Abstract
Breast feeding protects infants from many diseases, including necrotizing enterocolitis, peptic ulceration and infectious diarrhea. Conversely, maternal separation stress and Non-Steroidal Anti-Inflammatory Drugs (NSAID's) can induce intestinal injury and bleeding. This study aimed to evaluate in suckling rats if maternal separation/formula feeding leads to increased intestinal sensitivity to indomethacin (indo)-induced intestinal injury and to look at potential mechanisms involved. Nine-day-old rats were dam-fed or separated/trained to formula-feed for 6 days prior to indo administration (5 mg/kg/day) or saline (control) for 3 days. Intestinal bleeding and injury were assessed by measuring luminal and Fecal Hemoglobin (Hob) and jejunal histology. Maturation of the intestine was assessed by measuring luminal bile acids, jejunal sucrase, serum corticosterone, and mRNA expression of ileal Apical Sodium-Dependent Bile Acid Transporter (ASBT). At 17 days, formula-fed indo-treated pups had a 2-fold increase in luminal Hb compared to formula-fed control pups and had evidence of morphological injury to the small intestinal mucosa as observed at the light microscopic level, whereas indo had no effect on dam-fed littermates. In addition, formula-fed rats had significant increases in luminal bile acid, sucrase specific activity, serum corticosterone, and expression of ASBT mRNA compared to dam-fed rats. Maternal separation stress may cause early intestinal maturational changes induced by corticosteroid release, including increased epithelial exposure to bile acids. These maturational changes may have a sensitizing rather than protective effect against indo-induced injury in the new-born.
Highlights
Infants are exposed to Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) when they develop fever, during medical induction of Patent Ductus Arteriosus (PDA) closure, and when they are at risk for thromboembolic events
Study groups were designated as followed: Dam-fed control group remained with the nursing dam and received subcutaneous injections of saline (0.1 mL) starting on day of life 9 (DOL) 14 for 3 days; dam-fed indo group staying with the nursing dam but receiving subcutaneous injections of indo at a dose of 5 mg/kg body weight/day for 3 days; formula-fed control group separated from the dam and receiving saline injections for 3 days; and formula-fed indo group separated from dam and receiving indo injections for 3 days
The growth rate over the following 4 days was approximately 2 g/day in dam-fed pups versus 0.3 g/day in the formula-fed group. After this period for acclimation to formula-feeding leading to a lag in growth as the rats learned to selffeed, the growth rate for the formula-fed groups improved to approximately 2 g/day, compared to the approximately 2.5 g/day observed in the dam-fed groups during this period
Summary
Infants are exposed to Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) when they develop fever, during medical induction of Patent Ductus Arteriosus (PDA) closure, and when they are at risk for thromboembolic events. NSAIDs can induce gastroduodenal and small intestinal injury in both animals and humans via inhibition of prostaglandin synthesis, decrease in mesenteric blood flow and elimination by biliary excretion. Bile acid accumulation in the GI lumen may play a role in enhancing intestinal injury by this class of drugs [4] as suggested by prior adult animal studies that demonstrated prevention of NSAIDinduced damage in the distal small intestine by bile duct ligation [5]. Maternal separation has been shown to increase intestinal permeability [6] and to induce pro-inflammatory cytokines in the intestine [7]. Cow-milk formula feeding could increase both TH1 (IFNγ) and TH2
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