Gut bacterial-derived beneficial proteins in intestinal disease

The human gut microbiota is a vast and intricate microbial ecosystem that plays indispensable roles in host physiology, including nutritional metabolism, immune system development, and disease prevention. While current research has extensively focused on microbiota-derived small-molecule metabolites and virulence-associated factors, the functional contribution of gut bacteria-derived proteins remains comparatively underexplored. These proteins are emerging as key molecular mediators of host-microbe and microbe-microbe interactions. In this review, we synthesize current evidence to delineate the potential links between the spatial distribution, sources and ecological niches of gut microbiota and the repertoire of proteins they produce. We systematically categorize the functions and mechanisms of diverse bacterial-derived beneficial proteins, including enzymes, surface-associated proteins, outer membrane vesicle-associated proteins, and secreted effectors, highlighting their critical roles in antimicrobial defense, metabolic homeostasis, immune modulation, and antitumor activity from multiple perspectives. Particular emphasis is also placed on their distinct molecular strategies in mediating host interactions. Collectively, this analysis underscores the translational potential of gut microbiota-derived proteins, pointing toward innovative applications in the rational design of next-generation postbiotics, engineered bacterial proteins, and potential microbiome-based biologic therapeutics.