We utilized a bidirectional TSMR strategy with available GWAS summary datasets to explore the reciprocal causality between GERD and migraine, encompassing both the general condition and its MA and MO subtypes. The MR study indicates that GERD correlates with a higher probability for migraine and the MO, without a corresponding link to an elevated risk of MA. Furthermore, our research does not corroborate a causal connection between the genetic predisposition to migraine, including all subtypes, and an escalated risk of GERD. While some heterogeneity appeared in the GERD-migraine and MO-GERD studies, random effects IVW analysis remains robust against heterogeneity, suggesting a stable causal effect.
Prior research has suggested an association between various GI diseases and primary headache syndromes, including migraine. The brain-gut axis facilitates bidirectional communication linking the brain and the intestinal tract, mediated by neural, hormonal, and immune pathways. Early reports noted improvements in migraine symptoms when gastroesophageal reflux symptoms subsided in patients with comorbidities of both diseases30. Retrospective analyses have shown GERD occurs more frequently among migraine sufferers than among those without migraines, with similar rates of gastritis and stomach ulcers in both groups13, 31. Notably, a significant association has been observed between primary childhood migraine and infantile gastroesophageal reflux, particularly for migraine without aura32.
The causal link between migraine and GERD remains ambiguous due to a scarcity of research in this domain. Predominantly, epidemiological investigations have relied on case-control or cross-sectional methodologies, which obscure the temporal progression, thereby complicating the determination of causality. Additionally, prior observational research has faced constraints, including small participant groups, difficulties in addressing reverse causality, and the influence of confounding factors. Utilizing more robust study designs, such as bidirectional TSMR analysis, can facilitate a better understanding of the causal dynamics between exposures and outcomes within the current research framework.
We have identified a causal relationship between GERD and migraine, particularly its MO subtype, which may be explained by shared mechanisms involving the NF-κB pathway in the inflammatory processes of both conditions33, 34. Research suggests that migraine pathogenesis involves cortical spreading depression (CSD)35, a self-propagating wave of depolarization that moves throughout the cerebral cortex. This phenomenon could activate the trigeminal input pathway, leading to changes in blood-brain barrier permeability through matrix metalloproteinase activation and upregulation. These changes may induce inflammatory responses in pain-sensitive meninges, resulting in migraine headaches through central and peripheral reflex mechanisms. Molecular cascades during CSD activation may include pannexin-1 channel opening, caspase-1 activation, pro-inflammatory mediator release, and activation of NF-κB in astrocytes, transmitting inflammatory signals to trigeminal nerve fibers around cranial blood vessels36. Studies on GERD mechanisms suggest that inflammatory cell infiltration precedes esophageal epithelial surface erosion37, indicating inflammation as a key mediator of erosion. Additionally, research has shown that in esophageal inflammation models, epithelial keratinocytes secrete IL-8, indicating that gastroesophageal reflux could activate inflammatory mechanisms, which may subsequently impair esophageal barrier function38. This activation of inflammatory pathways, including the NF-κB pathway, by acidic substance-induced chemical injury to the esophageal mucosa can lead to the upregulation of various inflammatory mediators such as matrix metalloproteinase-3, matrix metalloproteinase-9, IL-1, IL-6, and IL-8. Therefore, we hypothesize that NF-κB may play a role in various stages of GERD pathogenesis and migraine occurrence. The inflammatory pathways involved in GERD development may also contribute to migraine attacks, necessitating further investigation.
The second possible explanation is speculated to be due to the phenomenon of delayed gastric emptying or gastric paresis, which is shared by both conditions. A prior study identified that delayed gastric emptying , or gastric paresis, substantially contributes to the onset of GERD39. Additionally, research indicates that individuals with migraines experience delayed gastric emptying both during and after their attacks, suggesting a potential association with gastroesophageal reflux disease40, 41.
Furthermore, dysfunction within the autonomic nervous system (ANS) was previously associated with headaches, especially migraines, and GI disorders42, 43. Therefore, ANS dysfunction may also be related to the pathogenesis of these two conditions. Abnormalities in visceral mechanosensation and vagal nerve function have been found to be associated with dyspepsia, and visceral neural dysregulation is also linked to migraines12. Additionally, individuals presenting with both headache and gastrointestinal symptoms tend to suffer from more intense and frequent episodes compared to those experiencing headaches in isolation44, 45. One possible reason is the increased interaction of shared underlying processes, leading to worse symptoms when headaches and gastrointestinal issues occur together44.
Currently, here is currently considerable debate about whether MO and MA result from the same pathogenic mechanisms. MO and MA exhibit notable differences in their clinical presentations. For instance, MO is more likely to occur after stressful events, exams, or during the post-menstrual relaxation phase in women. In contrast, MA attacks lack this characteristic and may be triggered by intense natural or artificial visual stimuli in some cases46. Regarding associations with key female reproductive events, MO is notably affected by menstruation, unlike MA. Approximately one-fifth of MA cases experience heightened attack risks in the perimenstrual phase, compared to approximately three-quarters of MO cases47. During gestation, MO commonly abates in most instances, whereas MA tends to continue or intensify, and occasionally emerges for the first time47. Oral contraceptives generally exert no adverse effects on MO, yet in the majority of cases, they can worsen MA.
MA is characterized by visual, language, sensory, or brainstem symptoms that typically precede the headache phase. The pathogenesis of MA is widely attributed to CSD, involving neuronal and glial depolarization which then transitions to cortical hyperpolarization, progressing at 3–5 mm/min. This process corresponds to significant alterations in ion homeostasis and neurotransmitter release48. Additionally, there is a temporary surge in cerebral blood flow due to the increased energy demands for restoring homeostasis49. While the pathophysiology of other aura types (such as speech, sensory, and brainstem) is less studied, evidence suggests that CSD may also underlie their mechanisms49.
Research has also demonstrated differences in cerebral hemodynamics between MO and MA, with MA characterized by significant vasodilation and trigeminal vascular sensitization (TVS), which can trigger aura50.
The study findings point to a potential causative link connecting GERD and the occurrence of migraine, particularly the MO subtype, underscoring the importance of closely monitoring migraine symptoms in GERD patients, which could be beneficial in clinical practice. Additionally, it's crucial to be attentive to mixed symptoms of GERD or migraine.
On the other hand, MO lacks the premonitory aura symptoms seen in MA, and its pathophysiology is not fully elucidated. Some theories propose that CSD may occur silently in subcortical regions, such as the hypothalamus, in MO patients48. However, studies have shown that drugs inhibiting CSD, such as tonabersat, significantly reduce the frequency of aura attacks but not MO attacks51, indicating potential differences in the underlying mechanisms between the two types of migraine.
Our bidirectional TSMR study offers several advantages. Firstly, we applied MR analysis with SNPs that have a strong association (F>10), akin to the experimental setup of RCTs, to yield robust evidence. Unlike RCTs, which can be constrained by cost and sample size, MR analysis circumvents issues of reverse causation and confounding. Secondly, by relying on GWAS databases with European population samples, our study mitigates bias from demographic variability. Thirdly, the insights from our analysis could inform healthcare policy, especially if a causal link between GERD and migraine, notably the MO subtype, is established, potentially influencing strategies for mitigating and managing the condition.
Nevertheless, this research acknowledges certain constraints, primarily the heterogeneity in the analysis of GERD versus migraine, and MO versus GERD. The heterogeneity in the former could be due to the inclusion of both MA and MO subtypes in migraine data, while the subsequent examination of GERD versus MO revealed no heterogeneity. Considering the presence of MA data in migraine may contribute to the heterogeneity. The presence of heterogeneity in the latter may be explained by the small sample size. Additionally, we used GERD data rather than data encompassing all digestive system-related diseases, so the current findings cannot be extrapolated to patients with other digestive system disorders. Further research on this topic is warranted. Secondly, as current investigations primarily focus on the link between GERD and migraine, and the number of such investigations is limited, specific studies addressing the connection between GERD and the MO subtype of migraine are sparse. Therefore, the analysis of potential mechanisms remains somewhat limited in this regard. Thirdly, GERD is categorized into reflux esophagitis (RE) and non-erosive reflux disease (NERD). Our study was unable to ascertain the connection among these subtypes with the severity of migraine, including low-frequency as well as high-frequency episodic forms. Additionally, gastroscopy, an essential diagnostic tool for GERD, may lead to an underestimation of diagnosed cases due to its invasive nature. This bias remains unavoidable. Fourthly, despite no significant difference in GERD prevalence among males and females, migraine prevalence is higher in females. However, our reliance on public databases precluded subgroup analyses based on factors like age and gender. Fifthly, the GWAS data's European focus restricts the generalizability of our findings to non-European demographics. Lastly, expanding GWAS sample sizes could strengthen IVs, highlighting the need for larger-scale studies for more comprehensive research. Therefore, additional research is necessary to confirm the results of our current study.