Human milk hyaluronan enhances innate defense of the intestinal epithelium.
Breast-feeding is associated with enhanced protection from gastrointestinal disease in infants, mediated in part by an array of bioactive glycan components in milk that act through molecular mechanisms to inhibit enteric pathogen infection. Human milk contains hyaluronan (HA), a glycosaminoglycan polymer found in virtually all mammalian tissues. We have shown that synthetic HA of a specific size range promotes expression of antimicrobial peptides in intestinal epithelium. We hypothesize that hyaluronan from human milk also enhances innate antimicrobial defense. Here we define the concentration of HA in human milk during the first 6 months postpartum. Importantly, HA isolated from milk has a biological function. Treatment of HT-29 colonic epithelial cells with human milk HA at physiologic concentrations results in time- and dose-dependent induction of the antimicrobial peptide human β-defensin 2 and is abrogated by digestion of milk HA with a specific hyaluronidase. Milk HA induction of human β-defensin 2 expression is also reduced in the presence of a CD44-blocking antibody and is associated with a specific increase in ERK1/2 phosphorylation, suggesting a role for the HA receptor CD44. Furthermore, oral administration of human milk-derived HA to adult, wild-type mice results in induction of the murine Hβ D2 ortholog in intestinal mucosa and is dependent upon both TLR4 and CD44 in vivo. Finally, treatment of cultured colonic epithelial cells with human milk HA enhances resistance to infection by the enteric pathogen Salmonella typhimurium. Together, our observations suggest that maternally provided HA stimulates protective antimicrobial defense in the newborn.
From the Department of Molecular Medicine and.
David R
DR
Hill
Hyunjin K
HK
Rho
Sean P
SP
Kessler
Ripal
R
Amin
Craig R
CR
Homer
Christine
C
McDonald
Mary K
MK
Cowman
Carol A
CA
de la Motte
D000284:Administration, Oral; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D015169:Colony Count, Microbial; D060467:Disease Resistance / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D019073:HT29 Cells; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D006820:Hyaluronic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D007113:Immunity, Innate / Q000187:drug effects*; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D007774:Lactation / Q000187:drug effects; D051379:Mice; D008856:Microscopy, Fluorescence; D008895:Milk, Human / Q000737:chemistry*; D010766:Phosphorylation / Q000187:drug effects; D049590:Postpartum Period; D021381:Protein Transport / Q000187:drug effects; D012481:Salmonella Infections, Animal / Q000276:immunology / Q000473:pathology; D012486:Salmonella typhimurium / Q000187:drug effects / Q000502:physiology; D017386:Sequence Homology, Amino Acid; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D023083:beta-Defensins / Q000378:metabolism
D000906:Antibodies; D018960:Hyaluronan Receptors; D051197:Toll-Like Receptor 4; D023083:beta-Defensins; D006820:Hyaluronic Acid; D048049:Extracellular Signal-Regulated MAP Kinases
Cd44; Defensins; Epithelium; Host Defense; Human Milk; Hyaluronate; Salmonella Infection; Toll-like Receptors (TLR)