Dairy Bioactive Compounds as Precision Modulators of Gut Microbiota: From Molecular Mechanisms to Personalized Immunometabolic Health

The gut microbiota (GM) has become a key mediator of host health, with dietary manipulations promising ways of modulating the microbiome. This review focuses on the role of dairy bioactive (DB) compounds as precision modulators of intestinal microecology, including the whey proteins (WPs), including lactoferrin (LF), α-lactalbumin (LA), β-lactoglobulin, lysozyme (LZ), lactoperoxidase, glycomacropeptide (GMP), milk oligosaccharides (MOs), and bioactive peptides (BPs). This review compiles the existing evidence illustrating their dual-action mechanism through direct prebiotic activity and the promotion of beneficial taxa (<i>Bifidobacterium</i>, <i>Lactobacillus</i>, <i>Faecalibacterium</i>), along with selective antimicrobial activity and pathogen suppression. These compounds improve intestinal barrier integrity through tight junction (TJ) protein regulation, regulating short-chain fatty acid production, and modulating immune signaling pathways. Clinical evidence shows significant benefits in metabolism and inflammation among various populations. However, individual responses vary according to host factors such as enterotypes, FUT2 genotype, and baseline microbiota composition, suggesting the need for personalized intervention strategies. This review addresses critical knowledge gaps in dose-response relationships, long-term efficacy, and mechanistic pathways and suggests future directions for precision nutrition. By modifying molecular mechanisms in clinical applications, we have identified DB compounds as promising candidates for targeted modulation of the microbiota to optimize health and disease management. The review also brings together molecular mechanistic and clinically implementable, personalized dietary strategies, which have not been fully captured by previous reviews. It pinpoints gaps in knowledge related to dose-response characterization, long-term trial design, and multi-omics stratification that collectively define a new precision nutrition framework. In this approach, dairy-based intervention is planned for each person based on their microbial, genetic, and metabolic characteristics.