Intestinal alkaline phosphatase to treat necrotizing enterocolitis

Abstract

Background Intestinal alkaline phosphatase (IAP) activity is decreased in necrotizing enterocolitis (NEC), and IAP supplementation prevents NEC development. It is not known if IAP given after NEC onset can reverse the course of the disease. We hypothesized that enteral IAP given after NEC induction would not reverse intestinal injury. Materials and methods NEC was induced in Sprague–Dawley pups by delivery preterm followed by formula feedings with lipopolysaccharide (LPS) and hypoxia exposure and continued up to 4 d. IAP was added to feeds on day 2 until being sacrificed on day 4. NEC severity was scored based on hematoxylin and eosin-stained terminal ileum sections, and AP activity was measured using a colorimetric assay. IAP and interleukin-6 expression were measured using real time polymerase chain reaction. Results NEC pups' alkaline phosphatase (AP) activity was decreased to 0.18 U/mg compared with controls of 0.57 U/mg (P < 0.01). Discontinuation of LPS and hypoxia after 2 d increased AP activity to 0.36 U/mg (P < 0.01). IAP supplementation in matched groups did not impact total AP activity or expression. Discontinuing LPS and hypoxia after NEC onset improved intestinal injury scores to 1.14 compared with continued stressors, score 2.25 (P < 0.01). IAP supplementation decreased interleukin-6 expression two-fold (P < 0.05), though did not reverse NEC intestinal damage (P = 0.5). Conclusions This is the first work to demonstrate that removing the source of NEC improves intestinal damage and increases AP activity. When used as a rescue treatment, IAP decreased intestinal inflammation though did not impact injury making it likely that IAP is best used preventatively to those neonates at risk.

Human ALPI deficiency causes inflammatory bowel disease and highlights a key mechanism of gut homeostasis

“…Importantly, oral ALPI supplementation protected ALPI-deficient mice from increased susceptibility to DSS-induced colitis (Ramasamy et al, 2011) and from chronic colitis induced by recurrent non-lethal infections by S. typhimurium (Yang et al, 2017). This treatment also significantly reduced intestinal inflammation in several mouse models of colitis and prevented LPS translocation (Ramasamy et al, 2011;Martínez-Moya et al, 2012;Rentea et al, 2012;Heinzerling et al, 2014;Biesterveld et al, 2015). Moreover, a small trial in patients with ulcerative colitis showed that administration of exogenous ALPI was not only well tolerated but also associated with short-term improvement in clinical scores (Lukas et al, 2010).…”

Factors Known to Influence the Development of Necrotizing Enterocolitis to Modify Expression and Activity of Intestinal Alkaline Phosphatase in a Newborn Neonatal Rat Model

“…35,36 Enteral barrier, local and systemic inflammation in an NEC model improved following IAP administration. 14,18,19 One important question remains as to whether the deficiency of IAP leads to an increased risk of NEC or whether NEC leads to decreased IAP expression. 37 Preterm rats have decreased expression of IAP when increased enteric inflammation ensues during NEC stressors.…”

“…17 Our previous research demonstrated that IAP is highly effective in the NEC in a rodent model, ameliorating enteral histologic injury, increasing enteral barrier function, and decreasing local and systemic inflammation. 14,[18][19][20] Expression of IAP is enterocyte differentiation dependent and IAP is regarded as a key enzyme when considering changes in the primary digestive and absorptive function. 21 While several regulators of IAP expression and transcription have been identified including cdx1 and cdx2, and Kruppel like factor 4, 22,23 it is unknown the impact that formula feeding and cesarean section have in the first few days of the neonatal rat model.…”

Experimental Anti-Inflammatory Drug Semapimod Inhibits TLR Signaling by Targeting the TLR Chaperone gp96

“…The neonates are generally supersensitive to the TLR ligands (31). The naïve intestinal epithelium of the neonates responds to TLR ligands (27, 28, 30), and these responses may play critical role in the pathogenesis of NEC (32-34, 61). Thus, Semapimod may prevent NEC by blocking TLR ligand signaling in the neonatal intestine.…”