Host–microbial co-metabolites modulated by human milk oligosaccharides relate to reduced risk of respiratory tract infections

Abstract

Human milk oligosaccharides (HMOs) are structurally diverse oligosaccharides present in breast milk, supporting the development of the gut microbiota and immune system. Previously, 2-HMO (2'fucosyllactose, lacto-N-neotetraose) compared to control formula feeding was associated with reduced risk of lower respiratory tract infections (LRTIs), in part linked to lower acetate and higher bifidobacteria proportions. Here, our objective was to gain further insight into additional molecular pathways linking the 2-HMO formula feeding and LRTI mitigation. From the same trial, we measured the microbiota composition and 743 known biochemical species in infant stool at 3 months of age using shotgun metagenomic sequencing and untargeted mass spectrometry metabolomics. We used multivariate analysis to identify biochemicals associated to 2-HMO formula feeding and LRTI and integrated those findings with the microbiota compositional data. Three molecular pathways stood out: increased gamma-glutamylation and N-acetylation of amino acids and decreased inflammatory signaling lipids. Integration of stool metagenomic data revealed some Bifidobacterium and Bacteroides species to be implicated. These findings deepen our understanding of the infant gut/microbiome co-metabolism in early life and provide evidence for how such metabolic changes may influence immune competence at distant mucosal sites such as the airways.

Functional effects of human milk oligosaccharides (HMOs)

“…Bifidobacteria are among the first colonizers of the infant gut and sustaining this abundance of Bifidobacteria is crucial to preserving the gut microbiota composition. Several studies have shown that HMOs influence the gut microbiota composition via bifidogenic and anti-pathogenic effects and by potentially interacting with the gut epithelium to alter the physical interactions between microbes and their hosts 66 . Breastfeeding, due to the supply of HMOs into the gut, promotes the growth of specific HMO-utilizing Bifidobacterium species which are nearly accounting for 50–90% of the total bacterial population found in the feces of breastfed newborns 67 .…”

“…Bifidobacteria abundance and metabolic activity could be associated to decreased respiratory tract infections 66 , 72 , 163 . Increased gamma-glutamylation and N-acetylation of amino acids, and decreased inflammatory signaling lipids, are the three most notable molecular pathways 66 .…”

An Extensively Hydrolyzed Formula Supplemented with Two Human Milk Oligosaccharides Modifies the Fecal Microbiome and Metabolome in Infants with Cow’s Milk Protein Allergy

“…infantis and increased levels of bifidobacteria-derived acetic acid were factors contributing to the protective effect of 2 -FL and LNnT against LRTI in infancy [15]. Additional metabolic pathways have been identified, including gamma-glutamylation and acetylation of amino acids, altered by the HMO formula feeding [16]. In our study, the microbial ecosystem of the EHF-fed infants with CMPA likely differed from that of healthy infants.…”

“…Martin et al described molecular changes related to HMO feeding and protection from LRTI, including an increase in gamma glutamylation and N-acetylation of amino acids, as well as a decrease in inflammatory lipids. Changes in amino acid and lipid metabolism were linked to Bifidobacterium and Bacteroides species, respectively [16].…”

Can Human Milk Oligosaccharides Modulate the Allergic Response and Improve the Management of Cow’s Milk Protein Allergy?

“…O'Mahony referenced a recent study in which HMOs fed to infants gave rise to an "enormous change in metabolism," including increased levels of sphingolipids, important for the development of intestinal invariant natural killer T cells, reduced levels of the T regulatory inhibitor 12,13-dihydroxylated fatty acid, and changes in the gamma-glutamylation of AAs associated with reduction in inflammatory cytokines. 11 The most well-described bacteria-derived metabolites with immunomodulatory activity in the gut are the short-chain fatty acids (SCFA), which comprise acetate, propionate, and butyrate. "SCFAs are really important early in life," explained O'Mahony.…”