Inulin-Based Prebiotic Delivery System Enhances Gut Microbiota Modulation to Alleviate Enteric Infections

Current antibiotic-based treatments for bacterial enteric infections often disrupt gut microbiota and face reduced efficacy due to gastrointestinal complexity and mucosal barriers. Here, we developed a genistein-loaded nanoparticle using whey protein isolate and prebiotic inulin (Gen_Wi) to improve the gut microbiome health. Gen_Wi nanoparticles mitigated oxidative stress and inflammation in intestinal epithelial cells by activating Nrf2 and suppressing NF-κB pathways, reducing TNF-α and IL-1β levels by nearly 39 and 55.6%, respectively. Remarkably, oral administration of Gen_Wi significantly mitigated <i>Salmonella</i>-induced intestinal damage, reducing bacterial colonization by 1000-fold, restoring goblet cell counts, and enhancing tight junction proteins. Mechanistic analysis revealed that Gen_Wi reshaped gut microbiota composition by promoting beneficial bacteria and increasing production of gut barrier-strengthening short-chain fatty acids, including acetate, propionate, and butyrate. These results highlight Gen_Wi as a prebiotic system that integrates prebiotic functionality with anti-inflammation to combat enteric infections through modulation of host-microbe interactions.