Intestinal Barrier Maturation in Very Low Birthweight Infants: Relationship to Feeding and Antibiotic Exposure

Abstract

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 weeks gestation (gestational age [GA]) during the first 2 weeks of life.

Study design: Eligible infants <33 weeks GA were enrolled within 4 days of birth in a prospective study of IP biomarkers (NCT01756040). Study participants received the nonmetabolized sugars lactulose/rhamnose enterally on study days 1, 8, and 15 and lactulose/rhamnose were measured in urine by high-performance liquid chromatography. Serum zonulin and fecal alpha-1-anti-trypsin, 2 other IP markers, were measured by semiquantitative Western blot and ELISA, respectively.

Results: In a cohort of 43 subjects, the lactulose/rhamnose ratio was increased on day 1 and decreased over 2 weeks, but remained higher in infants born at ≤28 weeks of gestation compared with IP in infants born at >28 weeks of gestation. 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 3 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 toward more prolonged antibiotic exposure (P = .092) and delayed initiation of feeding ≥4 days (P = .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 possibly by antibiotic exposures.

Trial registration: ClinicalTrials.gov: NCT01756040.

Keywords: alpha-1-anti-trypsin; intestinal permeability; prematurity; zonulin.

Figure 1

Study cohort recruitment. Forty-four of 199 eligible <33 weeks gestation infants were enrolled during the 18 month enrollment period April 15, 2013 to October 15, 2014. One infant died due to acute pulmonary hemorrhage after consent was obtained, but before the study solution was administered. At least one dose of study solution was administered to 43 subjects.

Figure 2

Urinary La/Rh ratio by (A) gestational age strata and study time points; (B) percent with normal intestinal barrier function (La/Rh ratio <0.05); and (C) cluster IP patterns and (D) exclusive breast milk feeding. Data are expressed as mean ± SD or percent. *p<0.05

Figure 3

Alternative measures of intestinal permeability. (A) Serum zonulin expressed relative to a healthy term control by gestational age strata and study time points; (B) Serum zonulin/urinary La/Rh ratio correlation; and (C) Fecal A1AT concentration (μg/g stool). Data are expressed as mean ± SD or percent. *p<0.05