Preterm infants are at increased risk for the development of serious nosocomial infections, especially very low birth weight infants at a NICU . In a recent review of the literature, we found that the intestinal bacterial colonisation in preterm infants is much more diverse than in term infants and that antibiotics cause a significant delay in the intestinal bacterial colonisation . Furthermore, the possibility to administer enteral nutrition is limited due to immaturity of the gastrointestinal tract in the presence of a developing immune system.
Human milk has anti-inflammatory effects and bifidogenic effects on the intestinal microflora [3, 4]. Term breastfed infants have less infections and develop less atopy compared with formula fed infants [5, 6]. Many factors have been implicated in this effect, including human milk oligosaccharides [7, 8]. Many attempts have been made to mimic this effect of human milk. Addition of prebiotics, consisting of neutral oligosaccharides, to infant formula has been found to show potential advantageous effects in term and preterm infants [9, 10]. Besides neutral oligosaccharides, breast milk also contains acidic oligosaccharides . In the past, research has mainly focussed on neutral oligosaccharides such as galacto-oligosaccharides and fructo-oligosaccharides (GOS/FOS). Supplementation of GOS/FOS in term and preterm infants results in: 1. Stimulation of a bifidogenic intestinal flora [11, 12]; 2. Reduction of pathogens in the intestine ; 3. Production of beneficial fermentation metabolites such as short chain fatty acids (SCFA) ; 4. Decrease of stool pH ; 5. Improved intestinal physiology (stool characteristics, motility) ; 6. Less infections and atopy [15, 16].
In breast milk 80% of the oligosaccharides are neutral (as in GOS/FOS), and 20% are acidic. Acidic oligosaccharides (AOS) can be derived from carrots with their active component pectin. Pectin is a common structural component of all higher plants. Cooking of pectin-containing vegetables induces the cleavage of the long-chain pectin polymers into acidic oligosaccharides. For already nearly 100 years, carrots are known to have health promoting effects. In 1908, carrot soup was used as treatment of diarrhoea . In 1997, Guggenbichler identified the anti-adhesive effect of acidic oligosaccharides .
The combination of acidic and neutral oligosaccharides may have several advantageous effects [10, 19–21]: 1. Improvement of the response to immunizations; 2. Stimulation of Th1 cytokine response (e.g. TNF-α, IFN-gamma) and decreasing the Th2 cytokine release (e.g. IL-10, IL-4, IL-5); 3. Stimulation of a bifidogenic intestinal flora; 4. Preventing adhesion of pathogens to epithelial tissues.
As a result of these effects, we hypothesise that preterm infants receiving a combination of GOS/FOS with AOS may have: 1. Less infections; 2. Better response to immunizations; 3. Less atopy later in life; 4. Less feeding intolerance.
As infections are still a major cause of morbidity and mortality in preterm infants, reducing the incidence of serious infections is very important. Controversy exists on the definitions for serious infections in neonates. Therefore in a previous study, we adjusted the criteria of the Centers for Disease Control and Prevention for serious infections in children < 1 year for use in neonates , and found in a prospective study these criteria applicable in preterm infants .
In conclusion, this double-blind randomised controlled trial aims to determine the effect of enteral supplementation of acidic and neutral oligosaccharides on infectious morbidity (primary outcome), immune response to immunizations, feeding tolerance and short-term and long-term outcome in preterm infants. In addition, an attempt is made to elucidate the role of acidic and neutral oligosaccharides in postnatal modulation of the immune response and postnatal adaptation of the gut.