|Bauchart-thevret, Caroline - Children's Nutrition Research Center (CNRC)|
|Stoll, Barbara - Children's Nutrition Research Center (CNRC)|
|Chako, Shaji - Children's Nutrition Research Center (CNRC)|
|Burrin, Douglas - Doug|
Submitted to: American Journal of Physiology - Endocrinology and Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/12/2009
Publication Date: 6/1/2009
Citation: Bauchart-Thevret, C., Stoll, B., Chako, S., Burrin, D.G. 2009. Sulfur amino acid deficiency upregulates intestinal methionine cycle activity and suppresses epithelial growth in neonatal pigs. American Journal of Physiology - Endocrinology and Metabolism. 296:E1239-E1250. Interpretive Summary: An important problem in feeding rapidly growing infants, especially those born prematurely, is the need for adequate protein in the diet. Methionine is a component amino acid of protein and cannot be made by the infant body and thus it is required in the diet. Methionine is also critical for cell growth and prevention of stress. Our previous studies showed that the intestine is an important site of methionine metabolism because of its high rate of epithelial cell growth. Thus we tested the impact of methionine deficiency on intestinal growth in neonatal piglets. We used our well-established piglet animal model to simulate the gut physiology of human infants. We gave the piglets specialized chemical forms of methionine labeled with isotopes that enabled us to track its metabolism through the gut and whole body. We found that piglets fed a diet that was devoid of sulfur amino acids (SAA), i.e., methionine and cysteine, exhibited a preferential reduction in intestinal mucosal growth and cell replication. We found that SAA deficiency also increased the activity of three key enzymes in the intestine that metabolize methionine to homocysteine and then recycle it back to methionine, a process that serves to conserve methionine. We also showed that when the piglet becomes deficient in SAA, the body and gut especially slow their metabolism of methionine for cysteine production in order to preserve methionine for synthesis of cellular proteins. These findings show why it is important for premature infants to consume sufficient methionine to support cellular functions beside protein synthesis in intestine cells.
Technical Abstract: We recently showed that the developing gut is a significant site of methionine transmethylation to homocysteine and transsulfuration to cysteine. We hypothesized that sulfur amino acid (SAA) deficiency would preferentially reduce mucosal growth and antioxidant function in neonatal pigs. Neonatal pigs were enterally fed a control or an SAA-free diet for 7 days, and then whole body methionine and cysteine kinetics were measured using an intravenous infusion of [1-13C;methyl-2H3]methionine and [15N]cysteine. Body weight gain and plasma methionine, cysteine, homocysteine, and taurine, and total erythrocyte glutathione concentrations were markedly decreased (-46% to -85%) in SAA-free compared with control pigs. Whole body methionine and cysteine fluxes were reduced, yet methionine utilization for protein synthesis and methionine remethylation were relatively preserved at the expense of methionine transsulfuration, in response to SAA deficiency. Intestinal tissue concentrations of methionine and cysteine were markedly reduced, and hepatic levels were maintained in SAA-free compared with control pigs. SAA deficiency increased the activity of methionine metabolic enzymes, i.e., methionine adenosyltransferase, methionine synthase, and cystathionine beta-synthase, and S-adenosylmethionine concentration in the jejunum, whereas methionine synthase activity increased and S-adenosylmethionine level decreased in the liver. Small intestine weight and protein and DNA mass were lower, whereas liver weight and DNA mass were unchanged, in SAA-free compared with control pigs. Dietary SAA deficiency induced small intestinal villus atrophy, lower goblet cell numbers, and Ki-67-positive proliferative crypt cells in association with lower tissue glutathione, especially in the jejunum. We conclude that SAA deficiency upregulates intestinal methionine cycle activity and suppresses epithelial growth in neonatal pigs.