title: Human milk oligosaccharides protect bladder epithelial cells against uropathogenic Escherichia coli invasion and cytotoxicity.
abstract: The invasive pathogen uropathogenic Escherichia coli (UPEC) is the primary cause of urinary tract infections (UTIs). Recurrent infection that can progress to life-threatening renal failure has remained as a serious global health concern in infants. UPEC adheres to and invades bladder epithelial cells to establish infection. Studies have detected the presence of human milk oligosaccharides (HMOs) in urine of breast-fed, but not formula-fed, neonates. We investigated the mechanisms HMOs deploy to elicit protection in human bladder epithelial cells infected with UPEC CFT073, a prototypic urosepsis-associated strain. We found a significant reduction in UPEC internalization into HMO-pretreated epithelial cells without observing any significant effect in UPEC binding to these cells. This event coincides with a rapid decrease in host cell cytotoxicity, recognized by LIVE/DEAD staining and cell detachment, but independent of caspase-mediated or mitochondrial-mediated programmed cell death pathways. Further investigation revealed HMOs, and particularly the sialic acid-containing fraction, reduced UPEC-mediated MAPK and NF-κB activation. Collectively, our results indicate that HMOs can protect bladder epithelial cells from deleterious cytotoxic and proinflammatory effects of UPEC infection, and may be one contributing mechanism underlying the epidemiological evidence of reduced UTI incidence in breast-fed infants.
authors.affiliation: Divisions of Pediatric Pharmacology and Drug Discovery.
authors.forename: Ann E
authors.initials: AE
authors.lastname: Lin
authors.forename: Chloe A
authors.initials: CA
authors.lastname: Autran
authors.forename: Sophia D
authors.initials: SD
authors.lastname: Espanola
authors.forename: Lars
authors.initials: L
authors.lastname: Bode
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
mesh_terms: D001422:Bacterial Adhesion / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004705:Endocytosis / Q000187:drug effects*; D004847:Epithelial Cells / Q000187:drug effects* / Q000382:microbiology*; D006801:Humans; D007155:Immunologic Factors / Q000378:metabolism*; D007223:Infant; D008895:Milk, Human / Q000737:chemistry*; D009844:Oligosaccharides / Q000378:metabolism*; D056689:Uropathogenic Escherichia coli / Q000187:drug effects / Q000502:physiology*
chemical_list: D007155:Immunologic Factors; D009844:Oligosaccharides
keywords: apoptosis; bladder epithelial cells; cell adhesion; human milk oligosaccharides; urinary tract infection; uropathogenic E. coli