A 3D Gut-Brain-Vascular Platform for Bidirectional Crosstalk in Gut-Neuropathogenesis

A ‘gut-brain axis’ is an intricate bidirectional connection between the gut and the central nervous system, serving as a key pathway for signal exchange. However, current in vitro models do not fully capture the dynamics of interactions between these organs, which limits mechanistic understanding and therapeutic exploration. Here, we present a 3D human gut-brain vascular (GBV) model that simulates bidirectional communication between these entities, allowing us to investigate disorders originating from both the gut and brain. We created a physiologically relevant gut-brain axis model, creating a 3D villus-like lumenized gut barrier, blood vascular-astrocyte interactions, and brain tissue that mimics neurovascular interactions. Next, we demonstrated gut-to-brain signaling by introducing bacterial-derived toxins into the gut side, allowing the toxins to penetrate the gut barrier and the neurovascular barrier, ultimately reaching the brain and leading to tauopathy, a key indicator of neurodegeneration. We observed brain-to-gut signaling by exposing the brain side to risk factors of Alzheimer’s (AD) and Parkinson’s (PD), which induces neuroinflammation, disrupts the vascular barrier, and subsequently affects gut epithelial integrity. Our gut-brain vascular model is a precisely engineered microphysiological system that emulates the human gut-brain-vascular axis and serves as a translational tool to identify therapeutic targets and evaluate pharmaceuticals for neurological and gastrointestinal disorders.