Regulation of infant gut microbiota and metabolic pathways by human milk oligosaccharides: a multi-omics investigation

The third-most solid component in breast milk is human milk oligosaccharides (HMOs)-crucial for the growth and development of infants. HMOs are divided into three main categories: fucosylated, nonfucosylated, and sialylated HMOs. However, comparative studies evaluating the variations of the impact of in vitro fermentation of these typical or dominant HMOs on the metabolic functions of an infant's gut microbiome remain limited. Therefore, we systematically analyzed the role of three typical HMOs-2'-fucosyl lactose, lactose-N-tetrose, and 3'-sialyllactose-in the structural reshaping of the infant intestinal flora; we also explored their impact on short-chain fatty acid (SCFA) production and metabolism, as well as their overall metabolic spectrum. We found that HMOs aided the growth of beneficial microorganisms, such as Bifidobacterium, Lactobacillus, and Enterococcus, while also reducing the number of harmful bacteria, including Escherichia-Shigella. Further, HMOs had a substantial impact on amino acid, purine, and lipid metabolic pathways and significantly increased SCFA levels. Correlation analyses revealed significant associations between Bifidobacterium and multiple lipid metabolites. Positive correlations between Lactobacillus and amino acid derivatives, as well as close links between Bacteroides and acetate production, were detected. Overall, these findings indicate that the gut flora-metabolite interplay is central to HMO function, and different HMOs variably regulate the gut microbiota composition and metabolic pathways. This study provides a theoretical basis for optimizing HMOs' fortification strategies in infant formulas.