Quercetin regulates lipid metabolism and inflammatory microenvironment of microglia after spinal cord injury through activating the butyrate-FFAR2/AMPK/TFEB gut-brain axis signaling pathway.

Spinal cord injury (SCI) leads to a microenvironment destruction characterized by inflammation, lipid metabolism dysregulation, and impaired tissue regeneration, collectively impeding functional recovery. Recent studies have shown that the gut-brain axis is an important pathway for regulating the microenvironment after SCI. Quercetin (QUE) is a natural flavonoid with powerful anti-inflammatory and metabolic regulation properties, showing promising prospects in promoting SCI repair. This study aimed to investigate the role of QUE in regulating the lipid-rich microenvironment of injured spinal cord through the gut-brain axis. Our results showed that QUE could enhance the diversity of gut microbiota, thereby increasing butyrate production, which can activate the free fatty acid receptor 2 (FFAR2) in spinal cord tissue. Activating FFAR2 can trigger the AMPK/TFEB signal cascade, promote lipid metabolism, and alleviate inflammation. These actions collectively alleviate the characteristic lipid accumulation and inflammatory response in the injured spinal cord lipid-rich microenvironment and reshape a regenerative microenvironment favorable for SCI functional recovery. This study provides new insights into the gut-brain axis repair mechanism in SCI and highlights the therapeutic potential of QUE as a metabolic regulator in SCI.