Activation of the G-protein coupled receptor GPR35 by human milk oligosaccharides through different pathways

Norbert Sprenger,Florence Rochat,Francis Foata,Sami Damak

doi:10.1038/s41598-020-73008-0

Norbert Sprenger, Florence Rochat + Show 2 more

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https://doi.org/10.1038/s41598-020-73008-0

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Journal: Scientific Reports	Publication Date: Sep 30, 2020
Citations: 18	License type: open-access

Affiliation: Nestlé (Switzerland)

Abstract

Numerous benefits of breastfeeding over infant formula are fully established. The superiority of human milk over bovine milk-based formula is partly due to human milk oligosaccharides (HMOs), a family of over 100 molecules present specifically and substantially in human milk that resemble mucosal glycans. To uncover novel physiological functions and pathways of HMOs, we screened a panel of 165 G-protein coupled receptors (GPCRs) using a blend of 6 HMOs (3′-O-sialyllactose (3′SL), 6′-O-sialyllactose (6′SL), lacto-N-tetraose (LNT), lacto-N-neo-tetraose (LNnT), 2-O-fucosyllactose (2′FL), and difucosyllactose (diFL)), and followed up positive hits with standard receptor assays. The HMO blend specifically activated GPR35. LNT and 6′SL individually activated GPR35, and they showed synergy when used together. In addition, in vitro fermentation of infant stool samples showed that 2′FL upregulates the production of the GPR35 agonist kynurenic acid (KYNA) by the microbiota. LNT + 6′SL and KYNA showed additive activation of GPR35. Activation by 6′SL and LNT of GPR35, a receptor mediating attenuation of pain and colitis, is to our knowledge the first demonstration of GPCR activation by any HMO. In addition, we demonstrated a remarkable cooperation between nutrition and microbiota towards activation of a host receptor highlighting the close interplay between environment and host-microbe interactions.

Highlights

IntroductionThe superiority of human milk over bovine milk-based formula is partly due to human milk oligosaccharides (HMOs), a family of over 100 molecules present and substantially in human milk that resemble mucosal glycans
Numerous benefits of breastfeeding over infant formula are fully established
We found that compared to lactose, 2-O-fucosyl lactose (2′FL), or a combination of 2′FL and LNnT significantly increased kynurenic acid (KYNA) by 1.76 X and 1.61 X (p = 0.01 and p = 0.046, respectively) in the fermentation supernatant (Fig. 5A)

Summary

Introduction

The superiority of human milk over bovine milk-based formula is partly due to human milk oligosaccharides (HMOs), a family of over 100 molecules present and substantially in human milk that resemble mucosal glycans. The superiority of human milk over cow milk based infant formula may partly be due to the benefits of human milk oligosaccharides (HMOs), a family of over 100 molecules present in human milk in substantial amounts, making the third most abundant solid component of human milk, after lactose and fat[2]. HMOs are composed of a lactose backbone to which are attached N-acetylglucosamine, fucose or sialic acid, in various amounts and linkages These vary from single additional molecule to large, more complex molecules[2]. This may be mediated through classical glycan binding proteins[25], or yet to be discovered mechanisms

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