Protein and Glutathione Kinetics in Protein Deficient Piglets with Colitis in Response to Nutritional Interventions: Protein Repletion or N‐Acetylcysteine Supplementation

Compromised nutritional status such as protein deficiency during colitis leads to impaired growth and development, and may aggravate disease severity. Enteral nutrition has shown promise in fostering intestinal mucosal healing and inducing remission. Few studies, however, have focused on protein and glutathione (GSH) metabolism in early recovery from colitis. In cases where the anabolic strategy of protein repletion is not possible, an anti‐inflammatory nutrition intervention may improve GSH status without increasing growth or protein synthesis. Our objective was to determine, in protein‐deficient piglets with colitis, if protein repletion or N‐acetylcysteine (NAC, a GSH precursor) supplementation would improve protein and GSH kinetics and reduce oxidative stress. All piglets (n=16) received a protein‐deficient (PD) diet with adequate energy continuously by gastrostomy and dextran sulfate sodium (DSS) (0.5g/(kg·d) i.g.) to induce colitis. After 10 days, DSS was discontinued and piglets were randomized to a control group (CTL, n=5) that continued on the PD diet, one of two intervention groups to receive either the PD diet plus NAC (NAC, n=5) or an isoenergetic diet with adequate protein (AP, n=6). On day 15, L‐[ring‐ 2 H 5 ]phenylalanine and [ 15 N, 1, 2‐ 13 C 2 ]glycine tracers were administered to determine protein and GSH synthesis, respectively. GSH and related sulfhydryls were derivatized immediately with N‐ethylmaleimide for analysis by LC‐MS/MS. Ferric reducing ability of plasma (FRAP) was used as an indicator of systemic antioxidant capacity. Growth was restricted (17±2 g/(kg.d)) during protein restriction. Protein repletion but not NAC supplementation increased weight gain to 53±5 g/(kg·d) (p<0.05). Albumin fractional (FSR) and absolute synthesis rate (ASR) were 4‐fold higher in AP piglets than CTL (FSR: 21 vs. 5%/d; ASR: 285 vs. 57 mg/(kg·d)); however albumin concentration remained low (21 g/L) and not different from other groups. Similar patterns were found in AP piglets for FSR and ASR of plasma and constitutive liver proteins. In contrast, NAC did not influence plasma or liver protein kinetics. AP piglets had higher plasma branched chain, urea cycle, and total essential amino acid concentrations (p<0.05), whereas NAC piglets were intermediate between AP and CTL. Notably neither glycine nor glutamine/glutamate was different between NAC and CTL. In erythrocytes, protein repletion resulted in higher concentrations in GSH and its intermediate γ‐glutamylcysteine, higher GSH FSR and ASR (p<0.02) with correspondingly higher FRAP (p<0.02). In contrast, even though NAC supplementation led to a 5‐fold higher cysteine concentration in jejunum, and moderately higher in erythrocytes, cecum, spiral colon, and lung (p<0.05), it had no effect on GSH concentration or synthesis in erythrocytes, and no effect on FRAP. These data suggest that cysteine may not be the only rate‐limiting intermediate in GSH synthesis during protein deficiency, and that protein repletion is a more effective strategy to improve protein and GSH kinetics and systemic antioxidant status in piglets with colitis. Support or Funding Information Supported by NSERC

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