Altered serum short-chain fatty acid profiles in episodic and chronic migraine and their modulation by preventive treatment

BACKGROUND: Short-chain fatty acids (SCFAs), including acetate, propionate, and butyrate, are gut-microbiota-derived metabolites implicated in gut–brain communication. This study aimed to characterize serum SCFA profiles in individuals with episodic migraine (EM) or chronic migraine (CM) compared with healthy controls (HC) and to examine associations between preventive treatment and these metabolites. METHODS: Adults with EM, CM, and age- and sex-matched HC were enrolled. Serum levels of acetate, propionate, and butyrate were quantified using liquid chromatography–tandem mass spectrometry. Group differences in SCFA levels were assessed using Quade’s nonparametric analysis of covariance, adjusting for age, sex, and body mass index. Multiple linear regression examined independent associations between preventive treatment and SCFA levels. Moderation analysis evaluated whether preventive treatment modified the association between SCFA levels and headache days per 30 days. RESULTS: Of the 476 participants (HC: n = 108; EM: n = 190; CM: n = 178), those with EM or CM without preventive treatment had lower serum butyrate levels than did HC (EM: p = 0.001; CM: p = 0.005), with no significant differences in acetate or propionate. Preventive treatment was independently associated with higher serum propionate levels (B = 0.805, 95% confidence interval [CI] = 0.395–1.215, p < 0.001) in those with CM but not in those with EM. Although preventive treatment did not significantly modify associations between SCFA levels and headache days per 30 days, higher butyrate levels were associated with a greater number of headache days in participants receiving preventive treatment (B = 7.967, 95% CI = 2.481–13.453, p = 0.005). CONCLUSIONS: Serum SCFA profiles differed according to migraine status and preventive treatment use. Our findings highlight potential interactions among migraine, preventive therapy, and SCFA metabolism, warranting longitudinal studies to clarify directionality and underlying mechanisms.