Alteration in epithelial permeability and ion transport in a mouse model of total parenteral nutrition

Objective: To investigate the effects of total parenteral nutrition administration on intestinal ion transport and intestinal epithelial permeability. Additionally, to assess the role of interferon-gamma on the total parenteral nutrition-induced loss of epithelial barrier function. Design: Randomized, controlled study. Setting: Experimental laboratory, University of Michigan Medical School, Ann Arbor. Subjects: Adult wild-type and interferon-gamma knockout mice. Interventions: Wild-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 of Cr-51-EDTA and H-3-mannitol. Intestinal intraepithelial lymphocyte-derived interferon-gamma 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 Results: Total 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-gamma protein expression significantly increased with the administration of total parenteral nutrition. Intestinal permeability in interferon-gamma knockout total parenteral nutrition mice was significantly lower than in wild-type mice receiving total parenteral nutrition. Conclusion: Total parenteral nutrition has significant effects on intestinal epithelial physiology, stimulating ion secretion and reducing epithelial barrier function. Interferon-gamma appears to play an important role in the loss of the epithelial barrier function that is associated with total parenteral nutrition.