Targeting the gut–brain axis in migraine: Effects of probiotic supplementation on migraine outcomes and inflammatory markers (CRP and TNF-α)

Abstract

The gut–brain axis has emerged as a potential therapeutic target in migraine management. Several randomized controlled trials (RCTs) have evaluated probiotic supplementation in migraine, yet their findings remain heterogeneous. The aim of this study was to systematically assess and quantitatively synthesize the effects of probiotics on migraine-related outcomes. A systematic review and meta-analysis of randomized controlled trials was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and registered in PROSPERO (CRD420261327461). Electronic databases were searched from inception to January 2026. Random-effects meta-analyses were performed to calculate pooled standardized mean differences (SMD) with 95% confidence intervals (CI). Primary outcomes included migraine attack frequency, migraine duration, and migraine severity. Secondary outcomes comprised inflammatory biomarkers, including high-sensitivity C-reactive protein (hs-CRP) and tumor necrosis factor-alpha (TNF-α). Risk of bias was assessed using the Cochrane Risk of Bias 2 (ROB 2) tool. Six RCTs involving 422 participants were included. Overall, probiotic supplementation significantly improved migraine-related outcomes compared with placebo (p<0.00001). Subgroup analyses demonstrated significant reductions in migraine attack frequency (p=0.002), migraine duration (p=0.0003), migraine severity (p=0.0006), and migraine disability assessment (MIDAS) score (p= 0.04). Substantial heterogeneity was observed across studies (I²=91%). Regarding inflammatory biomarkers, probiotic supplementation was not associated with significant reductions in hs-CRP (p=0.24) or TNF-α (p=0.66). The pooled analysis of inflammatory markers also showed no significant overall effect (p=0.28). Most trials were judged as having a low risk of bias or some concerns. In conclusion, probiotic supplementation is associated with significant improvements in migraine frequency, duration, severity, and disability, supporting its potential as an adjunctive therapeutic strategy in migraine management. The absence of significant effects on inflammatory biomarkers suggests that these clinical benefits may be mediated through alternative pathways within the gut–brain axis rather than systemic inflammation.