Bile acids induce ileal damage during experimental necrotizing enterocolitis.
OBJECTIVE
Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency of premature infants. While the effect of bile acids (BAs) on intestinal mucosal injury is known, we investigated the contribution of BAs during the development of NEC in neonatal rats.


METHODS
Premature rats were fed with cow's milk-based formula and subjected to asphyxia and cold stress to develop NEC. Jejunal and ileal luminal BAs, portal blood BAs, and messenger RNA and protein for the apical sodium-dependent bile acid transporter, the ileal bile acid binding protein, and the heteromeric organic solute transporter (Ostalpha/Ostbeta)were evaluated.


RESULTS
Ileal luminal BAs levels were increased significantly during disease development and the removal of ileal BAs significantly decreased the incidence and severity of disease. Furthermore, when NEC was reduced via treatment with epidermal growth factor (EGF), BA levels were reduced significantly. Jejunal luminal BA levels were similar between animals with NEC and controls, but portal/ileal luminal BA ratios were decreased significantly in animals with NEC. The apical sodium-dependent bile acid transporter was up-regulated at the site of injury in animals with NEC and decreased after EGF treatment; however, the ileal bile acid binding protein was up-regulated only in the NEC and EGF group. Ostalpha/Ostbeta expression was low in all groups, and only slightly increased in the NEC group.


CONCLUSIONS
These data strongly suggest that BAs play a role in the development of ileal damage in experimental NEC and that alterations in BA transport in the neonatal ileum may contribute to disease development.
Department of Pediatrics, Steele Children's Research Center, University of Arizona, Tucson, 85724, USA. mhalpern@peds.arizona.edu
Melissa D
MD
Halpern
Hana
H
Holubec
Tara A
TA
Saunders
Katerina
K
Dvorak
Jessica A
JA
Clark
Sarah M
SM
Doelle
Nazzareno
N
Ballatori
Bohuslav
B
Dvorak
D000818:Animals; D001647:Bile Acids and Salts / Q000633:toxicity*; D017931:DNA Primers; D004195:Disease Models, Animal; D020345:Enterocolitis, Necrotizing / Q000235:genetics / Q000473:pathology*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D006801:Humans; D007082:Ileum / Q000187:drug effects / Q000473:pathology*; D007231:Infant, Newborn; D007234:Infant, Premature; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology*; D007583:Jejunum / Q000473:pathology; D011168:Portal System; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods
D001647:Bile Acids and Salts; D017931:DNA Primers; D012333:RNA, Messenger; D004815:Epidermal Growth Factor