URSODEOXYCHOLIC ACID MODIFIES GUT-DERIVED ENDOTOXEMIA IN NEONATAL RATS

We developed a model for the translocation of intraluminal endotoxin i n the neonatal animal and used it to examine the capacity of a nonhepa totoxic bile acid, ursodeoxycholic acid (UDCA), to modify endotoxin tr anslocation and cytokine response. Three-d-old Sprague-Dawley rats wer e randomized to receive enterally either no drug, lipopolysaccharide ( LPS, 1 mg/animal), or UDCA (400 mu g/animal) alone, or UDCA followed b y LPS 1 h later. One h after LPS administration, the rats were killed and plasma endotoxin and tumor necrosis factor (TNF) were measured. Co ntrol animals had low circulating endotoxin (21.2 +/- 7.6 endotoxin un its) and TNF (0.06 +/- 0.02 ng/mL). Enteral administration of LPS I h before the rats were killed resulted in significant elevation of endot oxin (249.5 +/- 71.3, p = 0.008) and TNF (3.6 +/- 1.3, p = 0.019). UDC A alone did not alter endotoxin levels (8.7 +/- 2.1). UDCA 1 h before LPS prevented the rise in endotoxin (38.9 +/- 11.2 endotoxin units) an d TNF (0.2 +/- 0.05) significantly. Chenodeoxycholic acid was studied in a similar group of experiments and prevented neither the translocat ion of LPS nor the development of increased TNF levels in animals rece iving LPS. In conclusion, LPS can cross the intestinal barrier in the normal neonatal rat. UDCA, administered before LPS, can decrease the t ranslocation of LPS and prevent the cytokine response as measured by T NF levels. We speculate that UDCA, administered prophylactically, migh t reduce morbidity in clinical conditions leading to gut-derived endot oxemia.