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The intestinal barrier is a complex interface of the human body, possessing the largest contact surface to nutrients and antigens and containing a major part of the immune system. It has to deal with continuous exposure to a broad mixture of essential, harmful, or useless substances and particles. In the context of plastic pollution and the ubiquitous occurrence of micro- and nanoplastics, oral exposure to such particles is of particular interest. Standard intestinal in vitro models, however, are unable to mimic the role of the immune system in the particle-exposed intestine. To allow for a closer look on the effect of particles on the intestinal immune system, we here developed a co-culture model to enable investigation of the epithelial brush border monolayer in a healthy and inflamed state. The model is based on well-established Caco-2 intestinal epithelial cells cultured in a Transwell™ system. Intraepithelial immune cells were mimicked by THP-1-derived M0-macrophages and MUTZ-3-derived dendritic cells. To fulfill the requirements needed for the investigation of particles, the co-culture system was developed without an additional matrix layer. Cell–cell contacts were established between interstitial and immune cells, and the Caco-2 standard cell culture medium was used, which is well-characterized for its role in defining the identity of particle dispersions. The model was characterized using confocal microscopy, membrane integrity measurements, and cytokine release assays from inflamed and healthy cells. Finally, the new co-culture model was used for investigation on polylactic acid, melamine formaldehyde resin, and polymethylmethacrylate plastic micro- and nanoparticles.