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Structure-function Relationships of Human Milk Oligosaccharides on the Intestinal Epithelial Transcriptome in Caco-2 Cells and a Murine Model of Necrotizing Enterocolitis.

SCOPE
Necrotizing enterocolitis (NEC) is a devastating gastrointestinal emergency affecting preterm infants. Breastmilk protects against NEC, partly due to human milk oligosaccharides (HMOs). HMO compositions are highly diverse, and it is unclear if anti-NEC properties are specific to carbohydrate motifs. Here we compared intestinal epithelial transcriptomes of five synthetic HMOs and examined structure-function relationships of HMOs on intestinal signaling.


METHODS AND RESULTS
We interrogated the transcriptome of Caco-2Bbe1 cells in response to five synthetic HMOs using RNA sequencing: 2'-fucosyllactose (2'-FL), 3-fucosyllactose (3FL), 6'-siallyllactose (6'-SL), lacto-N-tetraose (LNT), lacto-N-neotetraose (LNnT). Protection against intestinal barrier dysfunction and inflammation occurred in an HMO-dependent manner. Each synthetic HMO exerted a unique set of host transcriptome changes and modulated unique signaling pathways. There was clustering between HMOs bearing similar side chains, with little overlap in gene regulation shared by all synthetic HMOs. Interestingly, most synthetic HMOs protected pups against NEC, exerting divergent mechanisms on intestinal cell morphology and inflammation.


CONCLUSIONS
These results demonstrate that while structurally distinct HMOs impact intestinal physiology, their mechanisms of action differ. This finding establishes the first structure-function relationship of HMOs in the context of intestinal cell signaling responses and offers a functional framework by which to screen and design HMO-like compounds. This article is protected by copyright. All rights reserved.