Accumulation of bile acids in ileum associated with intestinal damage rats with experimental necrotizing enterocolitis

Abstract

Necrotizing enterocolitis (NEC) is associated with the release of a variety of proniflamatory mediators in the small intestine. We have previously shown that through the enterohepatic axis, luminal ileal TNFa was significantly increased and correlated with severity of intestinal damage. Upregulation of IL-113 and TNFet reduces significantly the ileal sodium-dependent bile acid transporter (ASBT) in rats (Gastroenterology 2002; 123) and thus may lead to accumulation of bile in the terminal ileum. Increased concentrations of cytotoxic bile acids (BA) were reported to induce damage to intestinal mucosa. Objective: The aim of this study was to determine if changes in bile acid levels in the terminal ileum and serum are associated with the development of NEC. Design/Methods: Newborn rats were artificially fed cow milkbased rat milk substitute (RMS) and exposed to asphyxia and cold stress for 4 days to induce experimental NEC. Dam fed (DF) littermates were also exposed to asphyxia-cold stresses and served as controls. Total BA levels were determined in ileal flushes using an enzymatic assay (Diazyme). In addition, segments of terminal ileum were processed and evaluated histologicaly and by scanning electron microscopy (SEM). Results: Total BA were significantly increased (p<0.05) in RMS animals compared to the DF group (340 • 164 and 77 -+ 3 lg, mol, respectively). Serum total BA were not significantly different between animals with and without NEC (4.0-+ 2.3 and 3.7 + 1.7~mol, respectively). Severe morphologic changes consistent with those previously attributed to BA were observed in RMS rats. These changes were confirmed by histology. DF littermates had no ileal damage. Conclusions: Increased BA in terminal ileum may exacerbate the progression of intestinal damage. Evaluation of BA transport may lead to important advances in understanding NEC pathogenesis. Supported by NIH grants HD-39657, HD-26013 (to B.D.)