Submitted:
10 March 2025
Posted:
10 March 2025
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Abstract
Objective: This review explores the emerging role of the gut-brain axis [GBA] in migraine pathophysiology, emphasizing gut microbiota dysbiosis, intestinal permeability, and neuroinflammatory mechanisms. We analyze the interplay between gastrointestinal [GI] health and migraine and assess potential microbiome-targeted therapeutic strategies. Methods: A comprehensive literature search was conducted using PubMed, Scopus, and Web of Science for studies published in the last two decades on migraine and the GBA. Relevant research on gut microbiota composition, immune modulation, neurotransmitter synthesis, and microbiome-based interventions was reviewed. Clinical and preclinical studies investigating the comorbidity between gastrointestinal disorders and migraine were analyzed. Discussion: The gut microbiota profoundly affects the central nervous system through immune regulation, metabolite production, and neurotransmitter synthesis. Dysbiosis, characterized by an imbalance of commensal bacteria, has been linked to systemic inflammation, increased intestinal permeability, and activation of the trigeminovascular system, all contributing to migraine pathogenesis. Evidence suggests that conditions such as irritable bowel syndrome and inflammatory bowel disease frequently co-occur with migraine, indicating a shared pathophysiological basis. Emerging therapeutic interventions, including probiotics, prebiotics, dietary modifications, and fecal microbiota transplantation, have shown promise in modulating gut health and alleviating migraine symptoms. However, the causality between gut dysbiosis and migraine remains inconclusive, necessitating further longitudinal and interventional studies. Conclusion: The gut-brain axis is critical in migraine pathophysiology, with gut dysbiosis and neuroinflammation emerging as key contributors. Targeting gut microbiota may offer novel, non-invasive therapeutic strategies for migraine management, warranting further research.
Keywords:
migraine
; gut-brain axis
; microbiota
; dysbiosis
; neuroinflammation
; intestinal permeability
; probiotics
; gastrointestinal disorders
Introduction
Migraine is a complex neurological disorder characterized by recurrent episodes of moderate to severe headache, often accompanied by nausea, vomiting, and sensitivity to light and sound. It affects approximately 14% of the global population and ranks among the leading causes of disability worldwide [1]. Despite significant advances in understanding migraine pathophysiology, its precise etiology remains incompletely understood, and current therapeutic options are often limited in efficacy.
In recent years, scientific attention has increasingly focused on the bidirectional communication pathway between the gastrointestinal tract and the central nervous system, known as the gut-brain axis [GBA] [2]. This complex network involves neural, immune, endocrine, and metabolic pathways that enable cross-talk between the gut microbiota and the brain. The human gut microbiome, comprising approximately 100 trillion microorganisms, is pivotal in maintaining intestinal homeostasis, metabolizing nutrients, synthesizing vitamins, and regulating immune function [3].
Emerging evidence suggests a potential link between alterations in gut microbiota composition and various neurological disorders, including migraine [4]. The recognition of a high prevalence of gastrointestinal comorbidities among migraine patients has further stimulated interest in exploring this connection [5]. This review aims to synthesize current knowledge regarding the role of the GBA in migraine pathophysiology and evaluate potential microbiome-targeted therapeutic approaches.
The Gut-Brain Axis: Mechanisms of Bidirectional Communication
The GBA represents a complex communication network through which the central nervous system and the gastrointestinal tract interact and influence each other’s functions. Several pathways mediate this bidirectional communication:
Neural Pathways
The vagus nerve is a primary neural pathway connecting the gut and brain, transmitting information bidirectionally [6]. The enteric nervous system [ENS], often referred to as the “second brain,” contains approximately 500 million neurons and regulates gastrointestinal functions independently while maintaining constant communication with the central nervous system [7]. Afferent fibers transmit signals from the gut to the brain, while efferent fibers convey information from the brain to the gut, influencing gut motility, secretion, and immune function.
Immune Mechanisms
The gut microbiota plays a crucial role in shaping the development and function of the immune system. Intestinal microbes interact with immune cells in the gut-associated lymphoid tissue [GALT], influencing cytokine production and immune response [8]. Dysbiosis can trigger local and systemic inflammation, which may contribute to neuroinflammation by producing pro-inflammatory cytokines and activating microglia [9].
Endocrine Pathways
The hypothalamic-pituitary-adrenal [HPA] axis represents a key endocrine pathway in the GBA. Stress can alter the composition and intestinal permeability of the gut microbiota, while gut microbes can influence stress responses through the regulation of cortisol and other stress hormones [10].
Microbial Metabolites
Gut microbiota produces various neuroactive compounds, including short-chain fatty acids [SCFAs], neurotransmitters, and amino acid metabolites, which can directly or indirectly affect brain function [11]. For example, certain gut bacteria synthesize neurotransmitters such as serotonin, gamma-aminobutyric acid [GABA], dopamine, and norepinephrine, which play crucial roles in pain modulation and migraine pathophysiology [12].
Gut Microbiota Dysbiosis in Migraine
Alterations in Microbial Composition
Several studies have reported differences in gut microbiota composition between migraine patients and healthy controls. A case-control study by Gonzalez et al. [13] found decreased abundance of Firmicutes and increased levels of Bacteroidetes in migraine sufferers. Another study by Chen et al. [14] observed reduced diversity and richness of gut microbiota in chronic migraine patients compared to episodic migraine patients and healthy controls.
Specific bacterial genera associated with migraine include Bifidobacterium, Lactobacillus, Streptococcus, and Akkermansia [15]. These microorganisms are essential in maintaining gut barrier integrity, modulating inflammation, and producing neuroactive compounds.
Mechanisms Linking Gut Dysbiosis to Migraine
Increased Intestinal Permeability
Dysbiosis can compromise the integrity of the intestinal epithelial barrier, leading to a “leaky gut” and allowing bacterial lipopolysaccharides [LPS] and other inflammatory mediators to enter the bloodstream [16]. This increased intestinal permeability has been observed in migraine patients and may contribute to systemic inflammation and neuroinflammation [17].
Systemic Inflammation
The translocation of bacterial products from the gut to the systemic circulation can trigger immune responses and promote the release of pro-inflammatory cytokines such as tumor necrosis factor-alpha [TNF-α], interleukin-1β [IL-1β], and IL-6 [18]. These cytokines can cross the blood-brain barrier and activate trigeminal neurons, potentially triggering migraine attacks [19].
Neurotransmitter Imbalance
Gut microbiota influences the synthesis and metabolism of various neurotransmitters in migraine pathophysiology. For instance, approximately 90% of serotonin in the human body is produced in the gut by enterochromaffin cells under the influence of gut microbiota [20]. Alterations in serotonin levels have been implicated in migraine pathogenesis, and many antimigraine drugs target serotonin receptors [21].
Calcitonin Gene-Related Peptide [CGRP] Modulation
Gastrointestinal Comorbidities in Migraine
Irritable Bowel Syndrome [IBS]
Epidemiological studies consistently report a higher prevalence of IBS among migraine patients compared to the general population [24]. A systematic review by Cámara-Lemarroy et al. [25] found that IBS is 2-3 times more common in migraine sufferers. Both conditions share similar pathophysiological features, including visceral hypersensitivity, altered gut permeability, and dysregulation of the brain-gut axis.
Inflammatory Bowel Disease [IBD]
Several studies have documented an association between migraine and IBD, with a higher prevalence of migraine in patients with Crohn’s disease and ulcerative colitis [26]. Inflammatory mechanisms, including increased intestinal permeability and elevated levels of pro-inflammatory cytokines, may underlie this comorbidity.
Celiac Disease and Non-Celiac Gluten Sensitivity
Helicobacter pylori Infection
Some studies have suggested an association between Helicobacter pylori infection and migraine, with eradication therapy improving migraine symptoms in certain cases [29]. H. pylori may contribute to migraine through various mechanisms, including promotion of inflammation, release of vasoactive substances, and modulation of nutrient absorption.
Therapeutic Implications: Targeting the Gut-Brain Axis
Probiotics
Probiotics, defined as live microorganisms that confer health benefits when administered adequately, have shown promise in migraine management. A randomized controlled trial by Martami et al. [30] found that a multispecies probiotic preparation significantly reduced migraine frequency and severity compared to a placebo. Probiotics may exert their beneficial effects through multiple mechanisms, including restoration of gut barrier function, modulation of immune responses, and regulation of neurotransmitter synthesis.
Prebiotics
Prebiotics are non-digestible food components that selectively stimulate beneficial gut bacteria’ growth and/or activity. Although research specifically on prebiotics for migraine is limited, studies have shown that prebiotic supplementation can modify gut microbiota composition, reduce intestinal permeability, and decrease systemic inflammation [31]. A pilot study by Jackson et al. [32] reported improvements in stress and anxiety symptoms following prebiotic administration, suggesting potential benefits for migraine patients, given the relationship between stress and migraine.
Dietary Interventions
Ketogenic Diet
The ketogenic diet, characterized by high fat, adequate protein, and very low carbohydrate intake, has shown efficacy in reducing migraine frequency in several small studies [33]. This dietary approach may exert its antimigraine effects through multiple mechanisms, including modulation of gut microbiota, anti-inflammatory actions, and enhancement of mitochondrial function.
Low FODMAP Diet
The low FODMAP [Fermentable Oligosaccharides, Disaccharides, Monosaccharides, and Polyols] diet has been primarily used for managing IBS symptoms. Given the comorbidity between IBS and migraine, preliminary studies have investigated its potential benefits for migraine patients [34]. This dietary approach may reduce symptom severity by decreasing fermentation in the gut and modifying the gut microbiota composition.
Fecal Microbiota Transplantation [FMT]
FMT involves transferring fecal material from healthy donors to recipients to restore gut microbial diversity and function. While FMT has been primarily investigated for recurrent Clostridioides difficile infection and IBD, preliminary case reports suggest potential benefits for neurological conditions, including migraine [35]. However, randomized controlled trials are needed to establish the safety and efficacy of FMT for migraine management.
Challenges and Future Directions
Despite growing evidence linking the GBA to migraine pathophysiology, several challenges remain:
- Establishing causality: Most studies have been observational, making it difficult to determine whether gut dysbiosis is a cause or consequence of migraine.
- Heterogeneity of migraine: Migraine is a heterogeneous disorder with various subtypes and triggers, which may have different relationships with gut microbiota.
- Methodological issues: Variations in sample collection, processing, and analytical techniques across studies limit the comparability of results.
- Individualized approaches: The complexity of gut microbiota and individual variations necessitate personalized approaches to microbiome-targeted therapies.
Future Research Should Focus on
- Longitudinal studies tracking changes in gut microbiota composition and migraine symptoms over time.
- Large-scale randomized controlled trials evaluating the efficacy of microbiome-targeted interventions.
- Integrating multi-omics approaches [genomics, proteomics, metabolomics] to comprehensively assess the interactions between gut microbiota and the host.
- Development of biomarkers based on gut microbiota profiles to predict treatment response and disease progression.
- Investigation of the role of gut virome and mycobiome in migraine pathophysiology.
Conclusions
Emerging evidence supports a significant role for the gut-brain axis in migraine pathophysiology. Alterations in gut microbiota composition, increased intestinal permeability and associated neuroinflammatory processes appear to contribute to migraine susceptibility and symptomatology. The high prevalence of gastrointestinal comorbidities among migraine patients further strengthens this connection.
Targeting the gut-brain axis through probiotics, prebiotics, dietary modifications, and potentially FMT represents a promising approach for migraine management. These interventions offer several advantages, including a favorable safety profile, the potential to address comorbid conditions, and complementary mechanisms to conventional antimigraine treatments.
However, the clinical translation of these findings requires further research to establish causality, optimize treatment protocols, and identify patient subgroups most likely to benefit from microbiome-targeted interventions. As our understanding of the complex interactions between gut microbiota and the brain continues to evolve, so too will our ability to develop more effective strategies for migraine prevention and treatment based on the gut-brain axis.
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