The pathophysiology of migraine headache remains poorly understood; however, various theories have been proposed, including a “migraine center” in the brainstem that increases in activity and blood flow during migraine attacks,3 a neurogenic process with secondary changes in cerebral perfusion,4 modulation of dopaminergic neurotransmission,5 magnesium deficiency in the brain,6 and neurogenic inflammation, with the release of potent vasoactive pain-associated neuropeptides, including calcitonin gene-related peptide, substance P, and neurokinin A.8 Although these theories have evolved over the years, none has unequivocally provided robust evidence to fully explain the clinical spectrum of migraine.
Recently, evidence has accumulated to support a complex neurobiologic basis for migraine, with origins beyond the brain. The prevailing theory involves the gut-brain axis, which postulates a complex interplay between the brain and the gastrointestinal tract. However, the precise mechanism that links the brain and the gut and triggers a migraine event remains unclear. It has been suggested that undigested food particles and gut-associated bacterial components that act as endotoxins entering the bloodstream may play a role.9-11 In fact, it has been reported that gut permeability is increased and its barrier function compromised during various disease states such as gastrointestinal disorders, depression, and multiple sclerosis.11 The logical assumption is that restoring the intestinal barrier function may be a strategy to treat migraine attacks.
Although circumstantial evidence links gastrointestinal disorders with migraine headaches — including the similarity of their association with nausea, vomiting, and gastroparesis — a recent study by Doulberis and colleagues provides a comprehensive summary of the relevant published studies linking migraine and gastrointestinal or related disorders.12 The investigators found a clear association between migraine and various gastrointestinal diseases, including irritable bowel syndrome, inflammatory bowel disease, celiac disease, Helicobacter pylori infection, and cyclic vomiting syndrome, as well as food allergy and infantile colic.12 Philip Rosenthal, MD, professor of pediatrics at the University of California, San Francisco, confirmed: “In young children, several syndromes that cause gastrointestinal symptoms are associated with migraines. These syndromes can cause episodes of cyclic vomiting, abdominal pain (abdominal migraine), and dizziness (benign paroxysmal vertigo) and are often referred to as childhood periodic syndromes. In older children, irritable bowel syndrome, inflammatory bowel disease, and celiac disease may be associated.”
Both a population-based study involving 1038 subjects 15 years and older and a case-control study involving 424 children and adolescents 6 to 17 years old found similar associations between migraines and gastrointestinal functional disorders.13,14 In the case-control study, among the children with migraine, 32% were diagnosed with functional gastrointestinal disorders compared with 18% in the control group (P <.0001).14 Further, there was a significant association between migraine and dyspepsia (P <.0001), irritable bowel syndrome (P =.0002), and abdominal migraine (P =.002).14 The challenge, however, is that a meaningful comparison among these various studies cannot be made because of the heterogeneity of the study design, data collection, and analyses, and therefore a definitive conclusion linking specific gastrointestinal disorders and migraine cannot be made. In addition, the evidence of cause and effect between the gastrointestinal tract and migraine has not been established, although according to Dr Rosenthal, “a mechanism possibly related to permeable gut or intestinal inflammation [may be involved]. There are more nerves in the GI tract than in the brain.”
Gastrointestinal microbiota, and particularly an imbalance of the gut flora, has been implicated in the development of migraine,15 potentially associated with the increased permeability of the gut. Dai and colleagues concluded from their review of the literature that an improvement in gut microbiota and a reduction in inflammation can have positive effects on strengthening gut and brain function, inferring that probiotics may have a beneficial effect on the frequency and severity of migraine attacks.16 This inference was subsequently explored by Roos and colleagues in a randomized double-blind placebo-controlled trial to investigate whether probiotics could reduce migraine through their effect on intestinal permeability and inflammation.11 In the study, patients with migraine were randomly allocated to receive a multispecies probiotic (n =31) or placebo (n =32). Migraine events were assessed with the Migraine Disability Assessment Scale, the Headache Disability Inventory, and headache diaries. Intestinal permeability was assessed with the urinary lactose/mannitol test and fecal and serum zonulin, while inflammation was measured from interleukin-6, interleukin-10, tumor necrosis factor-α, and serum C-reactive protein.11 The investigators found no significant effect of multispecies probiotic on migraine frequency and intensity or on the markers of intestinal permeability and inflammation. Thus, the hypothesis that probiotics can relieve migraine through their effect on the intestinal epithelial barrier could not be corroborated.11 In discussing the results, Roos and colleagues explained that study limitations may explain the failure to demonstrate benefit of multispecies probiotic for migraine. Limitations of the study included a study population that had a selection bias and may not be truly representative of the migraine population, the small sample size of 63 patients may not be sufficiently powered to show a statistically significant benefit of multispecies probiotic, and variations in dosage and duration of treatment protocols among the studies. Further, the study could not account for confounding variables introduced by differences in patient susceptibility to probiotics and lack of control regarding additional medications and over-the-counter products that might interfere with inflammation and intestinal permeability.
Despite the limitations of the current studies, the general consensus from the various evidence to date suggests that it is reasonable for clinicians to have a heightened awareness of the potential relationship between gastrointestinal functional disorders and migraine. This awareness can trigger clinical suspicion that may influence approach to diagnosis and therapeutic management of migraine. Larger, multicenter, placebo-controlled clinical trials are needed to better define the link between gastrointestinal disorders and migraine and perhaps establish a cause and effect relationship.
- National Institute of Neurological Disorders and Stroke. Headache: Hope Through Research. April 2016. Accessed September 15, 2017.
- Burch RC, Loder S, Loder E, Smitherman TA. The prevalence and burden of migraine and severe headache in the United States: updated statistics from government health surveillance studies. Headache. 2015;55:21-34.
- Diener H-C. Positron emission tomography studies in headache. Headache. 1997;37:622-625.
- Cutrer FM, Charles A. The neurogenic basis of migraine. Headache. 2008; 48:1411-1414.
- Akerman S, Goadsby PJ. Dopamine and migraine: biology and clinical implications. Cephalalgia. 2007;27:1308-1314.
- Sun-Edelstein C, Mauskop. Role of magnesium in the pathogenesis and treatment of migraine. Expert Rev Neurother. 2009;9:369-379.
- van Hemert S, Breedveld AC, Rovers JM, et al. Migraine associated with gastrointestinal disorders: review of the literature and clinical implications. Front Neurol. 2014;5:1-7.
- Malhotra R. Understanding migraine: potential role of neurogenic inflammation. Ann Indian Acad Neurol. 2016;19:175-182.
- Covelli V, Pellegrino NM, Jirillo E. A point of view: the need to identify an antigen in psyconeuroimmunological disorders. Curr Pharm Des. 2003;9:1951-1955.
- Mennigen R, Bruewer M. Effect of probiotics on intestinal barrier function. Ann N Y Acad Sci. 2009;1165:183-189.
- de Roos NM, van Hemert S, Rovers JMP, Smits MG, Witteman BJM. The effects of a multispecies probiotic on migraine and markers of intestinal permeability-results of a randomized placebo-controlled study [published online May 24, 2017]. Eur J Clin Nutr. doi: 10.1038/ejcn.2017.57
- Doulberis M, Saleh C, Beyenburg S. Is there an association between migraine and gastrointestinal disorders? J Clin Neurol. 2017;13:215-226.
- Lankarani KB, Akbari M, Tabrizi R. Association of gastrointestinal functional disorders and migraine headache: a population base study. Middle East J Dig Dis. 2017;9:139-145.
- Le Gal J, Michel J-F, Rinaldi VE, et al. Association between functional gastrointestinal disorders and migraine in children and adolescents: a case-control study. Lancet Gastroenterol Hepatol. 2016;1:114-121.
- Hindiyeh N, Aurora SK. What the gut can teach us about migraine. Curr Pain Headache Rep. 2015;19:33.
- Dai YJ, Wang HY, Wang XJ, Kaye AD, Sun YH. Potential beneficial effects of probiotics on human migraine headache: a literature review. Pain Physician. 2017;20:E251-E255.