Even if plastic production ceased today, nanoplastics (NPs) would persist in the environment for decades, contaminating food and water sources and raising urgent concerns about their long-term impact on human health. The gastrointestinal tract is one of the most exposed and vulnerable sites, where NPs may impair epithelial integrity, trigger inflammation, and disrupt the gut microbiota. However, current evidence is based on acute, high-dose exposures in simplistic in vitro models that fail to capture the chronic, low-level, and cumulative nature of human exposure. Moreover, most studies use polystyrene particles, overlooking the toxicological diversity of food-relevant polymers as PP, PET, and PVC. Another critical gap is the frequent neglect of the intestinal mucus barrier role, a dynamic and protective interface that regulates NP absorption and may critically shape toxicity outcomes. These limitations gain urgency in the context of pre-existing intestinal inflammation, where compromised barriers may amplify susceptibility to NP-induced damage. This highlights the need for targeted and effective mitigation strategies. Probiotics, with their known ability to strengthen epithelial defenses, stimulate mucus production, and modulate inflammation, offer a promising but largely underexplored approach to reduce NP-related intestinal toxicity. PlasticGUT addresses these critical challenges through a mechanistic, hypothesis-driven study using advanced physiomimetic and pathological intestinal co-culture models. By integrating mucus-secreting epithelial cells and immune components, the project will assess how NPs from different polymers interact with the mucus layer and affect epithelial function under repeated low-dose exposure. Uniquely, PlasticGUT also explores the translational potential of selected and widely available probiotic strains to counteract NP-induced dysfunction through reinforcement of mucosal defenses and immunomodulation. Through this integrative approach, PlasticGUT will generate novel mechanistic insights into NP toxicity, identify biological susceptibility factors, and provide evidence-based guidance for the development of probiotic-enriched nutritional strategies to reinforce intestinal health. Ultimately, the project contributes to safer food systems and long-term public health protection, particularly for vulnerable populations, in an increasingly plastic-contaminated world.