A human gut-BBB-brain microphysiological model for studying Alzheimer's disease

The gut-brain axis (GBA) has emerged as a crucial contributor to neurodegenerative diseases, with growing evidence implicating gut-derived metabolic and signaling alterations in Alzheimer's disease (AD). However, the lack of human-relevant in vitro models limits our ability to explore the mechanisms of this axis effectively. To address this limitation, we developed a human induced pluripotent stem cell (iPSC)-derived gut-blood-brain barrier (BBB)-brain microphysiological system that enables systematic investigation of gut-brain interactions in AD under controlled conditions. Using this platform, we showed that communication between gut and brain compartments was associated with increased expression of neuronal and glial markers, as well as phenotypes indicative of enhanced maturation-associated molecular features. Integrating gut and brain compartments also revealed disease-associated molecular and cellular alterations not observed in brain organoids alone. Importantly, exposure of healthy brain organoids to signals from AD patient-derived gut organoids induced changes in neuronal and glial phenotypes, indicating that gut-derived factors may contribute to brain dysfunction in AD. Collectively, our findings establish a human iPSC-derived gut-BBB-brain platform for studying brain organoid responses under combined intestinal and BBB co-culture conditions and provide an experimental framework for exploratory studies of AD-associated inter-organ influences.