The paper, titled “Migraines Are Correlated with Higher Levels of Nitrate-, Nitrite-, and Nitric Oxide-Reducing Oral Microbes in the American Gut Project Cohort” is an observational study based on data gathered by the American Gut Project, which is led by Rob Knight, PhD at the University of California San Diego.
Nitrate-containing compounds have been identified as headache triggers and the common culprits for migraine sufferers are nitrate-containing food preservatives and nitrate-containing heart medications which trigger headaches in 80% of patients who are migraine-prone. In some cases, the headaches are so severe that about 10% of patients cannot use the medications. The researchers noted that the headaches seem to manifest in two ways: an immediate medium severity headache within 60 minutes or so of the ingestion of the medication, and a delayed response three to six hours later that results in a full-blown, much more severe migraine. The two pathways of these two manifestations appear to be different. The fast-developing headaches appear to be associated with the vasodilation mediated by nitric oxide (NO), whereas the researchers said the “delayed migraines, similarly to migraines triggered by foods, stress, and other factors, appear to be activated by the release of calcitonin gene-related peptide (CGRP), glutamate, cyclic GMP (cGMP), or S-nitrosylation-mediated changes in ion channel function.”
It was this last association with S-nitrosothiol that led the researchers to look at the makeup of the oral microbiome to determine if nitrate-reducing bacteria were present in greater numbers among the migraine sufferers than among non-sufferers.
“Because only bacteria, and not human cells, can reduce nitrate to nitrite, this may represent a symbiotic relationship by which our oral microbes maintain cardiovascular health using molecules present in our food. It has also been reported that in murine macrophages in vitro, the bacterial nitric oxide reductase NorB increases the decomposition rate of S-nitrosothiol (SNO). This represents a potential connection between nitric oxide reductases and nitrate-induced migraines,” they wrote.
Gene counting method
The researchers looked for nitric-oxide reducing bacteria in the oral and stool samples of those prone to migraines compared to those who weren’t. The method was to look for nitrate, nitrite, and nitric oxide reductase genes in the samples. Migraine sufferers showed a slightly higher level of these genes in their stool samples but a significantly higher amount in their oral samples.
“These results show for the first time a potential link between bacterial nitrate, nitrite, and nitric oxide reducers and migraines, by reporting their higher abundances 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 researchers concluded.
Paul Forsythe PhD of the Brain-Body Institute at McMaster University in Hamilton, Ontario has done a lot of work on the gut-brain connection and the communication via the vagus nerve. Forsythe said the paper is a reminder that all microbiomes in the body could have profound health implications for the host.
“Because the gut has by far the greatest microbial population and is the largest sensory organ in the body, a lot of focus has been put on the gut-brain axis. This paper is a reminder that we also need to consider the relationship between the brain and microbiota of other body compartments, particularly the oral and nasal microbiome,” he said.
Forsythe said that NO could play a significant role in the gut-brain connection as well as the one it appears to play in the oral microbiome.
“NO is an inhibitory neurotransmitter and regulates the function of the enteric nervous system. We know that modulation of the ENS is important in the ability of at least some microbes to signal to and influence brain function. Certainly the role of NO and other gaseous neurotransmitters (H2S and CO) in the microbiota-gut-brain axis could be very important and is understudied,” Forsythe said.