Lipopolysaccharide, VE-cadherin, HMGB1, and HIF-1α levels are elevated in the systemic circulation in chronic migraine patients with medication overuse headache: evidence of leaky gut and inflammation.

OBJECTIVE: Medication overuse headache (MOH) was recently shown to be associated with leaky gut in rodents. We aimed to investigate whether chronic migraine (CM) patients with MOH have elevated lipopolysaccharide levels and inflammatory molecules in blood circulation. MATERIALS AND METHODS: The study included women participants (40 CM patients with NSAID overuse headache, 35 episodic migraine (EM) patients, and 20 healthy non-headache sufferers). Migraine duration, monthly migraine headache days, MigSCog, HADS-D, HADS-A, and HIT-6 scores were recorded. Serum samples were collected to measure circulating LPS, LPS binding protein (LBP), tight junction protein occludin, adherens junction protein vascular endothelial cadherin (VE-cadherin), CGRP, HMGB1, HIF-1α, IL-6, and IL-17 levels. RESULTS: Serum LPS, VE-Cadherin, CGRP, HIF-1α, and IL-6 levels were significantly higher in the CM + MOH group compared to the EM group and healthy controls while serum LBP and HMGB1 were higher in the CM + MOH group compared to healthy controls. IL-17 and occludin levels were comparable between the three groups. Serum HMGB1 levels in EM patients were higher compared to the control group. Mig-SCog and HIT-6 scores were higher in the CM + MOH group compared to EM patients. HADS-A and HADS-D scores were significantly higher in the CM + MOH group compared to EM patients and healthy controls, and they were also higher in EM patients compared to healthy subjects. LPS levels were correlated with VE-cadherin and occludin levels. The number of monthly migraine headache days was positively correlated with serum LPS, HIF-1α, VE-cadherin, and IL-6 levels, HADS-A, HADS-D, HIT-6, and MigSCog scores. CONCLUSION: We have evidence for the first time that CM + MOH is associated with elevated serum LPS and LBP levels suggestive of LPS leak into the systemic circulation. Higher levels of nociceptive and/or pro-inflammatory molecules such as HMGB1, HIF-1α, IL-6, and CGRP may play a role in trigeminal sensitization and neurobiology of MOH. Intestinal hyperpermeability and consequent inflammatory response should be considered as a potential contributory factor in patients with MOH.

Distinct Food Triggers for Migraine, Medication Overuse Headache and Irritable Bowel Syndrome.

BACKGROUND: Irritable bowel syndrome (IBS) is an under-diagnosed common health problem that impairs quality of life. Migraine and IBS are comorbid disorders that are triggered by foods. We aim to investigate IBS frequency in medication overuse headache (MOH) patients and identify food triggers and food avoidance behavior. METHODS: Participants who completed the cross-sectional, observational and online survey were included (n = 1118). Demographic data, comorbid disorders, medications used, presence of headache, the diagnostic features of headache and IBS, migraine related subjective cognitive symptoms scale (MigSCog), consumption behavior of patients regarding 125 food/food additives and food triggers were asked about in the questionnaire. RESULTS: Migraine and MOH diagnoses were made in 88% and 30.7% of the participants, respectively. Non-steroidal anti-inflammatory drugs (NSAIDs) were the main overused drug (89%) in MOH patients. IBS symptoms were present in 35.8% of non-headache sufferers, 52% of migraine patients and 65% of MOH patients. Specific food triggers for MOH patients were dopaminergic and frequently consumed as healthy foods such as banana, apple, cherry, apricot, watermelon, olive, ice cream and yogurt. MigSCog scores were significantly higher in episodic migraine and MOH patients when IBS symptoms coexisted. CONCLUSIONS: The frequency of IBS was higher in MOH patients compared to migraine patients. Coexistence of IBS seems to be a confounding factor for cognitive functions. MOH specific triggers were mostly dopaminergic foods, whereas migraine specific food triggers were mostly histaminergic and processed foods. Personalized diets focusing on food triggers and interference with leaky gut must be integrated to MOH and migraine treatment to achieve sustainable management of these disorders.