Skip to main content Accessibility help

Whole-body and splanchnic amino acid metabolism in sheep during an acute endotoxin challenge

  • C. J. McNeil (a1) (a2), S. O. Hoskin (a1) (a3), D. M. Bremner (a1), G. Holtrop (a4) and G. E. Lobley (a1)...


Supplemented protein or specific amino acids (AA) are proposed to help animals combat infection and inflammation. The current study investigates whole-body and splanchnic tissue metabolism in response to a lipopolysaccharide (LPS) challenge with or without a supplement of six AA (cysteine, glutamine, methionine, proline, serine and threonine). Eight sheep were surgically prepared with vascular catheters across the gut and liver. On two occasions, four sheep were infused through the jugular vein for 20 h with either saline or LPS from Escherichia coli (2 ng/kg body weight per min) in a random order, plus saline infused into the mesenteric vein; the other four sheep were treated with saline or LPS plus saline or six AA infused via the jugular vein into the mesenteric vein. Whole-body AA irreversible loss rate (ILR) and tissue protein metabolism were monitored by infusion of [ring-2H2]phenylalanine. LPS increased (P<0·001) ILR (+17 %), total plasma protein synthesis (+14 %) and lymphocyte protein synthesis (+386 %) but decreased albumin synthesis (−53 %, P=0·001), with no effect of AA infusion. Absorption of dietary AA was not reduced by LPS, except for glutamine. LPS increased the hepatic removal of leucine, lysine, glutamine and proline. Absolute hepatic extraction of supplemented AA increased, but, except for glutamine, this was less than the amount infused. This increased net appearance across the splanchnic bed restored arterial concentrations of five AA to, or above, values for the saline-infused period. Infusion of key AA does not appear to alter the acute period of endotoxaemic response, but it may have benefits for the chronic or recovery phases.

  • View HTML
    • Send article to Kindle

      To send this article to your Kindle, first ensure is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

      Note you can select to send to either the or variations. ‘’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      Whole-body and splanchnic amino acid metabolism in sheep during an acute endotoxin challenge
      Available formats

      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

      Whole-body and splanchnic amino acid metabolism in sheep during an acute endotoxin challenge
      Available formats

      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

      Whole-body and splanchnic amino acid metabolism in sheep during an acute endotoxin challenge
      Available formats


Corresponding author

* Corresponding author: G. E. Lobley, email


Hide All
1. Bruins, MJ, Soeters, PB, Lamers, WH, et al. (2002) L-arginine supplementation in pigs decreases liver protein turnover and increases hindquarter protein turnover both during and after endotoxemia. Am J Clin Nutr 75, 10311044.
2. Le Floc’h, N, Deblanc, C, Cariolet, R, et al. (2014) Effect of feed restriction on performance and postprandial nutrient metabolism in pigs co-infected with Mycoplasma hyopneumoniae and swine influenza virus. PLOS ONE 9, e104605.
3. Hoskin, SO, Bremner, DM, Holtrop, G, et al. (2016) Responses in whole-body amino acid kinetics to an acute, sub-clinical endotoxin challenge in lambs. Br J Nutr 115, 576584.
4. Bruins, MJ, Soeters, PB & Deutz, NE (2000) Endotoxemia affects organ protein metabolism differently during prolonged feeding in pigs. J Nutr 130, 30033013.
5. Faure, M, Moennoz, D, Montigon, F, et al. (2003) Mucin production and composition is altered in dextran sulfate sodium-induced colitis in rats. Dig Dis Sci 48, 13661373.
6. Yu, F, Bruce, LA, Calder, AG, et al. (2000) Subclinical infection with the nematode Trichostrongylus colubriformis increases gastrointestinal tract leucine metabolism and reduces availability of leucine for other tissues. J Anim Sci 78, 380390.
7. Reeds, PJ, Fjeld, CR & Jahoor, F (1994) Do the differences between the amino acid compositions of acute-phase and muscle proteins have a bearing on nitrogen loss in traumatic states? J Nutr 124, 906910.
8. Shaw, JH & Wolfe, RR (1986) Glucose, fatty acid, and urea kinetics in patients with severe pancreatitis. The response to substrate infusion and total parenteral nutrition. Ann Surg 204, 665672.
9. Malmezat, T, Breuille, D, Pouyet, C, et al. (2000) Methionine transsulfuration is increased during sepsis in rats. Am J Physiol Endocrinol Metab 279, E1391E1397.
10. Essen, P, McNurlan, MA, Thorell, A, et al. (1996) Determination of protein synthesis in lymphocytes in vivo after surgery. Clin Sci (Lond) 91, 99106.
11. Stoll, B, Gerok, W, Lang, F, et al. (1992) Liver cell volume and protein synthesis. Biochem J 287, 217222.
12. Biolo, G & Tessari, P (1997) Splanchnic versus whole-body production of alpha-ketoisocaproate from leucine in the fed state. Metabolism 46, 164167.
13. Laurichesse, H, Tauveron, I, Gourdon, F, et al. (1998) Threonine and methionine are limiting amino acids for protein synthesis in patients with AIDS. J Nutr 128, 13421348.
14. Breuille, D, Bechereau, F, Buffiere, C, et al. (2006) Beneficial effect of amino acid supplementation, especially cysteine, on body nitrogen economy in septic rats. Clin Nutr 25, 634642.
15. Hou, Y, Wang, L, Zhang, W, et al. (2012) Protective effects of N-acetylcysteine on intestinal functions of piglets challenged with lipopolysaccharide. Amino Acids 43, 12331242.
16. Wernerman, J (2008) Clinical use of glutamine supplementation. J Nutr 138, 2040S2044S.
17. de Blaauw, I, Heeneman, S, Deutz, NE, et al. (1997) Increased whole-body protein and glutamine turnover in advanced cancer is not matched by an increased muscle protein and glutamine turnover. J Surg Res 68, 4455.
18. Lobley, GE, Connell, A, Lomax, MA, et al. (1995) Hepatic detoxification of ammonia in the ovine liver: possible consequences for amino acid catabolism. Br J Nutr 73, 667685.
19. Mackie, WS (1976) Plasma volume measurements in sheep using Evans’ blue and continuous blood sampling. Res Vet Sci 21, 108109.
20. Calder, AG, Garden, KE, Anderson, SE, et al. (1999) Quantitation of blood and plasma amino acids using isotope dilution electron impact gas chromatography/mass spectrometry with U-(13)C amino acids as internal standards. Rapid Commun Mass Spectrom 13, 20802083.
21. Lobley, GE, Holtrop, G, Bremner, DM, et al. (2013) Impact of short term consumption of diets high in either non-starch polysaccharides or resistant starch in comparison with moderate weight loss on indices of insulin sensitivity in subjects with metabolic syndrome. Nutrients 5, 21442172.
22. Connell, A, Calder, AG, Anderson, SE, et al. (1997) Hepatic protein synthesis in the sheep: effect of intake as monitored by use of stable-isotope-labelled glycine, leucine and phenylalanine. Br J Nutr 77, 255271.
23. Lobley, GE, Bremner, DM, Nieto, R, et al. (1998) Transfers of N metabolites across the ovine liver in response to short-term infusions of an amino acid mixture into the mesenteric vein. Br J Nutr 80, 371379.
24. Lobley, GE, Shen, X, Le, G, et al. (2003) Oxidation of essential amino acids by the ovine gastrointestinal tract. Br J Nutr 89, 617630.
25. Schroder, MT, Schafer, G & Schauder, P (1990) Characterization of glutamine transport into resting and concanavalin A-stimulated peripheral human lymphocytes. J Cell Physiol 145, 155161.
26. Soeters, PB, Hallemeesch, MM, Bruins, MJ, et al. (2002) Quantitative in vivo assessment of arginine utilization and nitric oxide production in endotoxemia. Am J Surg 183, 480488.
27. Fong, Y, Matthews, DE, He, W, et al. (1994) Whole body and splanchnic leucine, phenylalanine, and glucose kinetics during endotoxemia in humans. Am J Physiol 266, R419R425.
28. Vesali, RF, Klaude, M, Rooyackers, O, et al. (2005) Amino acid metabolism in leg muscle after an endotoxin injection in healthy volunteers. Am J Physiol Endocrinol Metab 288, E360E364.
29. Papet, I, Ruot, B, Breuille, D, et al. (2002) Bacterial infection affects protein synthesis in primary lymphoid tissues and circulating lymphocytes of rats. J Nutr 132, 20282032.
30. Januszkiewicz, A, Lore, K, Essen, P, et al. (2002) Response of in vivo protein synthesis in T lymphocytes and leucocytes to an endotoxin challenge in healthy volunteers. Clin Exp Immunol 130, 263270.
31. Hellerstein, MK & Munro, HN (1994) Interaction of liver, muscle, and adipose tissue in the regulation of metabolism in response to nutritional and other factors. In The Liver: Biology and Pathobiology, 3rd ed. pp. 11691181 [IM Arias, JL Boyer, N Fausto, WB Jacoby, DA Schachter and DA Shafritz, editors]. New York, NY: Raven Press.
32. Klasing, KC & Calvert, CC (1999) The care and feeding of an immune system: an analysis of lysine needs. In Protein Metabolism and Nutrition. EAAP, no. 96, pp. 253264 [GE Lobley, A White and JC Macrae, editors]. Wageningen: Wageningen Pers.
33. Breuille, D, Arnal, M, Rambourdin, F, et al. (1998) Sustained modifications of protein metabolism in various tissues in a rat model of long-lasting sepsis. Clin Sci (Lond) 94, 413423.
34. Effenberger-Neidnicht, K, Jagers, J, Verhaegh, R, et al. (2014) Glycine selectively reduces intestinal injury during endotoxemia. J Surg Res 192, 592598.
35. Deutz, NE, Reijven, PL, Athanasas, G, et al. (1992) Post-operative changes in hepatic, intestinal, splenic and muscle fluxes of amino acids and ammonia in pigs. Clin Sci (Lond) 83, 607614.
36. Lobley, GE, Connell, A, Revell, DK, et al. (1996) Splanchnic-bed transfers of amino acids in sheep blood and plasma, as monitored through use of a multiple U-13C-labelled amino acid mixture. Br J Nutr 75, 217235.
37. Lobley, GE, Bremner, DM & Brown, DS (2001) Response in hepatic removal of amino acids by the sheep to short-term infusions of varied amounts of an amino acid mixture into the mesenteric vein. Br J Nutr 85, 689698.
38. Nieto, R, Obitsu, T, Fernandez-Quintela, A, et al. (2002) Glutamine metabolism in ovine splanchnic tissues: effects of infusion of ammonium bicarbonate or amino acids into the abomasum. Br J Nutr 87, 357366.
39. Kao, C, Hsu, J, Bandi, V, et al. (2013) Alterations in glutamine metabolism and its conversion to citrulline in sepsis. Am J Physiol Endocrinol Metab 304, E1359E1364.
40. Lichter-Konecki, U, Hipke, CM & Konecki, DS (1999) Human phenylalanine hydroxylase gene expression in kidney and other nonhepatic tissues. Mol Gen Metab 67, 308316.
41. Ruot, B, Breuille, D, Rambourdin, F, et al. (2000) Synthesis rate of plasma albumin is a good indicator of liver albumin synthesis in sepsis. Am J Physiol Endocrinol Metab 279, E244E251.
42. Jahoor, F, Gazzard, B, Phillips, G, et al. (1999) The acute-phase protein response to human immunodeficiency virus infection in human subjects. Am J Physiol Endocrinol Metab 276, E1092E1098.
43. Orellana, RA, Suryawan, A, Wilson, FA, et al. (2012) Development aggravates the severity of skeletal muscle catabolism induced by endotoxemia in neonatal pigs. Am J Physiol Regul Integr Comp Physiol 302, R682R690.
44. de Oliveira, GP, Silva, JD, de Araujo, CC, et al. (2014) Intravenous glutamine administration reduces lung and distal organ injury in malnourished rats with sepsis. Shock 41, 222232.
45. Cruzat, VF, Bittencourt, A, Scomazzon, SP, et al. (2014) Oral free and dipeptide forms of glutamine supplementation attenuate oxidative stress and inflammation induced by endotoxemia. Nutrition 30, 602611.
46. Fan, J, Wu, L, Li, G, et al. (2015) Effects of enteral nutrition with parenteral glutamine supplementation on the immunological function in septic rats. Br J Nutr 113, 17121722.
47. Newsholme, P (2001) Why is L-glutamine metabolism important to cells of the immune system in health, postinjury, surgery or infection? J Nutr 131, 2515S2522S.
48. Poeze, M, Bruins, MJ, Kessels, F, et al. (2011) Effects of L-arginine pretreatment on nitric oxide metabolism and hepatosplanchnic perfusion during porcine endotoxemia. Am J Clin Nutr 93, 12371247.
49. Wang, L, Hou, Y, Yi, D, et al. (2015) Dietary supplementation with glutamate precursor alpha-ketoglutarate attenuates lipopolysaccharide-induced liver injury in young pigs. Amino Acids 47, 13091318.
50. Xu, FL, You, HB, Li, XH, et al. (2008) Glycine attenuates endotoxin-induced liver injury by downregulating TLR4 signaling in Kupffer cells. Am J Surg 196, 139148.
51. Hoskin, SO, Lobley, GE, Coop, RL, et al. (2002) The effect of cysteine and glutamine supplementation on sheep infected with Trichostrongylus colubriformis . Proc N Z Soc Anim Prod 62, 7276.
52. Malmezat, T, Breuille, D, Capitan, P, et al. (2000) Glutathione turnover is increased during the acute phase of sepsis in rats. J Nutr 130, 12391246.
53. Bauchart-Thevret, C, Stoll, B, Chacko, S, et al. (2009) Sulfur amino acid deficiency upregulates intestinal methionine cycle activity and suppresses epithelial growth in neonatal pigs. Am J Physiol Endocrinol Metab 296, E1239E1250.
54. Wolfe, RR & Miller, SL (1999) Amino acid availability controls muscle protein metabolism. Diabetes Nutr Metab 12, 322328.
55. Mittendorfer, B, Volpi, E & Wolfe, RR (2001) Whole body and skeletal muscle glutamine metabolism in healthy subjects. Am J Physiol Endocrinol Metab 280, E323E333.
56. Gore, DC & Wolfe, RR (2003) Metabolic response of muscle to alanine, glutamine, and valine supplementation during severe illness. JPEN 27, 307314.


Type Description Title
Supplementary materials

McNeil supplementary material
Tables S1-S2

 Word (17 KB)
17 KB


Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed