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To advance probiotic research, a comprehensive understanding of bacterial interactions with human physiology at the molecular and cellular levels is fundamental. <i>Lacticaseibacillus rhamnosus</i> LGG^® is a bacterial strain that has long been recognized for its beneficial effects on human health. Probiotic effector molecules derived from LGG^®, including secreted proteins, surface-anchored proteins, polysaccharides, and lipoteichoic acids, which interact with host physiological processes have been identified. In vitro and animal studies have revealed that specific LGG^® effector molecules stimulate epithelial cell survival, preserve intestinal barrier integrity, reduce oxidative stress, mitigate excessive mucosal inflammation, enhance IgA secretion, and provide long-term protection through epigenetic imprinting. Pili on the cell surface of LGG^® promote adhesion to the intestinal mucosa and ensure close contact to host cells. Extracellular vesicles produced by LGG^® recapitulate many of these effects through their cargo of effector molecules. Collectively, the effector molecules of LGG^® exert a significant influence on both the gut mucosa and immune system, which promotes intestinal homeostasis and immune tolerance.