Multidimensional development of gut-on-a-chip technology: from fabrication processes, models, gut microbiome to...

Gut-on-a-chip (GoC) platforms integrate microfluidics and 3D culture to replicate the intestinal microenvironment, offering physiologically relevant alternatives to traditional models. Coupled with multi-organ chips (e.g., gut-brain/gut-liver axes), they unveil microbiome-regulated systemic crosstalk via metabolite signaling-a key yet unresolved mechanism. This review highlights multidimensional advances in organ-on-chip (OoC) technologies for intestinal research, covering fabrication methods (e.g., soft lithography, bioprinting) and their applications in physiological, patient-derived, or indirectly acquired GoC models. We also emphasize breakthroughs in biomimetic intestinal-microbiome symbiosis and spatiotemporal multi-organ integration (e.g., gut-X axis), enabling emulation of complex inter-organ signaling. Yet, critical challenges persist: reproducibility is limited by fabrication variability and cell heterogeneity; standardization lacks universal benchmarks for physiological relevance; and long-term culture stability (e.g. 7-10 days) is constrained by epithelial senescence and microbial imbalance. These gaps highlight needs for standardized protocols, quality control metrics, and strategies to sustain functional homeostasis. By bridging gaps between traditional models and human biology, GoC technologies establish transformative tools for mechanistic studies and therapeutic discovery in gastroenterology and beyond.