Gut microbiota-derived phenylacetylglutamine mitigates neuroinflammation induced by intracerebral hemorrhage in mice

Abstract

Background

Emerging evidence highlights the pivotal role of gut microbiota and its metabolites in the pathogenesis of brain injury following intracerebral hemorrhage (ICH). Microglia-mediated neuroinflammation stands out as a crucial pathophysiological process post-ICH. However, the effects of gut microbiota on microglia-mediated neuroinflammation after ICH remain elusive. This study aims to address three key aspects: 1) the alteration in gut microbiota-related metabolites following ICH. 2) the impact of phenylacetylglutamine (PAGIn), a gut microbiota-derived compound, on microglia-mediated neuroinflammation after ICH, and 3) the detailed mechanism by which PAGIn regulates microglia-mediated neuroinflammation via β2 adrenergic receptor (β2AR) after ICH.

Methods

Young male mice were subjected to ICH through the administration of type VII collagenase. Plasma samples were collected for metabolomic profiling on day 3 after ICH. Microglia phenotype and neuroinflammation were assessed after ICH. Brain tissues were collected for bulk RNA sequencing following PAGIn treatment. Behavioral functions were assessed using the cylinder, corner and forelimb placement tests.

Results

Following ICH, levels of PAGIn in the plasma, brain tissues decreased. The supplementation of PAGIn exhibited a significant reduction in neuroinflammation, facilitated the transformation of microglia to anti-inflammatory phenotype, and alleviated neurological dysfunction. Furthermore, the protective effects of PAGIn post-ICH were mediated through the regulation of β2AR.

Conclusion

Gut microbiota-derived PAGIn played a crucially regulatory role in microglia-mediated neuroinflammation via β2AR after ICH. The supplementation of PAGIn following ICH in mice emerged as a potential therapeutic strategy to mitigate ICH-induced brain injury.