Research Review By Dr. Jeff Muir©

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Date Posted:

May 2021

Study Title:

Gut-brain Axis and migraine headache: a comprehensive review

Authors:

Arzani M, Jahromi SR, Ghorbani Z, Vahabizad F, Martelletti P, Ghaemi A, Sacco S, Togha M

Author's Affiliations:

Headache Department, Iranian Center of Neurological Research, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran; Department of Clinical Nutrition and Dietetics, Faculty of Nutrition and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Cardiovascular Diseases Research Center, Department of Cardiology, Heshmat Hospital, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran; Headache Department, Neurology Ward, Sina University Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy; Department of Virology, Pasteur Institute of Iran, Tehran, Iran; Neuroscience section, Department of Applied Clinical Sciences and Biotechnology, University of L’Aquila, L’Aquila, Italy.

Publication Information:

The Journal of Headache and Pain 2020; 21: 15. doi.org/10.1186/s10194-020-1078-9

Background Information:

The global prevalence of migraine headache is 14% (1), with recent evidence indicating that migraine is actually the leading cause of disability in those 50 years of age and younger (2, 3). Despite its prevalence, however, the exact pathogenesis of migraine headaches remains elusive. Several mechanisms have been suggested, including involvement of the gut-brain axis (4).

“Gut-brain axis” refers to the complex, bidirectional relationship between the gastrointestinal (GI) system and the central nervous system (CNS). Brain activity and hormonal actions allow the brain to influence the function of the gut, while a number of brain functions such as cognition and behaviour are in turn influenced by the gut (5, 6). Indeed, dysfunction of the gut-brain axis has been identified as a causal factor in a number of neurological disorders (ex. multiple sclerosis, Parkinson’s, Alzheimer’s).

These authors sought to compile the existing evidence regarding a link between the gut-brain axis and migraine headaches and present it in a narrative review. They completed a comprehensive review of the available literature, including an examination of the role of inflammation in migraine, plus the role of neuropeptides and the association between GI disorders and migraine headache.

Summary:

Inflammation and Migraine Headache:

Immune cells and their inflammatory mediators – interleukin 1ß, 6 and 18, plus tumour necrosis factor alpha (TNF-α) and interferon gamma have all been shown to sensitize afferent nerve endings and are known to play a role in inducing visceral pain (7, 8). These mediators are also increased during migraine attacks (9, 10). Further, substances like calcitonin gene-related peptide (CGRP), substance P (SP), vasoactive intestinal peptide (VIP) and neuropeptide Y (NPY) are thought to have an antimicrobial impact on a variety of gut bacterial strains.

Neuropeptides in Migraine Headache:
Glutamate (an excitatory neurotransmitter) affects both aspects of the gut-brain axis. It plays a role in cortical spreading depression, central sensitization and trigeminovascular stimulation, and has been noted at elevated levels in migraine sufferers (11, 12). Concurrently, it may affect inflammation and oxidative stress in the GI tract (13).

Neuropeptide Y (NPY) has been detected at all levels of the gut-brain axis and is known to affect blood flow in both the cerebrum and GI tract. It has also been found in elevated levels in the ictal phases of migraine sufferers (11).

CGRP is a main biomarker of migraine and inhibits gastric acid secretion and may suppress food intake (14). It is thought to be affected by the gut microbiota, although firm supportive evidence is currently minimal.

Cholecystokinin (CCK) is synthesized in both the small intestine and the mammalian brain and may play a role in endogenous pain signalling. Its level increases during migraine (15), although its role in dietary satiation and the observation that there is an increased risk of migraine in the obese are at odds (16). As such, its definitive role in migraine is unclear.

Serotonin Pathways in Migraine Headache:
Serotonin – via the tryptophan-kynurenine pathway – has been proposed as a method by which the gut microbiota can affect CNS function. Serotonin receptors have been identified on monocytes, macrophages, lymphocytes and dendrite cells, suggesting a role for this neurotransmitter in immune modulation. Additionally, serotonin plays an important role in inflammatory conditions such as Crohn’s disease and colitis (17), which further supports the gut-brain connection mediated by serotonin.

Migraine and Gastrointestinal (GI) Disorders:
 
Several researchers have demonstrated an association between migraine and GI disturbances including diarrhea, constipation (18), dyspepsia (19) and reflux (20). Causal mechanisms remain elusive, however.

Helicobacter pylori infection:
Helicobacter pylori (HP) has been found to be present in substantially higher proportions of migraine sufferers (45%) than health controls (33%) (21). Further, HP eradication may be associated with migraine symptom relief (22, 23). While the mechanism whereby HP induces migraine remains unknown, it is proposed that immune, inflammatory and vascular responses in the gastric mucosa may be responsible (21). CGRP, serotonin, substance P and other inflammatory factors have all been suggested as factors in the role of HP in migraine; however, more research is needed before firm conclusions can be made on this association.

Irritable Bowel Syndrome (IBS):
IBS and migraine share several demographic characteristics and are also both associated with comorbidities such as anxiety (24). The connection between the two conditions is reflected in the fact that IBS patients have a 40-80% higher prevalence of migraine, depression and fibromyalgia over non-IBS sufferers (25). Both migraine and IBS alter gut microflora composition, and similar food allergies/intolerances are known to initiate both conditions (26). The causative mechanisms are not known, but serotonin has been shown to play a role in modulating GI activities, with therapeutic agents that modulate serotonin receptors shown to be effective in addressing symptoms of both disorders (17).

Celiac Disease:
Neurologic manifestations including migraine have been observed in patients with CD, and CD patients have a higher prevalence of migraine than do healthy controls (27). The association between the two conditions has been suggested to be related to, among other causes, inflammatory cytokines induced by gluten. There is some evidence that gluten-free diet and CD treatment may improve headache symptoms (28).

Inflammatory Bowel Disease:
Data on the association between migraine and Crohn’s disease/colitis is scarce. Several low-level studies have noted associations between the conditions; however, exact mechanisms or a firm explanation of the connection remain elusive, with some authors suggesting that autoimmune-inflammatory responses and endothelial dysfunction noted in IBD may provide a causal link (29).

Dietary Considerations:

Dietary modifications have been suggested for migraine sufferers (30), although whether diet can be effective at minimizing symptoms remains unknown.

Probiotic Supplementation:
Probiotic administration has been examined in clinical studies, with a number of studies observing improvements in frequency and severity of migraine with probiotic use (31-33). The mechanism of action is unknown, but is suspected to be related to the promotion of short-chain fatty-acid (SCFA) production in the gut and the lowering of proinflammatory cytokine levels.

Carbohydrates:
A randomized trial compared patients who were allocated to receive either a low glycemic index diet or prophylactic medication for migraine and found that both groups demonstrated significant improvements in migraine attack frequency which were maintained for 90 days. Alterations in SCFA levels were suggested as a causal mechanism for this observation.

Fat:
In several studies, reducing dietary fat resulted in a reduction in headache intensity and frequency (34-36). These effects are attributed in part to: a balance between omega-3 and -6 fatty acids contributing to inflammatory control; omega-6 fatty acids promoting vasodilation; high-fat diets inducing hypercoagulability; and, dietary fat affecting serotonin release from platelets.

Vitamins:

Vitamin D3 supplementation has been shown to significantly reduce Helicobacter pylori (HP) count (37) and several studies have reported that serum vit D levels may be associated with increased risks of migraine (38, 39).

Weight Loss:

Obesity has been shown to increase the risk of episodic and chronic migraine (40), while weight reduction can decrease the intensity, frequency and duration of migraines (41). Elevated levels of CGRP and proinflammatory cytokines in obese adults and migraine sufferers have also been noted.

Clinical Application & Conclusions:

In general, the gut-brain axis appears to have an impact on migraine headache, although the exact mechanisms are not yet fully understood. Inflammatory factors (interleukins), neuropeptides, serotonin and stress hormones are all proposed to play a role, with neuropeptides thought to have an antimicrobial impact on the gut bacteria. Comorbidities between migraine and GI conditions (IBS, IBD, etc.) and Helicobacter pylori levels are also thought to play an integral role. Dietary strategies show some promise in addressing migraine symptoms, although more work is required before definitive recommendations can be made.

Study Methods:

The authors searched the existing literature for evidence regarding associations between the gut-brain axis and migraine headache. No specific search criteria were provided, as this was a narrative review. The authors identified three areas of interest: the role of inflammation in migraine headache, the role of neuropeptides in relation to migraine and the gut-brain axis, and the association between migraine and GI disorders.

Study Strengths / Weaknesses:

Strengths:
  • This was a thorough summary of the available evidence.
  • The authors conducted an in-depth examination of potential associations between migraine and the gut-brain axis, providing evidence where applicable.
Weaknesses:
  • As a narrative review, no clear search strategy or inclusion/exclusion criteria for relevant articles was indicated.
  • No specific data was discussed and no pooling of data was attempted.
  • The study itself represents a low level of evidence (narrative review).

Additional References:

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  2. Steiner TJ, Stovner LJ, Vos T. GBD 2015: migraine is the third cause of disability in under 50s. J Headache Pain 2016; 17(1): 104.
  3. Steiner TJ, Stovner LJ, Vos T, Jensen R, Katsarava Z. Migraine is first cause of disability in under 50s: will health politicians now take notice? J Headache Pain 2018; 19(1): 17.
  4. Dodick DW (2018) A phase-by-phase review of migraine pathophysiology. Headache 2018; 58(Suppl 1): 4–16.
  5. Mayer EA, Tillisch K, Gupta A (2015) Gut/brain axis and the microbiota. J Clin Invest 125(3):926–938
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  7. Cavaillon JM. Pro- versus anti-inflammatory cytokines: myth or reality. Cellular and molecular biology (Noisy-le-Grand, France). 2001; 47(4):695–702
  8. Murphy SF, Schaeffer AJ, Thumbikat P. Immune mediators of chronic pelvic pain syndrome. Nature reviews Urology 2014; 11(5): 259–269.
  9. Theoharides TC, Donelan J, Kandere-Grzybowska K, Konstantinidou A. The role of mast cells in migraine pathophysiology. Brain Res Brain Res Rev 2005; 49(1): 65–76.
  10. Ramachandran R. Neurogenic inflammation and its role in migraine. Semin Immunopathol 2018; 40(3): 301–314.
  11. Pathophysiology of Headaches From Molecule to Man. Paolo Martelletti RJ, editor: Springer, Cham; 2015
  12. Noseda R, Borsook D, Burstein R. Neuropeptides and neurotransmitters that modulate Thalamo-cortical pathways relevant to migraine headache. Headache 2017; 57(Suppl 2): 97–111.
  13. Filpa V, Moro E, Protasoni M et al. Role of glutamatergic neurotransmission in the enteric nervous system and brain gut axis in health and disease. Neuropharmacology 2016; 111: 14–33.
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