Alzheimer's disease is known as a representative neurodegenerative brain disease, but intestinal-related symptoms such as intestinal inflammation, barrier instability, and dysbiosis have also been consistently reported in patients and animals. Evidence has accumulated that the vagus nerve, a key pathway of the brain-gut axis, mediates bidirectional communication between the brain and gut; however, the directionality of pathological protein transmission, particularly the descending propagation from the brain to the gut and its functional consequences, has remained unclear.
Recently, a research team led by Professor Mook In-hee at Seoul National University College of Medicine reported that the pathological protein tau in Alzheimer's disease spreads from the brain to the gut (brain → gut) via the vagus nerve, and they were the first to demonstrate that this process leads to a weakening of the intestinal epithelial barrier. The findings of this study were published in the international journal in the gastroenterology field, "Gut."
The research team observed tau aggregates in the vagal dorsal motor nucleus (DMV) and the enteric nervous system (ENS) in an Alzheimer's disease animal model. They then confirmed the descending propagation of tau from the hippocampus to the vagal dorsal motor nucleus and the enteric nervous system over time, following the injection of tau fibrils (PFF) into the hippocampus. They also demonstrated that the transmission of tau to the enteric nervous system significantly decreases when the vagus nerve is severed.
Additionally, the research team constructed a chip that integrates human induced pluripotent stem cell (iPSC)-derived organoids, connecting vagal motor neurons, gut nerves, and colonic epithelium into a single chip. On this chip, tau was transmitted to the enteric nerves along the axons of the vagal motor neurons, and even though tau did not directly reach the epithelial cells, they confirmed that proteins forming the barrier of the epithelial cells decreased, resulting in barrier weakening mediated by the enteric nervous system. This platform represents the first case of functionally recreating the brain → gut nerve pathway in a human-derived system.
This achievement provided evidence for explaining the causes of gastrointestinal symptoms, such as intestinal inflammation, barrier instability, and dysbiosis, reported in Alzheimer's disease from the perspective of descending transmission of brain-derived tau. Moreover, it is expected to accelerate the development of therapeutic strategies targeting the brain-gut axis circuit, regulating interactions between the enteric nerves and epithelium, as well as verifying mechanisms and drug discovery using human organoid-on-a-chip.
Professor Mook In-hee noted, "This research is the first to prove that the pathological protein tau in the brain propagates to the gut via the vagus nerve in Alzheimer's disease, leading to a weakening of the barrier. Through this, we have identified the causes of gastrointestinal symptoms commonly observed in Alzheimer's patients and proposed the potential for developing new therapeutic strategies based on the brain-gut axis."
References
Gut (2025), DOI: https://doi.org/10.1136/gutjnl-2024-334571