Introduction: TPN leads to phenotypic and functional changes in the mucosal intraepithelial lymphocytes (IEL). Such IEL changes may cause a loss of epithelial barrier function and lead to an bacterial translocation (BT). This study addresses if these changes were due to a lack of enteral feeding, or to the TPN, itself. Methods: Mice received either oral feeding (Control), TPN alone (TPN), or TPN plus oral feeding (TPN + Food). Mice were sacrificed at 7 days, and bacteriological cultures from spleen, liver and mesenteric lymph nodes were obtained. Positive cultures were considered consistent with BT. The intestine was harvested, IEL isolated, stained for lymphocyte markers, and phenotypic distribution was analyzed by flow cytometry. IEL mRNA cytokine expression was assessed by RT-PCR. Apoptosis was histochemically detected by TUNEL staining. Results are expressed as mean ± SD, or mean (range). Statistics used ANOVA, P < 0.05 being significant.Results: BT significantly (P < 0.05) increased in the TPN group (53%) compared to Control (9%) and TPN + Food (14%) groups. TPN also resulted in a significant (P < 0.01) increase of epithelial cell apoptosis: TPN 7.6 ± 1.1% versus Control 2.9 ± 1.1%, and TPN + Food 2.1 ± 0.3%. Height of the villus/crypt complex was significantly (P < 0.05) decreased in TPN mice (315 ± 16 μm) compared to Control (431 ± 27 μm), and TPN + Food (421 ± 26 μm) groups. TablesTABLE—ABSTRACT 53GroupCD4+CD8−CD8αβ + thymus-dependentCD8+CD44+ matureControl4.7% (3.9–6.1)4.8% (3.0–6.5)29% (28–37)TPN0.6% (0.2–0.7)∗0.4% (0.1–0.8)∗10% (1.0–18)∗TPN + Food2.5% (1.5–2.2)7.4% (5.6–8.6)40% (38–46)CytokinesIL-2IL-4INF-γTNF-αControl0.32 ± 0.20.10 ± 0.10.15 ± 0.10.34 ± 0.1TPN0.13 ± 0.1∗0.73 ± 0.4∗0.29 ± 0.1∗0.55 ± 0.1∗TPN + Food0.31 ± 0.20.11 ± 0.10.14 ± 0.00.33 ± 0.1 show other results (∗P < 0.05 TPN vs. other 2 groups): Conclusions: This study demonstrates that the major factor responsible for TPN-induced BT and IEL changes is the lack of enteral feeding, and not the administration of the PN solution.