Sibelium exerts anti-migraine effects by remodeling the gut microbiota and regulating metabolic and immune pathways of the brain-gut axis.

Abstract

BACKGROUND/OBJECTIVES: Migraine is a highly disabling neurological disorder closely associated with the brain-gut axis. The mechanism of action of sibelium (flunarizine), a commonly used prophylactic medication, is unclear but may act through modulation of the gut microbiota. Based on the "brain-gut-microbiota axis" theory, the effects of sibelium on gut microbiota and the underlying mechanism for migraine prevention were investigated. METHODS: A nitroglycerin-induced migraine model was established in C57BL/6&#xa0;J mice to comprehensively evaluate the effects of sibelium on migraine behavior, neuroinflammation, and gut microbiota. RESULTS: Sibelium significantly delayed migraine onset (31.5%, p&#xa0;<&#xa0;0.01), shortened the duration of ear redness (53.4%), and reduced head-scratching frequency (59.4%) compared with vehicle only. At the molecular level, sibelium effectively reversed migraine-related neurotransmitter imbalances by reducing serum levels of CGRP, NO, and SP, increasing 5-HT concentration, and suppressing abnormal expression of c-Fos, CGRP, and IL-1&#x3b2; proteins in brain tissue. Based on the 16S rRNA sequencing analysis, sibelium improved gut microbiota diversity in model mice (Chao1 index increased by 17.9%), enriched beneficial genera (e.g., Lactobacillus and Bifidobacterium), and reduced the growth of the conditional pathogen Helicobacter by 85%. LEfSe analysis and correlation studies revealed that anti-inflammatory-related microbiota (e.g., Lachnospiraceae NK4A136 group) negatively correlated with pro-inflammatory factors (c-Fos, IL-1&#x3b2;; r&#xa0;=&#xa0;-0.68, p&#xa0;=&#xa0;0.001), and Lactobacillus positively correlated with IL-1&#x3b2; (r&#xa0;=&#xa0;0.78, p&#xa0;<&#xa0;0.001) after sibelium intervention. Functional prediction indicated that sibelium restored amino acid metabolism and immune pathway activity. CONCLUSIONS: Sibelium prevents and attenuates migraines by modulating the microbiota-immune-neural network within the gut-brain axis, providing a novel theoretical foundation for clinical intervention.