Gut microbiota regulates blood-cerebrospinal fluid barrier function and Aβ pathology

EMBO J. 2023 Sep 4;42(17):e111515. doi: 10.15252/embj.2022111515. Epub 2023 Jul 10.


Accumulating evidence indicates that gut microbiota dysbiosis is associated with increased blood-brain barrier (BBB) permeability and contributes to Alzheimer's disease (AD) pathogenesis. In contrast, the influence of gut microbiota on the blood-cerebrospinal fluid (CSF) barrier has not yet been studied. Here, we report that mice lacking gut microbiota display increased blood-CSF barrier permeability associated with disorganized tight junctions (TJs), which can be rescued by recolonization with gut microbiota or supplementation with short-chain fatty acids (SCFAs). Our data reveal that gut microbiota is important not only for the establishment but also for the maintenance of a tight barrier. Also, we report that the vagus nerve plays an important role in this process and that SCFAs can independently tighten the barrier. Administration of SCFAs in AppNL-G-F mice improved the subcellular localization of TJs at the blood-CSF barrier, reduced the β-amyloid (Aβ) burden, and affected microglial phenotype. Altogether, our results suggest that modulating the microbiota and administering SCFAs might have therapeutic potential in AD via blood-CSF barrier tightening and maintaining microglial activity and Aβ clearance.

Keywords: Alzheimer's disease; blood-cerebrospinal fluid barrier; gut microbiota; short-chain fatty acids; vagus nerve.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease* / pathology
  • Amyloid beta-Peptides
  • Animals
  • Blood-Brain Barrier / pathology
  • Fatty Acids, Volatile
  • Gastrointestinal Microbiome* / physiology
  • Mice
  • Microbiota*


  • Amyloid beta-Peptides
  • Fatty Acids, Volatile