Previously, we found that whey proteins form biomolecular coronas around titanium dioxide (TiO) nanoparticles. Here, the gastrointestinal fate of whey protein-coated TiO nanoparticles and their interactions with gut microbiota were investigated. The antioxidant activity of protein-coated nanoparticles was enhanced after simulated digestion. The structure of the whey proteins was changed after they adsorbed to the surfaces of the TiO nanoparticles, which reduced their hydrolysis under simulated gastrointestinal conditions. The presence of protein coronas also regulated the impact of the TiO nanoparticles on colonic fermentation, including promoting the production of short-chain fatty acids. Bare TiO nanoparticles significantly increased the proportion of harmful bacteria and decreased the proportion of beneficial bacteria, but the presence of protein coronas alleviated this effect. In particular, the proportion of beneficial bacteria, such as and , was enhanced for the coated nanoparticles. Our results suggest that the formation of a whey protein corona around TiO nanoparticles may have beneficial effects on their behavior within the colon. This study provides valuable new insights into the potential impact of protein coronas on the gastrointestinal fate of inorganic nanoparticles.