Core Fucosylation of Maternal Milk N-Glycan Evokes B Cell Activation by Selectively Promoting thel-Fucose Metabolism of GutBifidobacteriumspp. andLactobacillusspp

Abstract

The maternal milk glycobiome is crucial for shaping the gut microbiota of infants. Although high core fucosylation catalyzed by fucosyltransferase 8 (Fut8) is a general feature of human milk glycoproteins, its role in the formation of a healthy microbiota has not been evaluated. In this study, we found that the core-fucosylated N-glycans in milk of Chinese mothers selectively promoted the colonization of specific gut microbial groups, such as Bifidobacterium spp. and Lactobacillus spp. in their breast-fed infants during lactation. Compared with Fut8+/+ (WT) mouse-fed neonates, the offspring fed by Fut8+/− maternal mice had a distinct gut microbial profile, which was featured by a significant reduction of Lactobacillus spp., Bacteroides spp., and Bifidobacterium spp. and increased abundance of members of the Lachnospiraceae NK4A136 group and Akkermansia spp. Moreover, these offspring mice showed a lower proportion of splenic CD19+ CD69+ B lymphocytes and attenuated humoral immune responses upon ovalbumin (OVA) immunization. In vitro studies demonstrated that the chemically synthesized core-fucosylated oligosaccharides possessed the ability to promote the growth of tested Bifidobacterium and Lactobacillus strains in minimal medium. The resulting L-fucose metabolites, lactate and 1,2-propanediol, could promote the activation of B cells via the B cell receptor (BCR)-mediated signaling pathway. IMPORTANCE This study provides novel evidence for the critical role of maternal milk protein glycosylation in shaping early-life gut microbiota and promoting B cell activation of neonates. The special core-fucosylated oligosaccharides might be promising prebiotics for the personalized nutrition of infants.

High levels of fucosylation and sialylation of milk N‐glycans from mothers with gestational diabetes mellitus alter the offspring gut microbiome and immune balance in mice

“…in neonatal mice fed by the control and GDM mice was also compared, a decreasing pattern was found in GDM‐C offspring (Figure S4). As Bifidobacteria and Lactobacillus are the major microbial genera in gut of the healthy breast‐fed infants, they play important beneficial roles in regulating the growth and the immune development of the newborns, the decreasing of these bacteria may suggest an unfavorable status for infant health. On the contrary, the abundance of Bacteroides spp.…”

“…34 Studies from our group and others have shown relationships between milk N-glycans and the gut microbiome of breast-fed infants, which can affect their immune responses. [35][36][37] GDM is associated with a high risk of adverse consequences, including the inhibition of immune tolerance formation in infants. [38][39][40] It has been suggested that GDM does not affect the abundance of HMOs but alters the glycosylation patterns of N-glycans in human milk.…”

Unique Microbial Catabolic Pathway for the Human Core N -Glycan Constituent Fucosyl-α-1,6- N -Acetylglucosamine-Asparagine

“…Indeed, Lactobacillus gasseri ATCC 33323, which carries a gene cluster with asnA2, pepV, and alfR2 (Fig. 7), was recently shown to grow with 6=FN and N2F N-glycan (25). However, in the same work, L. casei ATCC 334 was reported to use L-fucose, which is contradictory to the fact that no fuc genes are present in its genome (60).…”

“…In commensal bacteria, the ability to remove N-glycans from glycoproteins has been described in a few Bifidobacterium species (23,24). Recently, the importance of core-fucosylated N-glycans from human milk in promoting the intestinal growth of Bifidobacterium and Lactobacillus species has been demonstrated in lactating infants from mothers carrying different alleles of the fucosyltransferase Fut8, responsible for core fucosylation (25). This provides the first in vivo evidence of the importance of this core structure in feeding intestinal commensals.…”

“…We have demonstrated that L. casei is able to metabolize the glycoamino acid 6=FN-Asn, which is the core structure of the N-glycan sites of ␣1,6-fucosylated glycoproteins. The relevance of the metabolism of this core structure for intestinal microbial ecology was recently established in vivo in humans and in mouse models with reduced ␣1,6-fucosylation of core structures (25). In this work, we filled the existing gap relative to the metabolic pathways involved in the utilization of core-fucosylated N-glycopeptides by bacteria.…”