Influence of Bovine Lactoferrin on Feeding Intolerance and Intestinal Permeability in Preterm Neonates
Influence of Bovine Lactoferrin on Feeding Intolerance and Intestinal Permeability in Preterm Neonates
Preterm infants are at increased risk of developing feeding intolerance due to functional
 immaturity of their gastrointestinal tract and may lead to discontinuation of enterak
 feeding.

 Lactoferrin promotes the growth of probiotic bacteria, stimulates differntiation and
 proliferation of enterocytes and expression of intestinal digestive enzymes , lead to
 improvement of feeding intolerance.

 So we hypothesized that supplementation of bovine lactoferrin would be benificial on feeding
 intolerance and decrease intestinal permeability in preterm infants with feeding intolerance.
Preterm infants are at increased risk of developing feeding intolerance (FI) due to
 functional immaturity of their gastrointestinal tract. Feeding intolerance often leads to
 discontinuation of enteral feeds, delayed achievement of full enteral feeding, increased
 length of hospital stay, sub-optimal nutrition, postnatal growth restriction, prolonged
 parenteral feeding with an increased risk of nosocomial infections and poor
 neurodevelopmental outcome.1,2 Although there is no consensus on the definition of FI, a
 gastric residual volume of more than 50% of the previous feeding volume, gastric
 regurgitation, abdominal distension and/or emesis, are used as indicators for FI.1,3
 Intestinal microflora plays an important role in the promotion and maintenance of intestinal
 functions such as mucosal trophism, gut barrier, sensori-motor function, hormone secretion,
 angiogenesis and immune defences.4 Many factors lead to unbalanced microflora colonization in
 the preterm infant as cesarean delivery, NICU stays, fasting and antibiotic use, leading to
 FI and necrotizing enterocolitis (NEC).5 Several strategies have been developed to improve
 the enteral feeding tolerance in preterm infants such as the implementation of standardized
 feeding protocols, the use of prokinetic agents and probiotics. The beneficial effect of
 probiotic supplementation on FI has been reported in several studies.6,7 Multiple mechanism
 of action has been proposed, including strengthening the intestinal mucosal barrier function,
 thereby inhibiting bacterial translocation, regulation of bacterial colonization, modulation
 of intestinal inflammation.8 Although probiotics may be a promising approach for the
 prevention of FI and NEC in preterm infants, several issues exist regarding strain
 specificity, schedule of supplementation, and long-term adverse effects.9 Lactoferrin (LF), a
 member of the transferrin family of iron-binding glycoproteins, is present in high amounts in
 colostrum and maternal milk.

 Lactoferrin is almost completely absent from processed formulae. Lactoferrin is the major
 factor responsible for the protective effects of breast milk-decreased rates of infection and
 NEC, improved neurodevelopment and better immune responses due to its antimicrobial,
 anti-oxidant, anti-inflammatory and immunomodulatory properties.10 Lactoferrin stimulates
 gastrointestinal cell proliferation and differentiation via extracellular signal-regulated
 kinase, limits IL-8 secretion, prevents NF-kB and hypoxia-inducible factor-1a activation,
 suggesting strong anti-inflammatory effects.11 Lactoferrin also promotes the growth of
 probiotic bacteria, stimulates differentiation and proliferation of enterocytes and
 expression of intestinal digestive enzymes.12 Its bifidogenic activity in the gut may improve
 tolerance to feeds.13 Very preterm infants receive little or no milk during early neonatal
 period and have low intake of LF.14 Because human LF is expensive, bovine lactoferrin has
 been considered as an alternate supplement to correct this deficiency, as it is about 70%
 homologous with human LF but has higher antimicrobial activity.15 Bovine LF has no known
 toxicity and is registered as GRAS (Generally Recognised As Safe) by the US Food and Drug
 Administration.16 A systematic review including 6 RCTs involving almost 1100 preterm infants
 concluded that there is an evidence of low quality suggesting that LF supplementation to
 enteral feeds with or without probiotics decreases late-onset sepsis and NEC stage II or III
 in preterm infants without adverse effects.17 A more recent systematic review, included 9
 trials that enrolled 1834 preterm infants indicated that LF supplementation in preterm
 neonates is safe without obvious adverse effects, could significantly reduce the incidence of
 NEC, and hospital-acquired infection. Moreover, LF could reduce the time to achieve full
 enteral feeding (the mean difference for days to achieve full enteral feeding in preterm
 infants was -2.19 days) and duration of hospitalization of preterm infants.18 A large RCT
 "The ELFIN Trial", included 2203 infants, has demonstrated that enteral LF supplementation
 (150 mg/kg per day until 34 weeks' postmenstrual age) does not reduce the risk of late-onset
 infection, other morbidity, or mortality in very preterm infants. However, this study did not
 rule out important potential benefits, particularly for infants who receive formula for over
 half of days of enteral feeds.19 The intestinal barrier provides highly selective protection
 of the human body against the environment. It has several facets, which include: intestinal
 microbiota; a protective mucus layer; intestinal epithelium cells with tight junctions (TJ);
 and cells of the immune system and enteric nervous system.20 Intestinal barrier maturation in
 preterm infants is gestational age and postnatal age-dependent and is influenced by feeding
 type and antibiotic exposure.21 Zonulin (ZO), is an established marker of intestinal
 permeability. Zonulin is one of the proteins that regulate the function of TJ between
 intestinal epithelial cells, which determines paracellular transport in the gut. It is one of
 the main factors securing the action of the "gate of the gut" mechanism by reversibly
 influencing TJ's tightness. Zonulin increase and disruption of TJ has been demonstrated in an
 animal model of NEC with intestinal TJ destruction proven by immune histochemical
 evaluation.22 Zonulin increases in newborns presenting symptoms of infection and/ or
 inflammation of the gut or being at risk of intestinal pathology.23 We hypothesized that
 supplementation of bovine LF would have beneficial effects on feeding tolerance and decrease
 intestinal permeability in preterm infants with FI.
Inclusion Criteria:

 -  preterm infants delivered at gestational age 26 to 34 weeks admitted to NICU OF
 mansoura university children hospital Diagnosed as feeding intolerance defined as
 gastric volume residual of more than 50% of the previous feeding volume, gastric
 regurgitation, abdominal distention and or emesis Receive premature cow's protein
 based formula enteral feeding

 Exclusion Criteria:

 Major congenital malformations Anatomical gastrointestinal anomalies Birth asphyxia
 Presence of NEC Neonate receiving Expressed breast milk Infant with history of cow's milk
 allergy

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