Maternal breast milk transforming growth factor-beta and feeding intolerance in preterm infants

Abstract

Background Feeding intolerance occurs commonly in the NICU. Breast milk contains a large pool of transforming growth factor-beta (TGF-beta). Few studies describe TGF-beta levels in preterm milk, and the relationship to feeding intolerance (FI) remains unexplored. We measured TGF-beta levels in preterm breast milk to investigate a correlation with FI in preterm infants. Methods Prospective observational trial of 100 mother-infant pairs, enrolling infants born below 32 weeks gestation and less than 1500 grams, and mothers who planned to provide breast milk. TGF-beta levels were measured using ELISA. Infant charts were reviewed for outcomes. Results TGF-beta declined postnatally, most elevated in colostrum (p<0.01). TGF-beta 2 levels were higher than TGF-beta 1 at all time points (p<0.01). Colostrum TGF-beta levels correlated inversely with birth weight (p<0.01) and gestational age (p<0.05). One week TGF-beta 2 levels were reduced in growth-restricted infants with FI (p<0.01). Of infants with NEC, TGF-beta 2 levels appeared low, but small sample size precluded meaningful statistical comparisons. Conclusions TGF-beta levels decline temporally in preterm milk. TGF-beta 1 colostrum levels correlate inversely with birth weight and gestational age. TGF-beta 2 may play a role in FI in growth-restricted infants. The relationship of TGF-beta 2 and NEC merits future investigation.

Does Caesarean Section or Preterm Delivery Influence TGF-β2 Concentrations in Human Colostrum?

“…The abundance of TGF-β2 in human colostrum has been previously reported and shown to be significantly associated with the induction of serum IgA production [28] that plays a pivotal role in innate defenses at all mucosal surfaces including the gastrointestinal, respiratory and urogenital tracts. The concentration of the TGF-β2 isoform is higher in the colostrum and milk collected in the first week after delivery from mothers of food-tolerant neonates compared to the milk of mothers of food intolerant neonates [18]. This finding supports the role of TGF-β2 in intestinal homeostasis.…”

“…Furthermore, TGF-β2 can inhibit the inflammatory response in immature human intestinal epithelial cells and suppress the expression of macrophage cytokines, thereby reducing the risk of necrotizing enterocolitis (NEC) in preterm neonates [15][16][17]. On the other hand, there are also data suggesting that higher levels of TGF-β2 may be related to NEC [18]. Furthermore, systemic review from 2019 suggests an increased risk of allergic diseases in infants whose mothers had higher levels of TGF-β2 in milk, but due to differences in studies' methodology and outcomes, this issue remains unclear [19].…”

Pathogenesis of NEC: Role of the innate and adaptive immune response

“…TGF-β can also initiate local production of IgA in the gut, providing additional protection 72 . Levels of TGF-β in human milk may predict feeding intolerance in growth restricted infants 73 . Both IL-10 and TGF-β have been shown to reduce inflammatory signaling by fetal human enterocytes in vitro 74 .…”

Cytokines and growth factors in the developing intestine and during necrotizing enterocolitis

“…Orally-ingested milk-borne TGF-β2 could possibly patch this deficiency, but there are several physiological constraints: (1) preterm human milk contains a large pool of TGF-β2, but most of it exists in a latent form or sequestered by chondroitin sulfate proteoglycans 79,80 and (2) mothers who give birth to growth-restricted preterm infants may produce very low levels of TGF-β 2 in milk. 81 This deficiency is further accentuated in infants receiving formula that contains no TGF-β 2 . In this context, our findings of the protective effects of enterally administered TGF-β 2 assume importance.…”