The administration of a pre-digested fat-enriched formula prevents necrotising enterocolitis-induced lung injury in mice

Necrotising enterocolitis (NEC) is a devastating disease of prematurity and a leading cause of death from gastrointestinal disease in the neonatal intensive care units of hospitals around the world^(1–3). One of the most devastating complications of NEC is the development of lung injury⁽⁴⁾, which is more severe than the lung injury which occurs in premature infants who do not develop NEC^(5,6). In seeking to understand the causes of NEC and its associated lung injury, a growing body of research⁽⁷⁾ has shown that NEC typically develops in the premature infant in the setting of an abnormal microbiome that is enriched in gram negative bacteria⁽⁸⁾, often after the administration of formula feeds⁽⁹⁾. These findings suggest that the interplay between formula administration and gut immaturity combines in the pathogenesis of this disease⁽¹⁰⁾. Prior studies – including our own – have focused on the first of these factors, showing that the premature intestine expresses high levels of the bacterial receptor, toll-like receptor 4 (TLR4), which becomes activated by the abnormal microbiome of the premature host, leading to barrier injury and NEC^(11,12). There has been less focus on the role of infant formula in NEC development, which represents a significant gap in our knowledge. This gap is particularly important given that the solid link between formula administration and NEC development reveals that specific components of the infant formula may contribute to both NEC development and the presence of NEC-induced lung injury⁽¹³⁾. The precise components of formula that induce NEC, and strategies to manipulate these components as a therapeutic approach for NEC and NEC-induced lung injury, thus remain of great interest.

In seeking to understand the mechanisms leading to the development of NEC-induced lung injury, our laboratory has recently shown that the activation of TLR4 on the intestinal epithelium leads to the release of the damage-associated molecule HMGB1, which can activate TLR4 on the pulmonary epithelium, resulting in NEC⁽¹⁴⁾. Mice lacking HMGB1 on the intestinal epithelium and mice lacking TLR4 in the lung epithelium were both protected from NEC, indicating that a link between the gut and the lung leads to disease development. Moreover, the presence of greater lung immaturity and impaired...