Objective To test the hypothesis that feeding and antibiotic exposures affect intestinal barrier maturation in preterm infants, we serially measured intestinal permeability (IP) biomarkers in infants <33 wks gestation (GA) during the first two weeks of life. Study design Eligible infants <33 wks GA were enrolled within 4 days of birth in a prospective study of IP biomarkers (NCT01756040). Study participants received the non-metabolized sugars lactulose/rhamnose (La/Rh) enterally on study days 1, 8 and 15 and La/Rh were measured in urine by HPLC. Serum zonulin and fecal alpha-1 antitrypsin, two other IP markers, were measured by semi-quantitative western blot and ELISA, respectively. Results In a cohort of 43 subjects, the La/Rh ratio was elevated on day 1 and decreased over 2 weeks, but remained higher in infants ≤28 wk GA compared with IP in infants >28 wk GA. Exclusive breastmilk feeding was associated with more rapid maturation in intestinal barrier function. A cluster analysis of 35 subjects who had urine samples from all time points revealed three IP patterns (Cluster 1, normal maturation [N=20 (57%)]; Cluster 2, decreased IP during the first week and subsequent substantial increase [N=5 (14%)]; and Cluster 3, delayed maturation [N=10 (29%)]). There were trends towards more prolonged antibiotic exposure (p=0.092) and delayed initiation of feeding ≥4 days (p=0. 0.064) in infants with abnormal IP patterns. Conclusions Intestinal barrier maturation in preterm infants is GA and postnatal age-dependent and is influenced by feeding with a maturational effect of breastmilk feeding and may be by antibiotic exposures.

Intestinal barrier immaturity, or “leaky gut,” is the proximate cause of susceptibility to necrotizing enterocolitis in preterm neonates. However, the impact of intestinal microbiota development on intestinal mucosal barrier maturation has not been evaluated in this population. In this study, we investigated a longitudinally sampled cohort of 38 preterm infants < 33 weeks gestation monitored for intestinal permeability (IP) and fecal microbiota during the first 2 weeks of life. Rapid decrease in IP indicating intestinal barrier function maturation correlated with significant increase in community diversity. In particular, members of the Clostridiales and Bifidobacterium were highly transcriptionally active, and progressively increasing abundance in Clostridiales was significantly associated with decreased intestinal permeability. Further, neonatal factors previously identified to promote intestinal barrier maturation, including early exclusive breastmilk feeding and shorter duration antibiotic exposure, associate with the early colonization of the intestinal microbiota by members of the Clostridiales, which altogether are associated with improved intestinal barrier function in preterm infants.

The study objective was to determine whether Ureaplasma respiratory tract colonization of preterm infants <33 weeks gestation is associated with an increased risk for necrotizing enterocolitis (NEC). One or more tracheal or nasopharyngeal aspirates for Ureaplasma culture and PCR were obtained during the first week of life from 368 infants <33 weeks gestation enrolled from 1999-2003 or from 2007-2009. NEC Bell stage ≥2 was confirmed by radiological criteria, and pathology, if available. Cord serum samples were analyzed for IL-6 and IL-1β concentrations and placentas were reviewed for histological chorioamnionitis in the first cohort. NEC was confirmed in 29/368 (7.9%) of the combined cohorts. The incidence of NEC was 2.2-fold higher in Ureaplasma-positive (12.3%) than Ureaplasma-negative infants (5.5%) <33 wk (OR 2.43, 95%CI 1.13-5.22, P=0.023) and 3.3-fold higher in Ureaplasma-positive (14.6%) than Ureaplasma-negative (4.4%) infants ≤28 wks (OR 3.67, 95%CI 1.36-9.93, P=0.01). Age of onset, hematologic parameters at onset, and NEC severity were similar between Ureaplasma-positive and negative infants. Cord serum IL-6 and IL-1β concentrations were significantly higher in Ureaplasma-positive than in Ureaplasma-negative NEC-affected infants. Ureaplasma may be a factor in NEC pathogenesis in preterm infants by contributing to intestinal mucosal injury and/or altering systemic or local immune responses.

19Intestinal barrier immaturity, or "leaky gut," is the proximate cause of susceptibility to 20 necrotizing enterocolitis in preterm neonates. However, the impact of intestinal 21 microbiota development on intestinal mucosal barrier maturation has not been 22 evaluated in this population. In this study, we investigated a longitudinally sampled 23 cohort of 38 preterm infants monitored for intestinal permeability (IP) and fecal 24 microbiota during the first two weeks of life. Rapid decrease in IP indicating intestinal 25 barrier function maturation correlated with significant increase in community diversity. In 26 particular, members of the Clostridiales and Bifidobacterium were highly 27 transcriptionally active, and progressively increasing abundance in Clostridiales was 28 significantly associated with decreased gut permeability. Further, neonatal factors 29 previously identified to promote intestinal barrier maturation, including early exclusive 30 breastmilk feeding and low antibiotic exposure, favor the early colonization of the gut 31 microbiota by members of the Clostridiales, which altogether are associated with 32 improved intestinal barrier function in preterm infants. 33 affecting approximately 7-10% of preterm neonates with mortality as high as 30-50% 13 . 57In this condition, bacteria across the intestinal wall leading to local and systemic 58 infection and inflammation, and bowel wall necrosis and perforation. Intestinal barrier 59 immaturity, characterized as elevated intestinal permeability (IP), or "leaky gut", is the 60 proximate cause of susceptibility to NEC in preterm neonates 14,15 . It is critical to 61 characterize the preterm infant intestinal microbiota to identify dysbiotic states 62 associated with increased intestinal leakiness, as well as beneficial bacteria associated 63 with improved intestinal barrier function, for subsequent stratification of early diagnosis, 64 early intervention and primary prevention of leaky gut and its sequelae. 65 66Despite the critical role of the microbial community in intestinal barrier function, its effect 67 on newborn IP is unknown. In particular, the microbiota of preterm neonates with 68 measured elevated IP, a high-risk population for NEC, has not been studied previously. 69We hypothesize that the intestinal microbiota plays a pivotal role in modulating IP and 70 that the presence of "beneficial" bacteria will be associated with improved intestinal 71 barrier function in preterm infants. In this study, we studied a cohort of 38 preterm 72 infants born prior to 33 weeks of gestation. IP was measured by urinary detection of 73 orally administered sugar probes lactulose and rhamnose using high pressure liquid 74 chromatography 16 with coinciding measures of the composition and function of the fecal 75 microbial communities were investigated. We sampled three time points, study day 1, 8, 76and 15, during the first two weeks of life, which is a critical period corresponding to the 77 initiation of the intestinal microbiota development process [16][17]...

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