A causal effects of gut microbiota in the development of migraine

Abstract

Background: The causal association between the gut microbiome and the development of migraine and its subtypes remains unclear.

Methods: The single nucleotide polymorphisms concerning gut microbiome were retrieved from the gene-wide association study (GWAS) of the MiBioGen consortium. The summary statistics datasets of migraine, migraine with aura (MA), and migraine without aura (MO) were obtained from the GWAS meta-analysis of the International Headache Genetics Consortium (IHGC) and FinnGen consortium. Inverse variance weighting (IVW) was used as the primary method, complemented by sensitivity analyses for pleiotropy and increasing robustness.

Results: In IHGC datasets, ten, five, and nine bacterial taxa were found to have a causal association with migraine, MA, and MO, respectively, (IVW, all P < 0.05). Genus.Coprococcus3 and genus.Anaerotruncus were validated in FinnGen datasets. Nine, twelve, and seven bacterial entities were identified for migraine, MA, and MO, respectively. The causal association still exists in family.Bifidobacteriaceae and order.Bifidobacteriales for migraine and MO after FDR correction. The heterogeneity and pleiotropy analyses confirmed the robustness of IVW results.

Conclusion: Our study demonstrates that gut microbiomes may exert causal effects on migraine, MA, and MO. We provide novel evidence for the dysfunction of the gut-brain axis on migraine. Future study is required to verify the relationship between gut microbiome and the risk of migraine and its subtypes and illustrate the underlying mechanism between them.

Keywords: Causal association; Gut microbiome; Mendelian randomization; Migraine; Migraine with aura; Migraine without aura.

Fig. 1

Study design of the two-sample Mendelian randomization for the effect of the genetically predicted gut microbiome on migraine, MA, and MO. SNP, single nucleotide polymorphism; MA, migraine with aura; MO, migraine without aura; IHGC, international headache genetics consortium; IV, instrumental variables; IVW, IVW, inverse variance weighted; RAPS, robust adjusted profile score; MR-PRESSO, MR Pleiotropy RESidual Sum and Outlier

Fig. 2

Causal effect of the gut microbiome on migraine in IHGC datasets based on MR analyses. From outside to inside, the P values of IVW, MR Egger, WMe, WMo, and SM are represented, respectively. IVW, inverse variance weighted; WMe, weighted median; WMo, weighted mode; SM, simple mode. MR, mendelian randomization; IHGC, international headache genetics consortium

Fig. 3

Causal effect estimates of the gut microbiome on migraine in IHGC datasets. OR, odds ratio; CI, confidence interval; IVW, inverse variance weighted method; RAPS, robust adjusted profile score; MR, mendelian randomization; IHGC, international headache genetics consortium

Fig. 4

Causal effect of the gut microbiome on MA in IHGC datasets based on MR analyses. From outside to inside, the P values of IVW, MR Egger, WMe, WMo, and SM are represented, respectively. MA, migraine with aura; IVW, inverse variance weighted; WMe, weighted median; WMo, weighted mode; SM, simple mode. MR, mendelian randomization; IHGC, international headache genetics consortium

Fig. 5

Causal effect estimates of the gut microbiome on MA in IHGC datasets. OR, odds ratio; CI, confidence interval; IVW, inverse variance weighted method; RAPS, robust adjusted profile score; MR, mendelian randomization; IHGC, international headache genetics consortium; MA, migraine with aura

Fig. 6

Causal effect of the gut microbiome on MO in IHGC datasets based on MR analyses. From outside to inside, the P values of IVW, MR Egger, WMe, WMo, and SM are represented, respectively. MO, migraine without aura; IVW, inverse variance weighted; WMe, weighted median; WMo, weighted mode; SM, simple mode. MR, mendelian randomization; IHGC, international headache genetics consortium

Fig. 7

Causal effect estimates of the gut microbiome on MO in IHGC datasets. OR, odds ratio; CI, confidence interval; IVW, inverse variance weighted method; RAPS, robust adjusted profile score; MR, mendelian randomization; IHGC, international headache genetics consortium; MO, migraine without aura

Fig. 8

The common bacterial traits in IHGC datasets and FinnGen datasets for migraine, MA, and MO. IHGC, international headache genetics consortium; MA, migraine with aura; MO, migraine without aura