Innate Recognition of Bacteria in Human Milk Is Mediated by a Milk-Derived Highly Expressed Pattern Recognition Receptor, Soluble Cd14

TLDR

Innate immunity to bacteria in the newborn gut is poorly understood, yet breastfeeding is linked to reduced gastrointestinal infections and inflammatory or allergic diseases. Human breast milk contains a 48‑kDa soluble CD14 that activates CD14‑negative intestinal epithelial cells via LPS or whole bacteria, triggering innate immune responses. Milk sCD14 concentrations are up to 20‑fold higher than serum levels, LPS‑binding protein is low, mammary epithelial cells produce sCD14, and it is absent in infant formulas and commercial cow milk but present in bovine colostrum, indicating a sentinel role for sCD14 in modulating neonatal gut immunity.

Abstract

Little is known about innate immunity to bacteria after birth in the hitherto sterile fetal intestine. Breast-feeding has long been associated with a lower incidence of gastrointestinal infections and inflammatory and allergic diseases. We found in human breast milk a 48-kD polypeptide, which we confirmed by mass spectrometry and sequencing to be a soluble form of the bacterial pattern recognition receptor CD14 (sCD14). Milk sCD14 (m-sCD14) concentrations were up to 20-fold higher than serum sCD14 from nonpregnant, pregnant, or lactating women. In contrast, lipopolysaccharide (LPS)-binding protein was at very low levels. Mammary epithelial cells produced 48-kD sCD14. m-sCD14 mediated activation by LPS and whole bacteria of CD14 negative cells, including intestinal epithelial cells, resulting in release of innate immune response molecules. m-sCD14 was undetectable in the infant formulas and commercial (cows') milk tested, although it was present in bovine colostrum. These findings indicate a sentinel role for sCD14 in human milk during bacterial colonization of the gut, and suggest that m-sCD14 may be involved in modulating local innate and adaptive immune responses, thus controlling homeostasis in the neonatal intestine.