Recent advances in microbiome research have highlighted the critical role of phytonutrients, prebiotics, probiotics, and postbiotics in modulating gut health, immune responses, and metabolic function. This review synthesizes mechanistic insights and emerging evidence to describe how these biotic compounds interact synergistically with the host microbiota. Phytonutrients, such as polyphenols and carotenoids, enhance microbial diversity and short-chain fatty acids (SCFA) production through microbial biotransformation, exerting antioxidative and anti-inflammatory effects via pathways like Nrf2/ARE and NF-κB. Prebiotics, including inulin, fructooligosaccharides (FOS), and galactooligosaccharides (GOS), selectively enrich beneficial microbes such as Bifidobacterium and Lactobacillus, leading to increased SCFA levels and improved gut barrier integrity. Probiotics, composed of live microbes like Lactobacillus and Bifidobacterium, contribute to health through competitive exclusion of pathogens, modulation of Treg/Th17 balance, and enhancement of tight junction proteins. Postbiotics — non-viable microbial products such as SCFAs, bacteriocins, and indole3-propionic acid — modulate immune signaling via Toll-like receptors (TLRs) and Nod-like receptors (also called Nucleotide-binding oligomerization domain-like receptors, NLRs),providing a safer alternative in immunocompromised populations. These agents collectively regulate cytokine networks (e.g., interleukins IL-10, IL-6, tumor necrosis factor TNF-α), improve metabolic outcomes via cAMPactivated protein kinase (AMPK) and Peroxisome proliferator-activated receptor gamma (PPAR-γ) pathways, and interact with the gut–brain axis. Integrative strategies, including synbiotics and designer biotic foods, offer promising therapeutic applications in chronic diseases such as inflammatory bowel disease (IBD), metabolic syndrome, and neurodegeneration. The review underscores the potential of precision nutrition approaches that combine biotic types to personalize health interventions. Ongoing clinical research and advances in genomics, metabolomics, and delivery systems are poised to enhance the efficacy, safety, and personalization of microbiome-targeted therapies.