GLUTAMINE AND INTESTINAL TRANSPORT AND MUCOSAL GROWTH

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Rotavirus diarrhea, the leading cause of infant diarrhea, is the result of impaired transport in an intestine dominated by undifferentiated enterocytes. Glutamine, the major intestinal metabolic fuel, is a growth factor for enterocytes and a stimulator of mucosal repair after damage. We have found that L-glutamine promotes neutral NaCl absorption across normal and rotavirus-infected piglet jejunum (probably via coupled Na/H and Cl/HCO3 exchanges). Others have found that L-glutamine enhances hepatocyte growth in culture by stimulating ornithine decarboxylase (ODC) activity. Furthermore, L-asparagine, structurally similar to glutamine, stimulates ODC and transmembrane Na/H exchange (in hepatoma cells), resulting in intracytoplasmic alkalinization, a putative signal for cell proliferation. In enterocytes, the effects of metabolic fuels on intracellular pH (pHi) and polyamine metabolism have not been determined. Our studies will focus on the mechanisms by which glutamine stimulates NaCl absorption and cell growth in an undifferentiated epithelium. We will use rotavirus-infected pig jejunum and isolated porcine epithelial cell monolayers (IPEC-J2) to model intestinal function. Specific Aim 1 assesses if glutamine stimulates coupled transmembrane Na/H and Cl/HCO3 exchanges or Na-K-2Cl cotransport. Objective 2 examines the relationship between glutamine, oxidative metabolism, cellular ATP stores, and Na, K-ATPase activity. Specific Aim 3 determines the effect of glutamine and its metabolism on pHi. Specific Aim 4 is designed to assess how glutamine stimulates ODC and initiates mucosal growth. Objective 5 determines if glutamine promotes mucosal recovery in viral enteritis. Our findings could improve the oral treatment of infants with intestinal damage and diarrhea.