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

Hulzebos, Christian V.; Zoonen, Anne G. J. F. van; Hulscher, Jan B F; Schat, Trijntje E.; Kooi, Elisabeth M. W.; Koehorst, Martijn; Boverhof, Renze; Krabbe, Paul F M; Groen, Albert K.; Verkade, Henkjan J.

doi:10.1371/journal.pone.0168633

Cited by 16 publications

(20 citation statements)

References 17 publications

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“…While exposure to varying levels of hydrophobic BAs has been shown to increase proliferation of cells in esophageal reflux and Barrett's esophagus [58][59][60] , cytotoxic effects of intermittent exposure to BAs in neonatal intestine has not been published. While previous research reported a statistically significant increase in total unconjugated BAs in NEC patients compared to controls 48 , we did not observe a statistically significant increase in mean BA quantity for any individual BA, BA group, or total BAs. However, our study differed from theirs in that we used matched pairs, analyzed more samples per subject, looked at slightly different outcomes, and had lower power due to a smaller sample size and correcting for multiple comparisons (that is, we required a lower p-value for "statistical significance").…”

Section: Discussioncontrasting

confidence: 99%

Elevated Coefficient of Variation in Total Fecal Bile Acids Precedes Diagnosis of Necrotizing Enterocolitis

Knapp

Kehring

Stepp

et al. 2020

Sci Rep

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Accumulation of bile acids (BAs) may mediate development of necrotizing enterocolitis (NEC). Serial fecal samples were collected from premature infants with birth weight (BW) ≤ 1800 g, estimated gestational age (EGA) ≤ 32 weeks, and <30 days old prior to initiation of enteral feeding. Nine infants that developed Bell's Stage ≥ II NEC were matched with control infants based on BW, EGA, day of life (DOL) enteral feeding was initiated and DOL of the first sample. From each subject, five samples matched by DOL collected were analyzed for BA levels and composition. Fifteen individual BA species were measured via LC-MS/MS and total BA levels were measured using the Diazyme Total Bile Acid Assay kit. No statistically significant differences in composition were observed between control and NEC at the level of individual species (p = 0.1133) or grouped BAs (p = 0.0742). However, there was a statistically significant difference (p = 0.000012) in the mean coefficient of variation (CV) between the two groups with infants developing NEC having more than four-fold higher mean CV than controls. Importantly, these variations occurred prior to NEC diagnosis. These data suggest fluctuations in total fecal BA levels could provide the basis for the first predictive clinical test for NEC.protective responses 20 , and the concomitant dysregulation of hepatic BA transporters 21 during development of NEC. This novel paradigm encompasses major disease-associated findings and risk factors: 1) the more premature an infant, the more likely they will develop NEC 10,11 . Many of the key processes of BA homeostasis are not fully developed in neonates, but reach maturity at weaning [22][23][24][25][26][27] . 2) Formula-fed preemies are 6-10 times more likely to develop NEC 12 and have higher fecal BA levels than breast-fed preemies 28 . Further, formula feeding is required to develop experimental NEC 29,30 . 3) The majority of BA reclamation occurs in the ileum and colon, the primary sites of NEC injury 31 , and ileal BA levels increase 24-hours before inflammation or histological damage in experimental NEC 32 . 4) Bacterial colonization is required for both development of NEC and formation of secondary BAs. While no specific pathogen has been conclusively associated with NEC 33-43 , disease cannot be developed in germ free conditions 13,14 and pneumatosis intestinalis, the most pathognomonic radiological finding of NEC, is thought to be caused by bacterial overgrowth 44 . Bacteria are also required for formation of more toxic, hydrophobic BAs 45-47 , which are higher in both experimental 18 and human NEC 48 .To further characterize how BAs are dysregulated in human NEC, we prospectively collected fecal samples from premature infants and determined BA levels and composition from matched-pairs diagnosed with NEC versus those without NEC. Contrary to a previous study 48 , we found no statistically significant differences in BA composition between control and NEC. However, there was a statistically significant difference (p = 0.000012) in the mean...

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Section: Discussioncontrasting

confidence: 99%

Elevated Coefficient of Variation in Total Fecal Bile Acids Precedes Diagnosis of Necrotizing Enterocolitis

Knapp

Kehring

Stepp

et al. 2020

Sci Rep

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“…Five to six days before NEC onset, fecal bile salt levels were significantly higher compared with age matched controls. The slower decay of fecal BS supports a potential role for altered BS metabolism or transport in NEC development (56). This difference in trajectory may be intrinsic to host phenotype, but is also linked to more modifiable factors including the gut microbiota, which has been previously shown to alter the expression of bile salt transporters (57).…”

Section: Non-microbial Biomarkersmentioning

confidence: 81%

The Microbiome and Biomarkers for Necrotizing Enterocolitis: Are We Any Closer to Prediction?

Rusconi

Good

Warner

2017

The Journal of Pediatrics

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“…Within this context, their contribution to NEC pathophysiology has recently been studied. In the week preceding NEC manifestation, fecal unconjugated BA levels were found to be higher in preterm infants, eventually developing NEC compared with gestation-matched controls [10]. More precisely, the intraluminal accumulation of conjugated BAs resulted in intestinal epithelial damage, similar to the histopathological findings in NEC [11].…”

Section: Introductionmentioning

confidence: 54%

“…In addition, the increased expression of the apical sodium-dependent bile acid transporter (ASBT) in the terminal ileum, a protein involved in the uptake of conjugated BAs into the enterocytes, was reported in preterm infants with NEC and in an experimental NEC model with rodents which correlated with the location of intestinal damage, suggesting increased BAs uptake by enterocytes [13,14]. Consequently, high concentrations of intraluminal BAs resulted in their accumulation within enterocytes, with concomitant enterocyte damage [10]. Moreover, a decreased expression of the ileal bile acid-binding protein (IBABP) was seen in the terminal ileum of rats in an experimental NEC model, suggesting insufficient transport from the apical to the basolateral side of enterocytes with consequent BAs accumulation within the enterocytes [14].…”

Section: Introductionmentioning

confidence: 99%

Prophylactic Intra-Uterine β-Cyclodextrin Administration during Intra-Uterine Ureaplasma parvum Infection Partly Prevents Liver Inflammation without Interfering with the Enterohepatic Circulation of the Fetal Sheep

et al. 2020

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Chorioamnionitis can lead to inflammation and injury of the liver and gut, thereby predisposing patients to adverse outcomes such as necrotizing enterocolitis (NEC). In addition, intestinal bile acids (BAs) accumulation is causally linked to NEC development. Plant sterols are a promising intervention to prevent NEC development, considering their anti-inflammatory properties in the liver. Therefore, we investigated whether an intra-amniotic (IA) Ureaplasma parvum (UP) infection affected the liver and enterohepatic circulation (EHC) and evaluated whether an IA administered plant sterol mixture dissolved in β-cyclodextrin exerted prophylactic effects. An ovine chorioamnionitis model was used in which liver inflammation and the EHC were assessed following IA UP exposure in the presence or absence of IA prophylactic plant sterols (a mixture of β-sitosterol and campesterol dissolved in β-cyclodextrin (carrier)) or carrier alone. IA UP exposure caused an inflammatory reaction in the liver, histologically seen as clustered and conflated hepatic erythropoiesis in the parenchyma, which was partially prevented by IA administration of sterol + β-cyclodextrin, or β-cyclodextrin alone. In addition, IA administration of β-cyclodextrin prior to UP caused changes in the expression of several hepatic BAs transporters, without causing alterations in other aspects of the EHC. Thereby, the addition of plant sterols to the carrier β-cyclodextrin did not have additional effects.

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

Cited by 16 publications

References 17 publications

Elevated Coefficient of Variation in Total Fecal Bile Acids Precedes Diagnosis of Necrotizing Enterocolitis

Elevated Coefficient of Variation in Total Fecal Bile Acids Precedes Diagnosis of Necrotizing Enterocolitis

The Microbiome and Biomarkers for Necrotizing Enterocolitis: Are We Any Closer to Prediction?

Prophylactic Intra-Uterine β-Cyclodextrin Administration during Intra-Uterine Ureaplasma parvum Infection Partly Prevents Liver Inflammation without Interfering with the Enterohepatic Circulation of the Fetal Sheep

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