Anemia induces gut inflammation and injury in an animal model of preterm infants

Abstract

BACKGROUND While very low birth weight (VLBW) infants often require multiple red blood cell transfusions, efforts to minimize transfusion‐associated risks have resulted in more restrictive neonatal transfusion practices. However, whether restrictive transfusion strategies limit transfusions without increasing morbidity and mortality in this population remains unclear. Recent epidemiologic studies suggest that severe anemia may be an important risk factor for the development of necrotizing enterocolitis (NEC). However, the mechanism whereby anemia may lead to NEC remains unknown. STUDY DESIGN AND METHODS The potential impact of anemia on neonatal inflammation and intestinal barrier disruption, two well‐characterized predisposing features of NEC, was defined by correlation of hemoglobin values to cytokine levels in premature infants and by direct evaluation of intestinal hypoxia, inflammation and gut barrier disruption using a pre‐clinical neonatal murine model of phlebotomy‐induced anemia (PIA). RESULTS Increasing severity of anemia in the preterm infant correlated with the level of IFN‐gamma, a key pro‐inflammatory cytokine that may predispose an infant to NEC. Gradual induction of PIA in a pre‐clinical model resulted in significant hypoxia throughout the intestinal mucosa, including areas where intestinal macrophages reside. PIA‐induced hypoxia significantly increased macrophage pro‐inflammatory cytokine levels, while reducing tight junction protein ZO‐1 expression and increasing intestinal barrier permeability. Macrophage depletion reversed the impact of anemia on intestinal ZO‐1 expression and barrier function. CONCLUSIONS Taken together, these results suggest that anemia can increase intestinal inflammation and barrier disruption likely through altered macrophage function, leading to the type of predisposing intestinal injury that may increase the risk for NEC.

The development of intestinal dysbiosis in anemic preterm infants

“…In our cohort, the similarity in intestinal microbiome between the anemia and non-anemia groups during the first postnatal month suggested that the differences in perinatal factors and in the early antibiotic exposure were less likely to influence the subsequent differences in their microbiomes. The changes toward a dysbiotic microbiome together with a decline in Hct levels in anemic infants, warrant further investigations, especially in light of the findings in preclinical models (5,6).…”

“…In very low birth weight (VLBW) infants, anemia has been implicated in the development of necrotizing enterocolitis (NEC), a severe inflammatory and necrotic bowel disease of prematurity with high rates of morbidity and mortality (1,2). More recent studies show that mucosal inflammation and injury, the hallmarks of NEC, are present in infants with anemia (3,4) and neonatal mouse models demonstrate that anemia itself is pro-inflammatory (5,6). In addition, one mouse model indicates that the severity of NEC correlates with the severity of anemia (6).…”

Erythropoietin prevents necrotizing enterocolitis in very preterm infants: a randomized controlled trial

“…Multiple observational studies have reported an association between severe anemia and the development of NEC [34][35][36]. Anemia can impair splanchnic perfusion and increase intestinal inflammation and barrier disruption leading to tissue hypoxia and anaerobic metabolism and thus predisposing to ischemic injury and possibly to NEC [37][38][39][40]. Thus, preventing anemia could be a strategy to prevent the development of NEC, and RBC transfusion is a commonly used method to achieve this [41,42].…”

Anemia of Prematurity and Oral Feeding Milestones in Premature Infants

“…Similarly, the critical value for abdominal tissue desaturation is noted when the HCT is less than 24%, predisposing premature infants for necrotizing enterocolitis and intestinal injury. [23][24][25] AOP also reported to be associated with increased incidence of intermittent hypoxic episodes in premature infants, especially after the first month of life, and RBC transfusions has been associated with reduction in apnea frequency in the short term. 26,27 In our study, premature infants with severe AOP during initial PO were more premature at birth, compared with controls.…”