We have a lot to thank our microbiome for. 

Now considered one of the body’s organs, the microbiome defends against pathogens, strengthens the intestinal walls preventing unwanted substances from getting into the bloodstream, helps absorb nutrients, produces vitamins and guides the development and functionality of the immune system [1].

When a healthy gut microbiome is perturbed, however, health issues can ensue. Migraine, a neurological condition affecting 14% of the population, is frequently experienced alongside gastrointestinal symptoms [15]. 

This blog post will draw on current research looking at different factors influencing the interaction between the gut and the brain in order to explore how the microbiome may be linked to the development of migraine. 

The Gut-Brain Axis

Studies have shown there exist pathways between the brain and the gut collectively referred to as the gut-brain axis. Connected via hormonal, neural and immune pathways, the transfer of information between the gut and the brain is bidirectional. Its dysfunction has been implicated in a number of neurological disorders such as migraine [2]. 

Although the mechanisms by which the gut and brain interact in migraineurs are not entirely clear, research shows that microbes play a key role in the gut-brain axis, influencing the brain through hormones, immune molecules and the specialized metabolites that they produce.The ability of microbes to influence migraines in this way is an area of active research.

Substances released from the gut under the influence of the microbiome can pass through the blood-brain barrier impacting the brain [3]. When a healthy microbiota is disturbed, this can affect the normal functioning of the gut-brain axis, the outcome of which is thought to be implicated in migraines.

Immune System, Microbes and Migraines

Microbes play an important role in ensuring the quality of our gut lining. An intact gut lining prevents large molecules, toxins and pathogens from entering the bloodstream, which would otherwise cause an immune response resulting in a cascade of inflammation in different parts of the body [5]. 

During an inflammatory response triggered by leakage of substances from our gut, our immune cells produce chemicals called cytokines which help to keep our immune system on high alert in times of stress. Studies have shown that migraine attacks can be triggered by these pro-inflammatory cytokines acting on nociceptors of the trigeminal nerve [6].

While an immune system on high alert is beneficial for times of illness or those short-lived ‘flight or fight’ moments in life, prolonged stress can keep cytokines cycling throughout the body; something to consider for migraineurs who live high-pressure lifestyles.

Migraines aren’t the only conditions to be linked to inflammatory responses associated with intestinal permeability. In several gut conditions characterized by increased gut permeability  (Irritable Bowel Disease, Celiac Disease, Irritable Bowel Syndrome, Colic, Gastroparesis, Gastrointestinal symptoms), enhanced pro-inflammatory immune responses have been reported. Interestingly, people who regularly experience GI symptoms have a higher prevalence of migraine headaches [8].

It’s been known for some time that certain foods trigger migraines. New research has shown however that it may not just be the food itself that brings on a migraine, but may also be the metabolites produced as a result of microbes digesting this food and the inflammation that ensues. 

For those suffering from migraines, reducing permeability of the intestine through lifestyle changes such as diet and stress, as well as maintaining a diverse microbial population, may be key to alleviating the prevalence of the condition. 

Neurotransmitters, Microbes and Migraines

More than just gatekeepers of the gut, microbes are also involved in the production of neurotransmitters; the chemical messengers of our body. Two such neurotransmitters thought to be involved in the genesis of the migraine pain are serotonin and gamma-aminobutyric acid (GABA).

When a person suffers a migraine, their serotonin levels are lower than normal. What exactly triggers this serotonin dip is currently unknown. One of the things we do know is that microbes in the gut can directly alter neurotransmitter levels [9], which may enable them to communicate with neurons and influence brain activity. 

Microbial influence on neurotransmitter levels has been demonstrated in germ-free mice who have significantly less serotonin in their blood than normal mice. Studies have shown that serotonin levels in germ-free mice could be restored by introducing spore-forming bacteria to their guts. Conversely, mice with natural microbiota, when given antibiotics, exhibited reduced serotonin production [10]. This shows that gut microbiota are influencing neurotransmitters in the host. 

Another neurotransmitter heavily influenced by the gut is gamma-aminobutyric acid (GABA). When this inhibitory neurotransmitter attaches to the GABA receptor in your brain, it produces a calming effect. Another of GABA’s functions is to modulate the pain threshold in the central nervous system. For this reason, it’s been hypothesised that abnormal levels of GABA in the body may play a role in migraine pathophysiology [11]. 

Bacterial Metabolites and Migraine

Bacterial metabolites play a major role in your overall health, ensuring the gut lining doesn’t become too porous and that the mucous layer in the gut lining stays thickened, as well as fortifying the blood-brain barrier by tightening connections between cells. Conversely, some metabolites can have a deleterious effect. For example, lipopolysaccharides entering the bloodstream can cause an immune response provoking migraine [12]. 

When migraines do occur however, pain may be reduced by metabolites such as butyrate which have been shown to have a general anti-inflammatory effect [13].

GI Conditions and Migraine

As if migraines weren’t bad enough, patients who present with migraine headaches suffer from GI conditions more frequently than healthy controls and vice versa. 

Although the exact processes that link the different GI conditions with migraine remains unclear, the complex interplay between the brain and the gut, as well as increased intestinal permeability and inflammatory responses, may explain their associations [14].

Gut microbes have been implicated in the pathophysiology of a relatively large number of GI disorders [15], some of the mechanisms of which have been discussed above (intestinal permeability, hormones, immune molecules and bacteria metabolites).

Highlighting the role microbes may play in migraines and GI disorders is a case involving a patient infected with the bacteria H.pylori who was suffering equally from recurrent migraine and gastrointestinal symptoms. Eradication of H.pylori from the patient resulted in rapid resolution of their symptoms [16]. Further research is required to confirm these anecdotal findings, but it is an interesting thought to ponder in terms of the way migraines are treated. 

Microbes, Migraine and the Future

Migraine is a debilitating condition, the cause of which has long eluded doctors and scientists. The microbiome is now offering a new arena in which to better understand the ways in which migraines occur. It’s important to acknowledge however that currently there is more speculation than concrete evidence of the microbiome’s relationship to migraine. Evidently, based on research into mice and humans, there are associations, highlighting that the gut may be contributing to the condition in ways never before considered. 

The more we know about how our gut microbes interact with our nervous system, the better we can support this important symbiotic relationship, and perhaps one day prevent the onset of migraines through strategies targeting the microbiome.

Brigid xx

References

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[2] Arzani, M., Jahromi, S.R., Ghorbani, Z. et al. Gut-brain Axis and migraine headache: a comprehensive review. J Headache Pain 21, 15 (2020). https://doi.org/10.1186/s10194-020-1078-9

[3] Logsdon AF, Erickson MA, Rhea EM, Salameh TS, Banks WA. Gut reactions: How the blood-brain barrier connects the microbiome and the brain. Exp Biol Med (Maywood). 2018 Jan;243(2):159-165. doi: 10.1177/1535370217743766. Epub 2017 Nov 23. PMID: 29169241; PMCID: PMC5788145.

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[9] Smith, Peter. “The tantalizing links between gut microbes and the brain.” Nature news, Springer Nature, Oct 14, 2015, https://www.nature.com/news/the-tantalizing-links-between-gut-microbes-and-the-brain-1.18557

[10] Yano, Jessica M et al. “Indigenous Bacteria from the Gut Microbiota Regulate Host Serotonin Biosynthesis.” Cell, vol. 161, no. 2, 2015, pp. 264-276, https://www.cell.com/cell/fulltext/S0092-8674(15)00248-2?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867415002482%3Fshowall%3Dtrue.

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[12] Yangzhi Xie, Guijuan Zhou, Yan Xu, Bing He, Yilin Wang, Rundong Ma, Yunqian Chang, Duanqun He, Chenlin Xu, Zijian Xiao, “Effects of Diet Based on IgG Elimination Combined with Probiotics on Migraine Plus Irritable Bowel Syndrome”, Pain Research and Management, vol. 2019, Article ID 7890461, 6 pages, 2019. https://doi.org/10.1155/2019/7890461

[13] Segain J, de la Blétière DR, Bourreille A, et alButyrate inhibits inflammatory responses through NFκB inhibition: implications for Crohn’s diseaseGut 2000;47:397-403.

[14] Dai, Yu-Jie. “Potential Beneficial Effects of Probiotics on Human Migraine Headache: A Literature Review.” Pain Physician, vol. 20, no. 2150-1149, 2017, pp. 251-255, https://www.painphysicianjournal.com/current/pdf?article=NDExNA%3D%3D&journal=102.

[15] Doulberis, Michael et al. “Is there an Association between Migraine and Gastrointestinal Disorders?.” Journal of clinical neurology (Seoul, Korea) vol. 13,3 (2017): 215-226. doi:10.3988/jcn.2017.13.3.215

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