Advancing in vitro gut fermentation: the convergence of gut-on-a-chip and digital twins

The gut has gained increasing recognition as a key organ affecting systemic physiological regulation, and the gut microbiota is strongly associated with various human diseases. In vitro gut fermentation systems provide a robust alternative to in vivo clinical experiments for functional food development and for studies of nutrition and drug metabolism. Despite their cost-effectiveness, ethical compliance, and precise control of experimental variables, critical challenges remain, most notably the lack of physiological host interactions and profound interindividual variability. Emerging technologies, specifically gut-on-a-chip platforms and digital twin systems, can be integrated with in vitro gut fermentation to overcome these fundamental limitations and markedly advance its translational applicability. Here, we review the current landscape of in vitro gastrointestinal-simulating methodologies and explore their convergence with these cutting-edge technologies to model the complex host-microbiome ecosystem.