Molecular-level host–microbe interactions: mechanisms, molecules, and modeling toward precision probiotics

INTRODUCTION: Advancing next-generation probiotics (NGPs) as precision therapeutics depends on a detailed understanding of host - microbe molecular interactions, as these organisms exert targeted effects through defined bioactive molecules rather than broad, nonspecific mechanisms. This review addresses the need to systematically organize emerging knowledge on microbe-derived molecules (MDMs) that underpin NGP efficacy. AREAS COVERED: This narrative review summarizes recent discoveries of MDMs isolated from NGPs and classifies them based on three principal molecular interaction interfaces: protein - protein/peptide, protein - lipid or glycopeptide, and protein - metabolite interactions. We discuss how these molecules - encompassing proteins/peptides, lipids, glycoconjugates, and small metabolites - modulate host immune and metabolic pathways to maintain homeostasis. The literature was identified through targeted searches of recent peer-reviewed studies focusing on host - microbe molecular mechanisms and probiotic-derived bioactives. We also review the application of molecular docking, molecular dynamics simulations, and artificial intelligence - based tools in predicting host - microbe interactions and accelerating therapeutic discovery. EXPERT OPINION: By integrating experimental insights with computational strategies, we propose a framework to guide the development of precision microbiome-based interventions tailored to specific diseases and individual microbiome profiles. These advances lay the foundation for rational design of targeted NGP therapies for metabolic, inflammatory, infectious, and neurodegenerative disorders.