Protein and amino acid metabolism in malnutrition and metabolic stress

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Malnutrition is the most prevalent nutritional problem worldwide, and is frequently complicated by infections. Inflammation and activation of the immune system, which are both normal responses to tissue injury and infection, result in 1) increased synthesis of glutathione (GSH) to balance the increased production of free radicals, and 2) increased synthesis of acute phase proteins. Both responses result in increased demands for a potentially meagre supply of amino acids. During malnutrition these responses may further compromise growth and may be compromised themselves to potentiate the malnutrition/infection vicious cycle.     Our stable isotope techniques to measure synthesis of GSH and individual plasma proteins allow comprehensive examination of the mechanisms of how pools of individual proteins or products of amino acids are affected in states of malnutrition and/or oxidative stress. We have developed a piglet model of colitis or inflammation of the gut, and have shown that inflammation does compromise growth and protein synthesis in muscle while increasing synthesis of plasma proteins as part of the acute phase response. We have shown further that maintaining nutritional status, as opposed to eating less, not only accommodates the acute phase response of colitis, but increases muscle protein synthesis and lessens severity of the damage to the colon.     Continuing this theme, we are investigating the more specific effects of protein and/or zinc deficiency. We aim to integrate our protein synthesis information with zinc kinetics, GI pathophysiology and the pro-inflammatory cytokine response to construct a more integrative explanation of the malnutrition/ inflammation synergy. The second theme is a new and innovative investigation of how growth factors may stimulate (and how challenges may compromise) repair of the intestine and stimulate protein and GSH synthesis. Results are expected to show HOW adaptations to malnutrition are affected, and to underscore the importance of diet and nutritional status in mounting effective responses to stresses.