Implication of the Microbiota in Migraine Pathogenesis

Higher levels of nitrate-reducing bacteria were found in the oral cavities of people with migraine than in the oral cavities of non-migraineurs, according to a study published in mSystems.¹

Evidence suggests that the “gut-brain axis” may play a role in migraine pathogenesis. Gut microbiota have been shown to indirectly influence serotonin levels and calcitonin gene-related peptide levels, which are associated with migraine pathogenesis.^2,3 However, no direct link has been made between gut microbiota and migraine headache thus far.³

Nitrate-containing foods and medications are common triggers for migraine, and nitrate-induced headache may be immediate or delayed. Immediate headache appears to be mediated by nitric oxide-induced vasodilation, while delayed headache appears to be partially dependent on S-nitrosylation-mediated changes in ion channel function, a process that requires nitric oxide. However, only bacteria have the ability to reduce nitrate to nitrite and, subsequently, nitric oxide.¹

Erik Viirre, MD, PhD, Embriette Hyde, PhD, and colleagues, of the University of California San Diego School of Medicine, evaluated whether migraineurs had higher abundance of bacterial nitrate, nitrite, and nitric oxide reductase genes than people without migraine using data from oral and stool samples from the American Gut Project (AGP).¹

“The AGP is a multicenter effort to gather oral and fecal microbiome samples, as well as comprehensive medical history associated with those samples, for the purpose of studying the microbiome in human health,” Dr Viirre told Clinical Pain Advisor.

Analyses of AGP samples have shed light on the characteristics of gut microbiota among adults with history of cesarean birth or food or seasonal allergies.^4,5

Data from 16s ribosomal RNA sequencing of 1996 stool samples and 172 oral samples were analyzed. The abundances of nitrate, nitrite and nitric oxide reductase genes in oral samples were strikingly higher among participants with migraine than among those without (P ≤.001 for all comparisons).

In the fecal sample analysis, there was a small but statistically significant increase in these genes among migraineurs compared with non-migraineurs (P ≤.001 for all comparisons).¹

“Our data suggest that migraineurs process nitrate- and nitrite-containing foods differently than the general population,” Dr Viirre said. “These findings reinforce [the notion] that these types of foods are potential triggers for migraine headache. As part of diet elimination programs, people are trying to figure out what their food triggers might be, and foods like hot dogs and preserved meats should certainly be on their hit list.”

But the findings from this study are only preliminary and need to be further explored and validated, according to Dr Hyde, who is also project manager for the AGP.

“Much like antiseptic mouthwash prevents the drop in blood pressure caused by eating green leafy vegetables, we would need to demonstrate that antiseptic mouthwash prevents food-induced migraines,” she said in an interview with Clinical Pain Advisor.

Carlos R. Cámara-Lemarroy, MD, of Universidad Autónoma de Nuevo León in Mexico, noted that one outstanding question is whether the degree of alterations in gut nitrate metabolism seen in migraineurs is high enough to have a physiological effect on the central nervous system.

“Future studies should also take into account confounding factors, such as diet modifications and medication use, among migraineurs,” he told Clinical Pain Advisor.

But if a link between nitrate-reducing bacteria and migraine headache is established, Dr Hyde believes that treating migraine by targeting the oral microbiome would be highly personalized.

“Because nitrates can have a beneficial effect on blood pressure, we might not want to target nitrate-reducing bacteria in patients suffering from or at risk for hypertension or cardiovascular disease.”

Summary and Clinical Applicability

Nitrate-containing compounds have been observed to be a headache trigger among migraineurs. The gut microbiome may be linked to migraine pathogenesis, and only gut bacteria can convert nitrates into nitrites and nitric oxide.

Researchers investigated whether differences in nitrate, nitrite, and nitric oxide reductase levels exist between migraineurs and people without migraine.

“These results show for the first time a potential link between bacterial nitrate, nitrite, and nitric oxide reducers and migraines, by reporting their higher abundance in the oral cavities of people with migraines than in the oral cavities of those who do not suffer from migraines.

Future studies should focus on further characterizing the connection between oral bacterial nitrate, nitrite, and nitric oxide reducers and migraines,” the authors wrote.

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References

1. Gonzalez A, Hyde E, Sangwan N, Gilbert JA, Viirre E, Knight R. 2016. Migraines are correlated with higher levels of nitrate-, nitrite-, and nitric oxide-reducing oral microbes in the American Gut Project Cohort. mSystems. 1(5):e00105-16.
2. Hindiyeh N, Aurora SK. What the Gut Can Teach Us About Migraine. Curr Pain Headache Rep. 2015;19(7):33. doi: 10.1007/s11916-015-0501-4.
3. Cámara-Lemarroy CR, Rodriguez-Gutierrez R, Monreal-Robles R, Marfil-Rivera A. Gastrointestinal disorders associated with migraine: A comprehensive review. World J Gastroenterol. 2016;22(36):8149-60. doi: 10.3748/wjg.v22.i36.8149. doi:10.1128/mSystems.00105-16.
4. Hua X, Goedert JJ, Pu A, Yu G, Shi J. Allergy associations with the adult fecal microbiota: Analysis of the American Gut Project. EBioMedicine. 2015;3:172-9. doi: 10.1016/j.ebiom.2015.11.038.
5. Goedert JJ, Hua X, Yu G, Shi J. Diversity and composition of the adult fecal microbiome associated with history of cesarean birth or appendectomy: Analysis of the American Gut Project. EBioMedicine. 2014;1(2-3):167-172.