Protein-Mediated Interactions Between Gut Microbiota, Probiotics and Host Immunity

The human gut microbiota plays a central role in shaping host immunity, metabolic homeostasis and resistance to infection. Beyond microbial metabolites, increasing evidence highlights the importance of microbial and probiotic-derived proteins as key mediators of host-microbe communication. These proteins participate in immune signalling, epithelial barrier regulation and competitive interactions with intestinal pathogens. This review synthesizes current knowledge on the protein biochemistry of gut microbes and probiotics, emphasizing their mechanisms of immune modulation and roles in host-pathogen interactions. We discuss surface-associated proteins, secreted effectors, peptides and extracellular vesicle associated proteins that influence innate and adaptive immune responses. Furthermore, we explore how probiotic strains counteract pathogenic microbes through protein-mediated mechanisms and immune training. Finally, we highlight translational implications, emerging technologies and future directions for protein focussed microbiome research. This integrative perspective aims to advance the mechanistic understanding of gut microbiota-immune interactions and inform the development of next generation probiotic and therapeutic strategies.