Gut-derived inflammation engages hippocampaladaptive blood-brain barrier response involving transthyretin

Here, we show that acute intestinal inflammation induces a transient, region-selective increase in BBB permeability in the mouse hippocampus followed by barrier recovery. Single-cell transcriptomic analysis identified transthyretin (TTR) as a shared inflammation-responsive candidate across major neurovascular cell populations, and hippocampal TTR protein increased during BBB recovery.

Acute exposure to bacterial outer membrane vesicles derived from Alzheimer’s disease (AD)-associated samples increased hippocampal TTR and reduced BBB permeability, whereas chronic exposure to AD-associated microbiota showed the opposite pattern, with reduced TTR accompanying impaired barrier permeability. TTR was also reduced in hippocampal capillaries from individuals with AD. Bidirectional manipulation demonstrated a functional role for TTR in barrier resilience: hippocampal TTR overexpression attenuated inflammation-induced BBB leakage, whereas TTR knockdown increased BBB permeability.