Gastrointestinal disorders associated with migraine: A comprehensive review

Table 1 Summary of gastrointestinal disorders associated with migraine

GI disorder	Association	Proposed implicated mechanism	Clinical implication
H. pylori infection	Infection rate of H. pylori: 45% in PWM vs 33% in controls[20]	Chronic inflammatory response with inflammatory and vasoactive mediators passing to the circulatory system	Screening of H. pylori infection in patient with migraine
	Main affected:
	CagA-positive strains[17]	↑ Interleukin-10 (CagA-positive strains)[25]	Improvement of migraine with H. pylori eradication[17,18,22]
	Asian > Europeans[20]	↑ CGRP[28]
Irritable bowel syndrome	6%-32% migraine-type headache in IBS patients vs 2.2%-18% in controls[33,35,36]	The brain-gut axis and the intestinal microbiota have been postulated[30,95]	Improvement of migraine with elimination diet[40]
		Serotonin, biopsychosocial dysfunction, heredity, genetic polymorphism, central/visceral hypersensitivity, somatic/cutaneous allodynia, neurolimbic pain network[30]
Gastroparesis	During a migraine attack gastric emptying delay and impairment of drug absorption has been demonstrated[44,45]	↑ Sympathetic response[43]	Increase absorption of antimigraine agents by administering antidopaminergic and 5-HT4 agonists with antiemetic/prokinetic properties[46]
		↓ Parasympathetic tone[43]
		Dysfunction of enteric autonomic system[41,47]
Hepato-biliary disorders	Association between migraine and biliary tract disorders[60]	CCK has been found to coexist with CGRP in the trigeminal ganglion[63]. When stimulated induce local increase of CCK which has a vasodilatory effect[63,66]. CGRP has shown to influence biliary motility. The impaired CGRP release has been associated to biliary tract disease in humans[65]	Low-fat diet improves frequency and severity of migraine[73]
	Genetic influence:
	In monozygotic pairs (OR = 3.5)
	In dizygotic pairs (OR = 1.7-2.7).
	Among the migraine characteristics, in those PWM with NAFLD, the presence of aura was higher (73.6% vs 26.5%), and the disease (9 yr vs 6 yr) and attack (72 h vs 48 h) durations were longer than in those without NAFLD[68]. Obesity and metabolic disturbances which are important determinants of NAFLD are also associated with an increased risk of migraine[69,70]		In connection with NAFLD: Weight loss and metabolic control have shown to improve migraine[70]
Celiac disease	28% prevalence of migraine in subject with biopsy-proven CD[84]	Neurological complications in CD may be caused by a general inflammatory response[92]	The screening for migraine in patients with CD seems to be justified.
	Higher prevalence of migraine in biopsy-proven CD group than in controls (21% vs 6%, OR = 3.79)[85]	Elevated levels of interferon-gamma and TNF-alpha (both independently implicated in migraine and CD) modulate neuropeptide CGRP[93].	Possible therapeutic effect with gluten-free diet[86-89]
	Main affected:
	Female
	Age < 65

GI: Gastrointestinal; PWM: Patients with migraine; CGRP: Calcitonin gene-related peptide; IBS: Irritable bowel syndrome; CCK: Cholecystokinin; NAFLD: Non-alcoholic fatty liver disease; CD: Celiac disease; TNF: Tumor necrosis factor.

Table 2 Future areas of interest on gastrointestinal disorders associated with migraine

Unanswered questions and future directions
H. pylori
Ethnicity difference between H. pylori and migraine association
Effects of different eradication therapy schemes in migraine
Impact of routine screening for H. pylori infection in PWM
Intrinsic role for antibiotic or antacid treatment used for H. pylori eradication in migraine
Effect of triptans (5-HT1B and 5-HT1D receptor agonist) in PWM depending their H. pylori infection status
Irritable bowel syndrome
Role of gluten-, wheat- and FODMAP-free diets in migraine
Effect of “dysbiosis” over serum level of cytokines and neurotransmitters in migraine
Gastroparesis
Nature, causes and consequences of gastroparesis in migraine
Determination of gastroparesis occurrence during the ictally and interictally periods in migraine
Hepato-biliary disorders
Prevalence of hepato-biliary disorders in different populations
Role of CCKB (CCK-2) receptor antagonists in migraine
Role of CCKA (CCK-1) receptors agonist in the treatment of obesity and migraine
Effect of coffee consumption in migraine in patients with NAFLD
Celiac disease
Routine screening for migraine in patients with CD
Role of interferon-gamma and TNF-alpha in the apparition/progression of migraine in patients with CD
Microbiome
Effects of normal microbiota and dysbiosis in CRGP regulation and expression
Effects of normal microbiota and dysbiosis in the serotoninergic system and migraine
Role of fecal microbiota transplantation in migraine
Other GI disorders
Reflux symptoms in patients with migraine as cause of the disease itself or a side effect of antimigraine medications

PWM: Patients with migraine; CCK: Cholecystokinin; NAFLD: Non-alcoholic fatty liver disease; CD: Celiac disease; TNF: Tumor necrosis factor; CGRP: Calcitonin gene-related peptide; GI: Gastrointestinal; H. pylori: Helicobacter pylori.