent manner in a model of resected rats. •Enteral citrulline supplementation in a rat model of short bowel syndrome preserved rat weight in a dose-dependent manner.•Citrulline supplementation prevented muscle atrophy in short bowel syndrome.•Citrulline supplementation increased arginine and ornithine contents in plasma and muscles in a dose-dependent manner.•Citrulline normalized muscle protein fractional synthesis rate and mammalian target of rapamycin complex 1 activation after intestinal resection.