Before the Gut: Human Milk Oligosaccharides and Oral Microbial Colonization in Infancy

Background/Objectives: Human milk oligosaccharides (HMOs) reach the oral cavity before any other compartment and resist hydrolysis by salivary enzymes, yet their behavior there has received far less attention than their intestinal fate. This review asks what follows from treating the mouth as a compartment rather than as a corridor. Methods: MEDLINE, Scopus and Web of Science were searched from inception to August 2026, combining oligosaccharide and oral terms, with forward citation tracking of the human studies. Each candidate mechanism was classified by its type of supporting evidence: human oral association, direct oral in vitro evidence, indirect evidence from other compartments, or unresolved hypothesis. Results: Only two human analyses, both from the same Western Australian cohort (BLOSOM), have related HMO exposure to infant oral bacterial communities; the larger concluded that the effect, while statistically detectable, was biologically limited. Residence time, and probably effective glycan concentration, differ from the intestinal case, as do the aerotolerant, Gemella- and Rothia-dominated community and the salivary films coating teeth and mucosa. In vitro, 6′-sialyllactose and free N-acetylneuraminic acid inhibited Streptococcus mutans biofilm formation, but only at concentrations (~100 mM) well above plausible oral exposure; 2′-fucosyllactose had no antibiofilm effect, reduced adhesion in two of three strains and did not support growth. Maternal FUT2 genotype shapes the oligosaccharide profile of milk, whereas the infant’s own FUT2 genotype governs fucosylation of the salivary glycoproteins those oligosaccharides encounter; neither has been measured in infant oral microbiome studies. Conclusions: Anti-adhesive and substrate-driven mechanisms may operate in parallel, and a possible asymmetry between commensal and cariogenic streptococci is framed as a testable hypothesis, as is the contribution of swallowed oral communities to gut colonization. Current evidence supports no change in practice regarding supplemented formula, donor milk, oropharyngeal colostrum, or breastfeeding and caries.