Nitrates, including cardiac medications and food additives, are common headache triggers, mediated by nitric oxide, a potent vasodilator. Anaerobic bacteria in the mouth generate physiologically relevant levels of nitric oxide via the salivary nitrate-nitrite-nitric oxide pathway. Although these may have beneficial effects on cardiovascular health, they may also potentially trigger migraine.
The goal of this study by Viirre and colleagues was to compare nitrate, nitrite, and nitric oxide reductase genes in oral and stool samples from migraineurs vs nonmigraineurs, using high-throughput sequencing technologies.
Study Synopsis and Perspective
Researchers may have uncovered a mechanism behind nitrate-based triggers in migraine. They found that compared with people who do not experience migraines, those who do have significantly more nitrate, nitrite, and nitric oxide reductase genes in oral and fecal samples.
For this study, the investigators examined these genes in stool and oral samples from the American Gut Project, a global crowd-funded citizen science effort.
"The magic of this microbiome project is that they have technologies that not only can identify what species there are, but also the quantity of them," said study author and migraine specialist, Erik Viirre, MD, PhD, professor of neurosciences, University of California at San Diego.
"That's the key; everybody has millions of bacteria with hundreds of species in their body; it's the relative quantity of these bacteria that's important."
Their study was published online October 18 in mSystems, published by the American Society for Microbiology.
Nitrates are composed of 1 nitrogen atom and 3 oxygen atoms. When bacteria in the mouth break down nitrates, one of the oxygen atoms is removed, resulting in nitrites. When in the bloodstream, nitrites can be converted into nitric oxide.
The link between nitrates and headaches is not new. For example, it is known that consuming foods containing nitrates, such as wine, chocolate, and processed meats, triggers a headache in some people. As well, cardiac medications containing nitrates (eg, nitroglycerine) may cause severe headaches.
Immediate or Delayed
Nitrate-induced headaches typically manifest as relatively mild "immediate" headaches developing within 1 hour of medication ingestion or more severe "delayed" headaches occurring 3 to 6 hours after nitrate intake.
The literature suggests differing mechanisms behind these 2 types of headaches. Immediate headaches appear to be connected to nitric oxide-mediated vasodilation, whereas delayed headaches, similar to migraines triggered by foods, stress, or other factors, appear to be activated by release of calcitonin-gene-related peptide, glutamate, cyclic guanosine monophosphate, or S-nitrosylation-mediated changes in ion channel function.
For this analysis, the researchers sequenced bacteria found in 172 oral samples and 1996 fecal samples from donors who self-reported migraine status. Samples came from adults 20 to 69 years old with a body mass index of 18.5 to 30 kg/m2, and no self-reported history of inflammatory bowel disease, diabetes, or antibiotic use in the past year.
The authors found differences in samples from people with migraines vs those without.
There were small but significant (P ≤.001) increases in nitrate, nitrite, and nitric oxide reductase genes in stool samples collected from migraineurs.
In oral samples, nitrate, nitrite, and nitric oxide reductase genes were all significantly more abundant in migraineurs (P ≤.001).
The researchers also used dominant oral operational taxonomic units (OTUs) to identify and quantify the various bacteria. The OTUs that significantly differed between migraineurs and nonmigraineurs belonged to the genera Streptococcus and Pseudomonas, both of which have species with the potential to reduce nitrate.
The study showed that the percentages of sub-OTUs for both Streptococcus and Pseudomonas were smaller in migraineurs than in nonmigraineurs. If these bacteria process nitrates, the findings would suggest that this process is reduced in people with migraine, resulting in more nitrates in their body, they say.
Dr Viirre stressed that they have found only a correlation and cannot "make the leap" to say that these bacteria are the actual cause of headaches.
"Many other factors are associated with migraine, including genetic factors and hormonal factors, and all kinds of other things. So unfortunately, we can't draw a straight path between what these bacteria process and the actual activation of the headaches."
Dr Viirre and his colleagues are keen to do a prospective study to regularly track the incidence of headaches among patients as well as their bacterial flora.
"The key advance here is the capability to do these broad quantitative analyses of bacteria at relatively low cost; this is the genome project kind of spinoff."
Should this type of study bear out the connection between migraines and bacteria, there might be several plausible interventions, said Dr Viirre.
One possibility is to alter the bacterial flora. "In other words, if we figured out which species we wanted to promote, and we knew a way of doing that with diet, then we could do that."
A more aggressive step would be to actually intervene with chemicals instead of food, said Dr Viirre. "In future, we might be able to create chemicals that would enhance the growth of what we think are relatively important bacteria."
Perhaps antibiotics could be used in some way to alter the bacterial content in such a way as to create the proper balance. However, Dr Viirre stressed that at this point, these are all speculations.
This research was crowdfunded through individual contributions from American Gut Project participants.
mSystems. Published online