Apical sodium-dependent bile acid transporter upregulation is associated with necrotizing enterocolitis

Abstract

Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency of premature infants. Previously, we showed that luminal bile acids (BAs) are increased and correlated with disease development and that the apical sodium-dependent BA transporter (ASBT), which transports BAs from the ileal lumen into enterocytes, is upregulated in rats with NEC. We hypothesized that intraenterocyte, rather than luminal, BAs are associated with NEC and that upregulation of ASBT may be a mechanism by which this occurs. Neonatal rats with or without the ASBT inhibitor SC-435, mice in which ASBT was knocked out, and mice that overproduce BAs were subjected to the NEC protocol. Disease development, ASBT, and the farnesoid X receptor protein, along with luminal and intraenterocyte BA levels, were assessed. In addition, ileal sections from premature infants with and without NEC were examined for ASBT via immunohistology and real-time PCR. When BAs were not transported into enterocytes (rats given SC-435 and ASBT knockout mice), severity and incidence of NEC were reduced. In contrast, in mice that overproduce BAs, ASBT was elevated, intraenterocyte BAs were increased, and disease development was increased. ASBT staining was more intense on the apical membrane of ileal enterocytes from premature infants with NEC than premature infants with non-NEC diagnoses. In addition, ASBT mRNA levels were significantly higher in infants with NEC. These data show that accumulation of intraenterocyte BAs contributes to disease development, elevated ASBT increases disease severity in experimental models of NEC, and ASBT is elevated in human NEC. These data confirm that BAs and upregulation of ASBT play a crucial role in NEC pathogenesis and suggest that inhibition of ASBT could be utilized as a therapeutic modality against this disease.

Bile acids regulate intestinal cell proliferation by modulating EGFR and FXR signaling

“…While this may be beneficial in cancer models, proliferation is desirable for injury repair. Furthermore, FXR may be overactive when levels of DCA increase in the terminal ileum (26,27), where, typically, the presence of DCA is minimal. In a disease such as NEC, where DCA levels are increased (25,26), activation of FXR by DCA could contribute to intestinal injury.…”

“…Indeed, DCA levels are abnormally elevated in the ileum of rodents subjected to experimental NEC (26). Cholestyramine, which sequesters BAs in the gut, reduces the incidence of experimental murine NEC, suggesting that alterations in the BA pool are a cause, rather than an effect, of the disease (26,27). In IBD, disruption of ileal BA transporters leads to an imbalance in the luminal BA pool secondary to impaired BA detoxification (39).…”

Fecal Bile Salts and the Development of Necrotizing Enterocolitis in Preterm Infants

“…Previously, biliary hypersecretion of BSs has been shown to promote NEC development in mice, whereas intraluminal capture of BS in the intestine by binding agents (e.g. cholestyramine) has been shown to mitigate NEC in a rodent model [6]. Intestinal damage occurs when high concentrations of intraluminal intestinal BS lead to intracellular intestinal accumulation.…”

N-glycosylation is essential for ileal ASBT function and protection against proteases

“…On the other hand, a decrease in ASBT expression was shown in disorders with lipid abnormalities such as familial type IV hypertriglyceridemia (16). Further, ASBT function and expression are increased in diseases that are associated with bile acid overload in the liver like necrotizing enterocolitis (NEC) and progressive familial intrahepatic cholestasis (PFIC) (10,19). Therefore, much attention has been focused on investigating ASBT regulation and defining molecular targets for modulating its function and expression.…”