From oral and intestinal organoids to an integrated oral–gut organoid-on-a-chip
Research on the oral–gut axis has progressed from association studies to mechanistic understanding. However, the pathways by which oral-derived microorganisms, metabolites, and inflammatory signals traverse gastrointestinal barriers and affect intestinal homeostasis remain poorly defined. A major reason is the lack of controllable, human-relevant in vitro models. Existing approaches, including animal models, two-dimensional cultures, and conventional organoids, have major limitations, such as interspecies differences, simplified architecture, incomplete niche representation, and insufficient inter-organ connectivity. Various organoid-on-a-chip systems have been experimentally validated for modeling tissue-specific processes under controlled conditions, yet an integrated platform that connects the oral cavity and the intestine has not been realized. This review outlines key requirements for recapitulating oral–gut axis pathogenesis in vitro, including human-relevant cellular composition, long-term coculture, niche reconstruction, and inter-organ transport. We then examine the technological advances of intestinal organoid-on-a-chip platforms, focusing on anaerobic control, epithelial barrier reconstruction, real-time monitoring, and immune cell integration. We also summarize advances in oral organoid models for mucosal simulation, microbial coculture, and vascularization. Building on these advances, we discuss design principles from multi-organ systems—modular integration, fluidic coupling, functional scaling, and physiologically based pharmacokinetic and pharmacokinetic/pharmacodynamic-assisted design—that can guide oral–gut integration. We further identify key challenges in constructing such systems, including oxygen gradient control, gastric acid barrier reconstruction, and modeling of dynamic processes such as microbial translocation and rhythmic transport. Addressing these challenges will be essential for establishing a robust platform. Together, these considerations provide a rationale and design basis for future efforts to develop an integrated oral–gut organoid-on-a-chip platform that would enable modeling of bidirectional interactions between oral and intestinal pathologies.

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