ObjectiveTo investigate the effects of total parenteral nutrition administration on intestinal ion transport and intestinal epithelial permeability. Additionally, to assess the role of interferon-&ggr; on the total parenteral nutrition-induced loss of epithelial barrier function.DesignRandomized, controlled study.SettingExperimental laboratory, University of Michigan Medical School, Ann Arbor.SubjectsAdult wild-type and interferon-&ggr; knockout mice.InterventionsWild-type mice received total parenteral nutrition or enteral diet (control group) for 7 days. Segments of small bowel from the mice were mounted in Ussing chambers. Short circuit current, as an indictor of active ion transport, was constantly monitored. Epithelial barrier function was assessed by measuring transepithelial resistance and transmural passage of51Cr-EDTA and3H-mannitol. Intestinal intraepithelial lymphocyte-derived interferon-&ggr; protein expression was detected with enzyme-linked immunosorbent assay and confirmed by using intracellular staining and flow cytometry. To investigate the effect of total parenteral nutrition on intestinal ion transport, we used a secretory agonist, carbachol, and an absorptive agent, glucose.Measurements and Main ResultsTotal parenteral nutrition significantly increased small-bowel permeability. Ion transport in the total parenteral nutrition group was significantly increased. To stimulate ion transport, we found that increases in short circuit current induced by carbachol and glucose were higher in the total parenteral nutrition group compared with the control group. Intestinal intraepithelial lymphocyte interferon-&ggr; protein expression significantly increased with the administration of total parenteral nutrition. Intestinal permeability in interferon-&ggr; knockout total parenteral nutrition mice was significantly lower than in wild-type mice receiving total parenteral nutrition.ConclusionTotal parenteral nutrition has significant effects on intestinal epithelial physiology, stimulating ion secretion and reducing epithelial barrier function. Interferon-&ggr; appears to play an important role in the loss of the epithelial barrier function that is associated with total parenteral nutrition.