Muribaculaceae regulate β-muricholic acid to target S1PR2 signaling and reduce neurological injury in intracerebral hemorrhage.

BACKGROUND: Intestinal flora imbalance after intracerebral hemorrhage (ICH) aggravates neuroinflammation and secondary brain injury through the gut-brain axis, although the specific mechanism remains unclear. This study focuses on the regulatory effects of Muribaculaceae and β-muricholic acid (β-MA, a primary bile acid) on neurological injury after ICH, aiming to reveal the molecular mechanism by which it improves the prognosis of ICH through the sphingosine-1-phosphate receptor 2 (S1PR2).

METHODS: A mouse ICH model was constructed by collagenase induction to evaluate the changes in gut microbiota diversity and metabolites. After intervention with Muribaculum intestinale (MI), neurological function was assessed by behavioral tests, and pathological changes of brain tissue were analyzed by Hematoxylin-Eosin and Nissl staining. Subsequently, intestinal barrier function, inflammatory factors, and total bile acid (TBA) levels were examined in ICH mice. In addition, cell viability, apoptosis, oxidative stress, inflammatory factors, and β-MA levels were analyzed in the heme-induced SH-SY5Y cell model. Molecular docking and drug affinity responsiveness target stability (DARTS) were used to analyze the interaction between β-MA and S1PR2. Intervention with a S1PR2 agonist (CYM-5520) was used to further verify the mechanism.

RESULTS: Altered gut microbiota composition, elevated lipopolysaccharide levels, reduced expression of tight junction proteins, inflammatory activation, and disrupted bile acid metabolism were observed in ICH mice. Supplementation with MI ameliorated neural damage, cerebral edema, and neuronal loss in an intake dose-responsive manner, enhanced intestinal barrier integrity, and increased TBA levels. As a primary bile acid, β-MA directly mitigated hemin-induced oxidative stress and inflammation in neural cells. Mechanistically, β-MA downregulated the expression of S1PR2, but overexpression of S1PR2 counteracted the protective effects of β-MA. Furthermore, the administration of CYM-5520 attenuated the neuroprotective effects conferred by MI in vivo.

CONCLUSION: Muribaculaceae alleviated neurological injury after ICH by upregulating β-MA levels, thereby inhibiting the S1PR2 signaling pathway. This research offers a novel approach to treating ICH by focusing on the gut microbiota-bile acid metabolism-neuroprotection axis.