Emerging evidence suggest that human exposure to micro-plastics is rising and it most happened via ingestion and/or inhalation (Wright SL et al. 2017). In fact, plastics particles were detected in various product for human consumption such as seafood, honey, sugar, and drinking water (von Moos et al. 2012; Liebezeit et al. 2013; Koelmans et al. 2019). Once ingested, they can reach the intestinal epithelium. Their biocompatibility or toxic effects on gastro-intestinal barrier is matter of debate, also because of the lack of suitable models of physiological digestion and gastro-intestinal barrier. The simplest model developed is represented by Caco-2 cells cultured on semi-permeable filter supports for 21 days, a time point that make them differentiating into enterocyte-like cells, with transport and permeability features like human intestinal tissue (Lundquist et al 2016). A more complex model is composed of the co-culture of Caco-2 and HT29-MTX cells that to methotrexate (MTX) develop the ability to produce mucus (Gamboa et al. 2013): this model includes the mucus-secreting goblet cells important for the presence of mucus layer in the intestine. To better mimic the intestinal physiology, another cell type (Raji B) can be added to the co-culture to allow Caco-2 differentiation into gut-associated lymphoid tissue microfold cells (M-cells) that can transport micro- and nanoparticles through transcytosis process (Gullberg et al. 2000).