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Oral–gut–brain axis in migraine: A new frontier in neuroinflammation and microbial therapeutics
*Corresponding author: Siddhant Mehrotra, Junior Resident 2nd Year, Department of Pharmacology and Therapeutics, King George’s Medical University, Lucknow, Uttar Pradesh, India. drsidmehrotrakgmu@gmail.com
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Received: ,
Accepted: ,
How to cite this article: Mehrotra S, Srivastava N, Jain A, Singh S, Dixit RK. Oral–gut–brain axis in migraine: A new frontier in neuroinflammation and microbial therapeutics. Indian J Physiol Pharmacol. doi: 10.25259/IJPP_660_2025
Abstract
Migraine is a multifaceted neurovascular condition impacting more than one billion people worldwide. Historically attributed to the trigeminovascular system and neuropeptide imbalance, recent developments indicate a substantial involvement of microbial populations in the pathogenesis of migraines. This review analyses contemporary evidence connecting the oral, intestinal and nasal microbiota to migraine through immunological, vascular and neurological pathways. The gut microbiome affects central sensitisation, vagus nerve activation and blood–brain barrier permeability. Salivary microbiota, especially nitrate-reducing species, may influence nitric oxide pathways, thereby impacting cerebral vasodilation. Alterations in nasal microbiota may influence trigeminal and olfactory signalling, presenting an additional microbial pathway to neuroinflammation. We examine evidence from multi-omics research, Mendelian randomisation and observational cohorts, indicating that the oral–gut–brain axis is a feasible target for therapeutic intervention in migraine. We will conclude by examining the prospects of microbial therapies and biomarker identification in individualised migraine treatment.
Keywords
Blood–brain barrier
Central sensitisation
Gut microbiota
Microbial dysbiosis
Migraine
Nasal microbiome
Neuroinflammation
Nitric oxide
Oral microbiome
Probiotics
INTRODUCTION
Migraine is a common and debilitating primary headache illness that impacts approximately one billion people worldwide.[1] Traditionally regarded as a neurovascular event characterised by cortical spreading depression and trigeminovascular activation, increasing data suggest the involvement of systemic factors such as inflammation, hormone variations and microbial dysbiosis. Recent developments in neuro-gastroenterology and microbiome research have established the notion of an oral–gut–brain axis, in which microbial ecosystems in the gastrointestinal, mouth and nasal regions affect central nervous system functioning and disease vulnerability.[2] Recent discoveries indicate that the microbiota, through their metabolites, neuroactive substances and immunomodulatory functions, significantly influence pain pathways, blood–brain barrier integrity and neuroinflammatory processes. This paradigm change has focused emphasis on the therapeutic manipulation of microbiota in the management of chronic neurological disorders such as migraine.[3]
ORAL-GASTROINTESTINAL-BRAIN AXIS
The oral–gut–brain axis is a bidirectional signalling network that encompasses the enteric nervous system, vagus nerve, immunological pathways, hormone signals and microbial metabolites.[4] Although the gut-brain axis has been widely researched, the current findings indicate that the oral and nasal bacteria also play a substantial role in neurovascular function.[5] The gut microbiota synthesises several neurotransmitters and neuromodulators, such as serotonin, dopamine, g-aminobutyric acid and short-chain fatty acids (SCFAs), which can affect central nervous system excitability and pain modulation.[6] These chemicals interact with the brain either directly through the vagus nerve or indirectly through immunological or endocrine signalling. Dysregulation of this axis, whether from infection, antibiotic exposure, inadequate food or stress, can result in modified pain sensitivity and neuroinflammatory conditions frequently observed in migraine sufferers.[7,8]
THE ROLE OF GUT MICROBIOTA IN MIGRAINE PATHOPHYSIOLOGY
Dysbiosis, characterised by changes in gut microbial diversity and composition, has been noted in migraine patients relative to healthy controls.[9,10] A reduction in advantageous bacterial species, including Faecalibacterium prausnitzii and Bifidobacterium species, coupled with an elevation in pro-inflammatory species such as Escherichia coli and Clostridium, has been documented.[11] These modifications have operational consequences. Decreased synthesis of SCFAs undermines intestinal barrier integrity, facilitating the transfer of microbial products, including lipopolysaccharide (LPS), which triggers systemic immunological responses.[12] Peripheral inflammation can sensitise the trigeminovascular system and decrease the threshold for migraine attacks.[13] Animal studies additionally substantiate a causal relationship between gut microbiota and migraine. Rodents that are germ-free or have undergone antibiotic treatment display heightened nociceptive behaviours and modified cortical excitability, which are normalised with probiotic intervention.[14] These data suggest that microbial makeup and function may serve as both a biomarker and a modifiable risk factor for migraine.
| S.No. | Title | Author and year | Type of study | Key findings | Conclusion |
|---|---|---|---|---|---|
| 1 | Bidirectional communication along the microbiota–gut–brain axis | Cryan et al., 2019[2] | Major review | Elucidated the neuronal, immunological and metabolic signalling pathways between gut microbiota and the central nervous system | It is proposed that microbial dysbiosis may influence neurological function through immunological and neuroendocrine pathways |
| 2 | Gut microbiota and neurological disease mechanisms | Ma et al., 2019[12] | Review | Demonstrated that microbial metabolites and immunological mediators affect CNS disease | Facilitated the understanding of gut-derived inflammation in persistent neurological pain. |
| 3 | Human microbiome and neurotransmitter modulation | Zheng et al., 2019[24] | Animal study using human FMT | Transferring microbiota from patients modified the glutamate–GABA equilibrium and behaviour in mice | Presented causal evidence indicating that microbial composition influences neurochemistry and pain |
| 4 | Probiotic supplementation trial in migraine | Martami et al., 2019[29] | Randomised, double-blind clinical trial | Probiotic use diminished the frequency of headaches and inflammatory indicators | Presented clinical evidence endorsing microbiota modification in migraine treatment |
| 5 | Microbiota–brain axis in neuropsychiatric disorders | de la Cruz-Pavlovich et al., 2020[14] | Systematic review | Condensed mechanistic evidence from mental health research | Proposed translational potential of microbiome-derived treatments for neurological illnesses |
| 6 | Role of SCFAs in gut–brain communication | Silva et al., 2020[7] | Review | Emphasised SCFAs as anti-inflammatory metabolites safeguarding gastrointestinal and neurological health | Recognised SCFA deficiency as a potential contributor to neuroinflammation in migraine |
| 7 | Gut–brain axis in migraine | Arzani et al., 2020[3] | Descriptive review | Gathered data connecting gut dysbiosis to modified neuroimmune pathways in migraine | Proposed that an altered microbial equilibrium contributes to migraines through inflammation and metabolite signalling |
| 8 | Gut microbiota and SCFA pathways in migraine | Arzani et al., 2022[26] | Review | Documented diminished SCFA-associated microbial pathways in migraine populations | Correlated metabolic deficiencies in short-chain fatty acids with inflammation and blood–brain barrier disruption |
| 9. | Diet, microbiota and migraine management | Russo et al., 2022[30] | Integrative review | Consolidated data on dietary and microbiota interventions in migraine | Determined that dietary and microbial manipulation had therapeutic potential. |
FMT: Faecal microbiota transplantation, GABA: γ-aminobutyric acid, SCFAs: Short-chain fatty acids
ORAL MICROBIOME AND NITRATE-INDUCED NEUROVASCULAR STIMULI
The oral microbiome, although less studied than the gut microbiome, is crucial for nitrate metabolism and the modulation of vascular tone.[15] Certain oral bacteria, including Veillonella, Actinomyces and Rothia, transform dietary nitrates into nitrites, which are then converted into nitric oxide (NO) throughout the body.[16] NO is a recognised migraine trigger owing to its vasodilatory effects on cerebral arteries and its capacity to modify calcitonin gene-related peptide, which is a crucial neuropeptide associated with migraines. Research indicates that individuals with migraines have a greater prevalence of nitrate-reducing bacteria in their oral cavity, which may predispose them to heightened NO reactions following nitrate-rich meals.[17,18] Furthermore, excessive use of antibacterial mouthwashes may disturb this fragile microbial equilibrium, impacting systemic NO homeostasis.[19] Oral hygiene, dietary nitrate consumption and microbiota-focused interventions may thus serve as modifiable elements in migraine prevention.
NASAL MICROBIOTA AND NEUROIMMUNE INTERACTION
The nasal cavity contains a varied albeit less populous microbial community in comparison to the oral and gut microbiota. This niche is anatomically next to the olfactory bulb and trigeminal nerve ends, which are closely associated with migraine pathogenesis.[19] Alterations in the nasal microbiota have been linked to upper airway inflammation, elevated pro-inflammatory cytokines and compromised epithelial barrier integrity. These alterations may facilitate local immunological activation and the sensitisation of trigeminal afferents.[20] Specific commensals, such as Corynebacterium accolens, possess anti-inflammatory capabilities and their reduction has been associated with respiratory and neurological disorders.[21] Despite the fledgling state of study regarding the nasal microbiome’s role in migraine, its capacity to influence local neuroimmune responses renders it a significant, emergent element of the oral–gut–brain axis.[22]
BIOLOGICAL BASIS OF ACTION
SCFAs, serotonin and neuroinflammation are multiple molecular processes linking microbiota to vulnerability to migraines.[23] The most extensively researched include SCFAs, including butyrate, propionate and acetate, possess anti-inflammatory properties, enhance gut barrier integrity and modulate microglial activity in the brain.[24] Butyrate has demonstrated the ability to diminish the expression of pro-inflammatory cytokines and safeguard against blood– brain barrier disruption.[25] Advanced techniques encompass postbiotics (metabolically active microbial products) and faecal microbiota transplantation (FMT), which has demonstrated tentative efficacy in various neurological disorders such as autism and Parkinson’s disease.[25] Serotonin production in the gastrointestinal tract is modulated by microbial metabolites, specifically SCFAs and bile acids. Given that over 90% of serotonin is synthesised in the gastrointestinal tract, dysbiosis may modify serotonergic activity, thereby influencing pain sensitivity, mood and vascular function.[26,27] Neuroinflammation induced by microbial-derived LPS and other metabolites can activate toll-like receptors, inflammasomes and cytokine cascades, thereby sensitising trigeminal pathways and reducing the threshold for migraine onset. Comprehending these mechanical connections not only enhances the biological validity of the microbiome-migraine relationship but also reveals new avenues for intervention. Multi-omics and causal inference multi-omics methodologies – incorporating metagenomics, metabolomics, transcriptomics and proteomics – have facilitated a more thorough understanding of the functional role of microbiota in migraine.[28]
THERAPEUTIC MODULATION OF THE MICROBIOME
Modulating the microbiome is a possible therapeutic approach for migraine control. Clinical research and experimental models indicate that probiotics, especially strains of Lactobacillus and Bifidobacterium, can diminish the incidence, severity and duration of headaches.[29] These probiotics improve gut barrier integrity, mitigate systemic inflammation and reinstate microbial diversity altered in individuals with migraines. Prebiotics, including inulin and fructo-oligosaccharides, preferentially enhance the proliferation of beneficial bacteria and augment SCFA synthesis.[30] Symbiotics which integrate prebiotics and probiotics, may provide synergistic advantages; however, the evidence is still limited. Considering the impact of oral and nasal microbiomes on NO and immune regulation, localised treatments like microbiota-preserving dental items or nasal sprays may serve as potential adjuncts in the future.
INTEGRATIVE METHODOLOGIES
Altered pathways in butanoate metabolism, tryptophan breakdown and bile acid production have been identified in the microbiome of migraine sufferers. Mendelian randomisation (MR) research has commenced investigating causality by employing host genetic polymorphisms as surrogates for microbial characteristics. An MR study associated genetically predicted levels of Bifidobacterium with a reduced risk of migraines. These methods provide additional evidence beyond mere association and substantiate microbiota-based causal pathways in the pathophysiology of migraine.
CHALLENGES AND PROSPECTS
Notwithstanding increasing interest, numerous barriers impede clinical translation. Microbiota composition exhibits significant interindividual diversity influenced by genetics, nutrition, geography and lifestyle. Standardised protocols for microbiome gathering, sequencing and analysis are absent. Longitudinal cohort studies incorporating comprehensive phenotyping and reliable microbiome profiling are essential for elucidating temporal connections and identifying predicting microbial biomarkers. Ethical considerations with therapies such as FMT necessitate prudence.[31] In the future, precision microbiome therapy customised to an individual’s microbial profile, genetics and clinical phenotype may revolutionise migraine treatment beyond mere symptom management to addressing underlying causes.
CONCLUSION
The oral–gut–brain axis provides a transformational perspective for comprehending and addressing migraine pathogenesis. The gut, oral and nasal microbiota affect essential pathways in inflammation, neuromodulation and vascular tone, all of which are pivotal in migraine. Increasing evidence from animal models, human research and integrative omics indicates that the microbiome serves not just as a biomarker but also as a modifiable therapeutic target. Future research must confront current constraints by thorough, mechanistic investigation. Microbiota-targeted therapies – spanning probiotics to tailored oral hygiene – could transform the migraine treatment paradigm in the next decade.
Ethical approval:
Institutional Review Board approval is not required.
Declaration of patient consent:
Patient’s consent is not required as there are no patients in this study.
Conflicts of interest:
There are no conflicts of interest.
Use of artificial intelligence (AI)-assisted technology for manuscript preparation:
The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.
Financial support and sponsorship: Nil.
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