Anti-inflammatory mechanisms of bioactive milk proteins in the intestine of newborns

Abstract

The human newborn infant is susceptible to gut inflammatory disorders. In particular, growth-restricted infants or infants born prematurely may develop a severe form of intestinal inflammation known as necrotizing enterocolitis (NEC), which has a high mortality. Milk provides a multitude of proteins with anti-inflammatory properties and in this review we gather together some recent significant advances regarding the isolation and proteomic identification of these minor constituents of both human and bovine milk. We introduce the process of inflammation, with a focus on the immature gut, and describe how a multitude of milk proteins act against the inflammatory process according to both in vitro and in vivo studies. We highlight the effects of milk proteins such as caseins, and of whey proteins such as alpha-lactalbumin, beta-lactoglobulin, lactoferrin, osteopontin, immunoglobulins, trefoil factors, lactoperoxidase, superoxide dismutase, platelet-activating factor acetylhydrolase, alkaline phosphatase, and growth factors (TGF-β, IGF-I and IGF-II, EGF, HB-EGF). The effects of milk fat globule proteins, such as TLR-2, TLR-4, sCD14 and MFG-E8/lactadherin, are also discussed. Finally, we indicate how milk proteins could be useful for the prophylaxis and therapy of intestinal inflammation in infants and children.

Introduction

Before birth, the gastrointestinal tract (GIT) has matured to digest human milk and to tolerate the invasion by billions of bacteria. It produces mucins and defensins and has normal proliferation, restitution and cellular homeostasis. Not surprisingly, GIT inflammatory reactions are common in newborn infants, particularly in compromised infants such as those born preterm and/or growth-restricted. The most severe GIT inflammatory condition of very preterm infants is necrotizing enterocolitis (NEC), which has a high mortality (10–50%, Uauy et al., 1991, Neu and Walker, 2011b). Causative factors of NEC in preterm newborns include reduced peristalsis, impaired epithelial barrier function and GIT immaturity characterized by impaired enterocyte restitution (Fig. 1). Other factors include a leaky mucosal barrier, dys-colonization, bacterial translocation, reduced mesenteric perfusion and excessive milk feeding. The type of milk diet is also important as formula feeding may lead to a different bacterial colonization and function of the gut, relative to mother's milk or donor human milk (Lin and Stoll, 2006, Henry and Moss, 2009).

Studies in both infants and animal models suggest that human milk protects against NEC, while formula-feeding could predispose to NEC (Maayan-Metzger et al., 2012, Moller et al., 2011, Sangild et al., 2006, Nadler et al., 2000). In this review, we use the interactions between human and bovine milk components and NEC development to illustrate how milk bioactive proteins may act as anti-inflammatory agents. We refer also to studies on the effects of milk proteins against experimentally induced colitis in more mature rodent models. Although there are differences between colitis and NEC, similarities between these two forms of inflammation exist (Pothoulakis et al., 1998). Likewise, there are similarities to the pro-inflammatory state induced by parenteral feeding, and in both piglets and rodent models intake of milk components exert marked effects in this state (Liu et al., 2009). We highlight these as potential mechanisms by which human and bovine milk proteins protect against inflammation in the neonate. The main focus is on the direct anti-inflammatory actions of human and bovine milk proteins on intestinal cells although it is acknowledged that part of the effects also may be mediated indirectly via the anti-bacterial effects of milk components. We focus on mature bovine and human milk, acknowledging the fact that many of the milk growth factors, immunomodulatory components and antimicrobials are found in highest concentrations in colostrum, the milk secreted during the first days after birth.