Scientific literature is shedding light on the centrality of GI for human health and wellbeing. Indeed, the physiologic effects of nutrients, bioactives and even toxic compounds (including foodborne pathogens) are mediated by their absorption rate in the intestine and by their interaction with gut microbiota and its host ecosystem. Testing food, feed, supplements or drugs in clinical studies gives rise to ethical issues, and the transferability of animal data across species is often problematic because of differences in physiology, metabolism and chemical susceptibilities. According to a recent survey of European Commission (EURL ECVAM, 2021), complex in vitro models (CIVMs) approaches should be adequate not only for regulatory use-contexts, but also for application in the research field provided that standardized CIVMs are developed, enabling a consensus on their use. A new COST Action would fill the knowledge gap on in vitro colon models providing consensus protocols and robust data sets to improve our knowledge of the events taking place in the intestinal milieu, including the complex interactions between the microbiota and the host. Moreover, innovative educational tools will be suggested to increase knowledge on gut models in young researchers and widen to society to avoid any unhealthy consumer choices coming from misleading messages. Bringing together different experts in Gastroenterology, Microbiology, Physiology, Nutrition, Food Science, Biochemistry, Bioinformatics, Biotechnology etc., the new COST Action could represent an effective strategy for the development of healthy food and for the counteraction of diseases.