Establishing a Core Infrastructure for Enhancing Gut Health, Disease and Microbiome Research Using Advanced Non-Animal Models

Modelling the gastrointestinal tract (GIT) is essential to understanding human health and disease, as it plays critical roles in digestion, immune responses, appetite regulation, and microbiome interactions.

Animal models, however, fail to capture the complexity of the human GIT due to physiological, genetic and microbiome differences, limiting their ability to fully replicate human pathomechanisms.

Alternative immortalised human cell lines or even organoid cultures (containing near-physiological epithelial cell-type heterogeneity) also fail to recapitulate the complex interactions between epithelial, immune, stromal cells and microbes that underpin homeostatic or pathological states of the human GIT in vivo.

Microphysiological systems are improved models, especially when integrated with organoids (organoid-on-chips). However, no single organoid-on-chip system encompasses all features necessary to entirely replace animal models.

This project aims to address these challenges by establishing a core facility infrastructure to investigate gut health and diseases without animal models.

This facility will contain multiple, interconnected yet complementary organoid-on-chip systems and state-of-the-art in vitro digestive and microbiome modelling platforms informed by human data.

This infrastructure will require special laboratory environments (allowing organoid-microbe co-culture, ventilation), multidisciplinary expertise (immunology, gut biology, microbiology, bioengineering) and human samples (patient-derived organoid, immune cells, microbes).

Having already established these requirements as well as a UK-wide partnership network of academic, industrial, and clinical collaborators to improve in vitro gut studies, the Imperial Organoid Facility is uniquely equipped to host this infrastructure.

The Facility's existing systems include the InfoGest digestive model, HuMiX academic gut-on-chip system (only one in the UK), which supports microbial co-cultures, and commercial PhysioMimix (CN-Bio). These technologies enable studying specific host-microbe / host-diet interactions in well-defined GIT locations.

To dynamically model the entire GIT in a single experiment with interconnected chips, we propose the addition of Emulate and Dynamic42 chip systems and the SHIME whole GIT digestive platform. Co-locating them provides more accurate representations of biological processes compared to static in vitro models.

This setup enables complex dynamics informed by our sampling along the human GIT, thereby offering more accurate in vitro modelling and addressing a key unmet need according to our university-wide surveys and interactive workshops to adapt non-animal models.

This project will create a unique infrastructure for GIT modelling that supports interdisciplinary collaborations which could lead to the increased uptake and adoption of state-of-the-art in vitro organoid-on-chip systems nationally.

With specialised expertise, technology, scientific network, and in-kind support from industrial partners, this infrastructure is poised to advance non-animal methods in gut research.