Does Abnormal Bile Acid Metabolism Contribute to NEC?

Abstract

Bile acids (BAs) facilitate emulsification, absorption and transport of fats and sterols in the intestine and liver and are essential for normal digestion. However, accumulation of BAs in the intestine can result in damage to the intestinal epithelium. Using the neonatal rat model of NEC, we have recently shown that BAs accumulate in both the ileal lumen and enterocytes of neonatal rats with NEC and the increased BA levels are positively correlated with disease severity. Importantly, when BAs are not allowed to accumulate, neonatal rat pups develop significantly less disease. In addition, BA transporters are altered during disease development. These data indicate that BAs play an important role in the development of experimental NEC, and suggest that the inability of neonatal rats to adequately regulate BA transporters may be a mechanism by which ileal damage occurs.

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

“…Interestingly, reports that the microbiome dictates the BA pool (2,20,31) and that bacterial dysbiosis is seen in intestinal diseases such as NEC (25,26) and IBD (39) may point to a mechanism by which the microbiome alters the host intestine. Indeed, in the formula-feeding-hypoxia neonatal rat model of NEC, DCA levels are elevated (vs. dam-fed littermates) in the lumen of the terminal ileum by 24 -48 h (26, 27), while histological damage is not seen until 72 h. DCA levels are much lower in human infants that are breast-fed (29), and breast feeding has long been considered protective from NEC (45).…”

“…and contribute to diseases such as neonatal necrotizing enterocolitis (NEC) (25) and inflammatory bowel disease (IBD) (39). Indeed, DCA levels are abnormally elevated in the ileum of rodents subjected to experimental NEC (26).…”

“…In diseases such as NEC, where the intestinal microbiome is altered (9,25), the BA pool changes, potentially contributing to injury by increasing toxic BA metabolites. Cell proliferation is required for intestinal mucosal renewal after injury in normal and disease states.…”

“…In IBD, disruption of ileal BA transporters leads to an imbalance in the luminal BA pool secondary to impaired BA detoxification (39). Intestinal bacteria are responsible for modification of BAs, and an altered BA pool is the hallmark of many gastrointestinal diseases (8,25).…”

Intestinal bile acid physiology and pathophysiology

“…It should be noted however that ASBT is expressed in the kidney without being accompanied by IBABP [16] , and also that FXR knockout mice, which do not express IB-ABP, show enhanced rather than inhibited intestinal BA absorption, suggesting that IBABP may function as a negative regulator of intestinal BA reabsorption, at least in the mouse [17] . Interestingly, low IBABP expression has been linked to the risk of necrotizing enterocolitis in an animal model, suggesting that inefficient transfer of BA to the basolateral membrane may ultimately result in epithelial damage and inflammation [18] . Finally, BAs exit the enterocyte via the recently characterized OSTα/β transporter [19] , an obligate heterodimer which functions in a Na + -independent manner and also transports prostaglandin E 2 , estrone-3-sulfate, dehydroepiandrosterone sulfate [13] .…”