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Whole-body nitrogen metabolism is altered during parenteral feeding as a result of gut atrophy and/or lack of splanchnic first-pass metabolism. We developed in vivo models to describe the metabolic and physiologic effects of first-pass metabolism by the small intestine/liver, liver or non-splanchnic tissues. Fifteen 2- to 4-d-old piglets were fed identical diets continuously for 8 d via gastric (IG), portal (IP) or central venous (IV) catheters. Despite similar weight gain, IV and IP pigs had higher nitrogen output and hence lower nitrogen retention (80%) compared with IG pigs (87%) (P = 0.002). Body protein content was also higher in IG pigs (583 mg/g dry matter) compared with IV (550) and IP pigs (534) (P = 0.003). Despite similar intestinal lengths, total small intestinal and mucosal weights were approximately 40% lower in IV and IP pigs than in IG pigs. Free urea cycle amino acids were altered in plasma and mucosa, suggesting that limited arginine synthesis by an atrophied gut may have limited protein deposition. Although villous atrophy was observed in the duodena and jejuna of IV and IP pigs, reduced crypt depth was observed only in IV pigs. Crypt depth was similar in all four gut sections from IG and IP pigs, suggesting that nutrient flux through the liver affects gut growth. Overall, metabolic responses to IV (non-splanchnic) and IP (liver) feeding were similar as a result of gut atrophy, whereas responses to IG (small intestine + liver) and IP (liver) feeding were different, suggesting that small intestinal atrophy affects nitrogen metabolism to a greater extent than liver by-pass. [ABSTRACT FROM AUTHOR]