A Narrative Review of Intestinal Microbiota's Impact on Migraine with Psychopathologies.

Migraine is a common and debilitating neurological disorder characterized by the recurrent attack of pulsating headaches typically localized on one side of the head associated with other disabling symptoms, such as nausea, increased sensitivity to light, sound and smell and mood changes. Various clinical factors, including the excessive use of migraine medication, inadequate acute treatment and stressful events, can contribute to the worsening of the condition, which may evolve to chronic migraine, that is, a headache present on >15 days/month for at least 3 months. Chronic migraine is frequently associated with various comorbidities, including anxiety and mood disorders, particularly depression, which complicate the prognosis, response to treatment and overall clinical outcomes. Emerging research indicates a connection between alterations in the composition of the gut microbiota and mental health conditions, particularly anxiety and depression, which are considered disorders of the gut-brain axis. This underscores the potential of modulating the gut microbiota as a new avenue for managing these conditions. In this context, it is interesting to investigate whether migraine, particularly in its chronic form, exhibits a dysbiosis profile similar to that observed in individuals with anxiety and depression. This could pave the way for interventions aimed at modulating the gut microbiota for treating difficult-to-manage migraines.

[A comparative assessment of microbiocenosis of saliva and oropharynx in patients with migraine]. / Sravnitel'naya otsenka mikrobiotsenoza slyuny i rotoglotki u patsientov s migren'yu.

OBJECTIVE: To identify changes in the microbiome of saliva and to compare it with the microbiome of the oropharynx of patients with migraine. MATERIAL AND METHODS: Sixty patients with migraine (21-56 years old), were examined using a headache diary, MIDAS and VAS. A microbiological examination of saliva and smear from the mucosa of the posterior wall of the oropharynx with evaluation by the method of mass spectrometry of microbial markers (MSMM) with the determination of 57 microorganisms was performed. All patients had comorbid chronic diseases of the gastrointestinal tract and upper respiratory tract (URT), according to anamnestic data and examination by specialists. RESULTS: A significant increase in the content of markers of resident (conditionally pathogenic) microorganisms characteristic of chronic diseases of URT (strepto- and staphylococci); markers of transient microorganisms characteristic of intestinal microflora (clostridia, gram-negative rods, anaerobes) that are normally absent; viral markers of cytomegaloviruses and herpes groups; a decrease in the content of fungi were identified in saliva. A comparative analysis of the microbiome of saliva and oropharynx showed: 1) a significant decrease in the concentration of coccal flora Enterococcus spp., Streptococcus mutans, Staphylococcus aureus, anaerobic bacteria Clostridium difficile and Clostridium perfringens in saliva; enterobacteria Helicobacter pylori; gram-negative rods Kingella spp., fungi and Epstein-Barr virus; 2) an increase in salivary concentrations of Staphylococcus epidermidis, anaerobic Clostridium ramosum and Fusobacterium spp./Haemophilus spp. and gram-negative bacilli Porphyromonas spp. CONCLUSION: A comparative assessment of the microbiota of a smear from the posterior wall of the oropharynx and saliva using MMSM showed the presence of dysbiosis both in the oropharynx and in the saliva of patients with migraine. However, there were fewer deviations from the norm in saliva, therefore, for diagnostic purposes, a smear from the posterior wall of the oropharynx is more significant as a biomarker for patients with migraine.

Effects of Gluten on Gut Microbiota in Patients with Gastrointestinal Disorders, Migraine, and Dermatitis.

As gluten may trigger gastrointestinal disorders (GIDs), its presence or absence in the diet can change the diversity and proportion of gut microbiota. The effects of gluten after six weeks of a double-blind, placebo-controlled intervention with a gluten-free diet (GFD) were studied in participants with GIDs suffering from migraines and atopic dermatitis (n = 46). Clinical biomarkers, digestive symptoms, stool, the Migraine Disability Assessment questionnaire, and zonulin levels were analyzed. Next-generation sequencing was used to amplify the 16S rRNA gene of bacteria and the internal transcribed spacer (ITS) regions of fungi. The GFD increased Chao1 fungal diversity after the intervention, while the fungal composition showed no changes. Bacterial diversity and composition remained stable, but a positive association between bacterial and fungal Chao1 diversity and a negative association between Dothideomycetes and Akkermansia were observed. GIDs decreased in both groups and migraines improved in the placebo group. Our findings may aid the development of GID treatment strategies.

A 16S rRNA gene sequencing based study of oral microbiota in migraine patients in China.

Migraine is a primary headache characterized by moderate or severe headache attacks, accompanied with reversible neurological and systemic symptoms. There are rare biomarkers for the disease. While emerging evidence has indicated the connection between gut microbiota and migraine, the relation between oral microbiota and migraine is barely known. Thus, the objective of the current study was to explore a possible correlation between oral microbiota and migraine. We compared the oral microbiota communities of migraine patients (26) with healthy subjects (29) via 16S rRNA gene sequencing. Alpha diversity indices were higher in migraine group compared with control group, whereas beta diversity indices also showed significant difference. A total of 23 genera were found differentially abundant between migraine and control groups. To conclude, there was a significant compositional difference in oral microbiota in migraine patients compared with healthy subjects.

Gut-brain Axis and migraine headache: a comprehensive review.

The terminology "gut-brain axis "points out a bidirectional relationship between the GI system and the central nervous system (CNS). To date, several researches have shown that migraine is associated with some gastrointestinal (GI) disorders such as Helicobacter pylori (HP) infection, irritable bowel syndrome (IBS), and celiac disease (CD). The present review article aims to discuss the direct and indirect evidence suggesting relationships between migraine and the gut-brain axis. However, the mechanisms explaining how the gut and the brain may interact in patients with migraine are not entirely clear. Studies suggest that this interaction seems to be influenced by multiple factors such as inflammatory mediators (IL-1ß, IL-6, IL-8, and TNF-α), gut microbiota profile, neuropeptides and serotonin pathway, stress hormones and nutritional substances. Neuropeptides including CGRP, SP, VIP, NPY are thought to have antimicrobial impact on a variety of the gut bacterial strains and thus speculated to be involved in the bidirectional relationship between the gut and the brain. According to the current knowledge, migraine headache in patients harboring HP might be improved following the bacteria eradication. Migraineurs with long headache history and high headache frequency have a higher chance of being diagnosed with IBS. IBS and migraine share some similarities and can alter gut microflora composition and thereby may affect the gut-brain axis and inflammatory status. Migraine has been also associated with CD and the condition should be searched particularly in patients with migraine with occipital and parieto-occipital calcification at brain neuroimaging. In those patients, gluten-free diet can also be effective in reducing migraine frequency. It has also been proposed that migraine may be improved by dietary approaches with beneficial effects on gut microbiota and gut-brain axis including appropriate consumption of fiber per day, adhering to a low glycemic index diet, supplementation with vitamin D, omega-3 and probiotics as well as weight loss dietary plans for overweight and obese patients.

Gut Microbiota Dysbiosis Enhances Migraine-Like Pain Via TNFα Upregulation.

Migraine is one of the most disabling neurological diseases worldwide; however, the mechanisms underlying migraine headache are still not fully understood and current therapies for such pain are inadequate. It has been suggested that inflammation and neuroimmune modulation in the gastrointestinal tract could play an important role in the pathogenesis of migraine headache, but how gut microbiomes contribute to migraine headache is unclear. In the present study, we investigated the effect of gut microbiota dysbiosis on migraine-like pain using broad-spectrum antibiotics and germ-free (GF) mice. We observed that antibiotics treatment-prolonged nitroglycerin (NTG)-induced acute migraine-like pain in wild-type (WT) mice and the pain prolongation was completely blocked by genetic deletion of tumor necrosis factor-alpha (TNFα) or intra-spinal trigeminal nucleus caudalis (Sp5C) injection of TNFα receptor antagonist. The antibiotics treatment extended NTG-induced TNFα upregulation in the Sp5C. Probiotics administration significantly inhibited the antibiotics-produced migraine-like pain prolongation. Furthermore, NTG-induced migraine-like pain in GF mice was markedly enhanced compared to that in WT mice and gut colonization with fecal microbiota from WT mice robustly reversed microbiota deprivation-caused pain enhancement. Together, our results suggest that gut microbiota dysbiosis contributes to chronicity of migraine-like pain by upregulating TNFα level in the trigeminal nociceptive system.

Integrating Pathophysiology in Migraine: Role of the Gut Microbiome and Melatonin.

BACKGROUND: The pathoetiology and pathophysiology of migraine are widely accepted as unknown. METHODS: The current article reviews the wide array of data associated with the biological underpinnings of migraine and provides a framework that integrates previously disparate bodies of data. RESULTS: The importance of alterations in stress- and pro-inflammatory cytokine- induced gut dysbiosis, especially butyrate production, are highlighted. This is linked to a decrease in the availability of melatonin, and a relative increase in the N-acetylserotonin/melatonin ratio, which has consequences for the heightened glutamatergic excitatory transmission in migraine. It is proposed that suboptimal mitochondria functioning and metabolic regulation drive alterations in astrocytes and satellite glial cells that underpin the vasoregulatory and nociceptive changes in migraine. CONCLUSION: This provides a framework not only for classical migraine associated factors, such as calcitonin-gene related peptide and serotonin, but also for wider factors in the developmental pathoetiology of migraine. A number of future research and treatment implications arise, including the clinical utilization of sodium butyrate and melatonin in the management of migraine.

Association between Helicobacter pylori infection and migraine: a meta-analysis.

AIM: To quantify the association between Helicobacter pylori (H. pylori) infection and migraine. METHODS: A systematic literature search of PubMed and EMBASE was conducted from inception to December 2013. Studies that provided data dealing with H. pylori infection in patients with migraine, as well as healthy controls, were selected. Meta-analysis was carried out using the odds ratio (OR) with a fixed or random effects model, and a 95%CI for the OR was calculated. An unconditional logistic regression model was used to analyze potential parameters related to H. pylori prevalence. Subgroup analyses were conducted as methods of detection and evidence grade. RESULTS: Five case-control studies published between 2000 and 2013 were finally identified, involving 903 patients, with a total H. pylori infection rate of 39.31%. The prevalence of H. pylori infection was significantly greater in migraineurs than in controls (44.97% vs 33.26%, OR = 1.92, 95%CI: 1.05-3.51, P = 0.001). A sensitivity test indicated that no single study dominated the combined results. Univariate regression analysis found that publication year, geographical distribution and evidence grade were relevant to the results and were the main reason for the heterogeneity. Subgroup analysis found a significantly greater infection rate of H. pylori in Asian patients with migraine, but no statistically significant infection rate in European patients. The ORs were 3.48 (95%CI: 2.09-5.81, P = 0.000) and 1.19 (95%CI: 0.86-1.65, P = 0.288), respectively. CONCLUSION: The pooled data suggest a trend of more frequent H. pylori infections in patients with migraine.

The effect of Helicobacter pylori eradication on migraine: a randomized, double blind, controlled trial.

BACKGROUND: Recent studies have shown a positive correlation between Helicobacter pylori (H. pylori)infection and migraine headache. OBJECTIVE: To study the impact of H. pylori eradication on migraine headache. STUDY DESIGN: Double blind, randomized, controlled clinical trial. SETTING: Sixty-four patients diagnosed with migraine-type headache were included in the study. The patients were randomly allocated into 2 groups: a treatment group that received migraine treatment and H.pylori eradication treatment, and a control group that received migraine treatment and a placebo in place of H. pylori eradication treatment. METHODS: There were 25 women and 7 men in the treatment group and 22 women and 10 men in the control group. The MIDAS (Migraine Disability Assessment) questionnaire was used to assess the severity of symptoms, before and after treatment. RESULT: There was no significant difference between treatment group patients and control group patients with respect to age (44.6 ± 8.8 vs. 43.8 ± 13.8), clinical symptoms and signs. In the beginning of the study, patients in the treatment group had a higher MIDAS compared to patients in the control group (28.87 ± 6.18 vs. 25.43 ± 7.13, P < 0.05). There was no significant difference between the treatment and control groups, with respect to the MIDAS, after treatment (20.09 ± 1.14 vs. 20.00 ± 1.150, P = 0.5). General linear model, repeated measures demonstrated that the reduction in the MIDAS score was more prominent in the treatment group (Mean Square 164.25, F: 2.02, P = 0.05). LIMITATIONS: Short-term follow up. CONCLUSION: H. pylori eradication may have a beneficial role on migraine headache. This shows the significance of H. pylori treatment in the management of migraine headache among Iranian patients.

Double-blind, placebo-controlled antibiotic treatment study of small intestinal bacterial overgrowth in children with chronic abdominal pain.

BACKGROUND AND OBJECTIVES: Chronic abdominal pain (CAP) in children may be a precursor to irritable bowel syndrome (IBS) in adults. The prevalence of abnormal lactulose breath tests (LBT) suggesting small intestinal bacterial overgrowth (SIBO) has been reported as 91% in children with CAP and 35% in healthy controls. In addition, patients with IBS with SIBO who responded to nonabsorbable antibiotic treatment with normalization of LBT reported 75% global improvement in symptoms. The aim of the study was to test whether treatment with a nonabsorbable antibiotic may reduce symptoms in children with CAP. METHODS: Seventy-five children ages 8 to 18 years with CAP based on Rome II criteria were enrolled. Subjects underwent baseline LBT and completed symptom-based questionnaires. They were then randomized in a 2:1, double-blind fashion to receive a 10-day course of 550 mg of rifaximin or placebo 3 times per day (t.i.d.). LBT and questionnaires were repeated 2 weeks after treatment. RESULTS: Forty-nine children received rifaximin and 26 received placebo. There were no differences in demographics between groups. Ninety-four percent who received rifaximin and 92% who received placebo had abnormal baseline LBT, suggesting SIBO (not significant [NS]). There was no significant difference in symptom improvement between groups; however, only 20% of children treated with rifaximin achieved a normalized repeat LBT, demonstrating successful treatment of SIBO. CONCLUSIONS: Similar to adults with IBS, the prevalence of abnormal LBT suggesting SIBO in children with CAP is high; however, treatment with 10 days of rifaximin has low efficacy in normalizing LBT in this group. Additional studies are needed to determine whether a treatment approach with higher efficacy would lead to improvement in children with CAP.

An unusual presentation of neurosyphilis as a probable migraine.

We describe a case which initially presented as persistent and untreatable probable migraine, which was subsequently diagnosed as neurosyphilis during the clinical evaluation. All symptoms regressed after appropriate treatment. We suggest that the possibility of neurosyphilis should be taken into account in the differential diagnosis of a persistent headache which does not respond to medication.

[Helicobacter pylori infection: from gastric to systemic disease]. / Manifestazioni extragastriche dell'infezione da Helicobacter pylori.

H. pylori infection, through a chronic stimulation of the immune system and the occurrence of molecular mimicry mechanisms, is responsible for the majority of the gastroduodenal diseases and also for some extragastric disorders, including sideropenic anemia and idiopathic thrombocytopenic purpura; other diseases are under investigation.

Association between Chlamydia pneumoniae IgG antibodies and migraine.

In this study, there is a confirmed association between cerebral infarction with migraine and Chlamydia pneumoniae infection, but the association between C. pneumoniae IgG antibodies and migraine in the general population has not been investigated. C. pneumoniae IgG antibody levels were compared in 329 adult Chinese patients, who met the International Classification of Headache Disorders 2nd Edition (ICHD II) criteria for migraine, and in 329 healthy subjects. Factors such as gender, age, smoking, consumption of pickle, and body mass index were evaluated. One hundred and ninety-five (59.2%) migraine sufferers and 70 (21.27%) controls were C. pneumoniae IgG antibody-seropositive (P<0.05). Based on a multivariate stepwise logistic model, the odds' ratios for C. pneumoniae IgG antibody seropositivity, body mass index, smoking, and consumption of pickle were 3.397 (P=0.000), 0.858 (P=0.014), 1.692 (P=0.012), and 5.469 (P=0.0000), respectively. In conclusion, C. pneumoniae IgG antibodies may be a risk factor for migraine.

Helicobacter pylori infection as an environmental risk factor for migraine without aura.

Helicobacter pylori (H. pylori) infection has recently been associated with various extraintestinal pathologies and migraine. The aim of this study was to investigate the correlation of the H. pylori infection with the pathogenesis of migraine without aura, especially in cases not affected by endogenous risk factors, like hereditary pattern or hormonal fluctuations.A total of 49 outpatients (37 females and 12 males; age range: 19-47 years; mean age: 31,+/-14 years) affected by migraine without aura was evaluated. We divided them in 2 subgroups: a) with positive familial history, and/or with menstrual type of migraine b) with negative familial history and with menstrual unrelated type of migraine. H. pylori infection was diagnosed by the 13 C- urea breath test (INFAI - test). Control subjects consisted of 51 patients without any primary headache history (38 females; mean age of 32,+/-14,4 years; range 21-49 years), who underwent upper gastrointestinal (GI) endoscopy for investigation of anaemia or non ulcer dyspepsia. H. pylori detection was based on the histologic analysis of gastric mucosa biopsy. The prevalence of H. pylori infection was significantly higher in the migraineurs without aura compared to controls (p=0.016). The prevalence of H. pylori infection was significantly high in the mixed and in the female group of our patients without other predisposing factors for migraine without aura (81 and 87% respectively), while in the same groups with predisposing factors (menstruation and/or family history) the prevalence was only 36 and 37% respectively (p=0,001 for the first group and p=0,002 for the second group). Our results seem to highlight the role of H. pylori infection as a probable independent environmental risk factor for migraine without aura, especially in patients that are not genetically or hormonally susceptible to migraine.