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 glycoconjugates, 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-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.