TRANSCRIPT:

Spotlight on Migraine

The Professional Series

Season 3, Episode 14

Migraine, Irritable Bowel Syndrome, and the Brain-Gut-Microbiota Axis

Gretchen E. Tietjen, MD

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Voice-over: Welcome to Spotlight on Migraine, The Professional Series, hosted by the Association of Migraine Disorders. Join us as we dive deeper into migraine topics with guests from the medical field. This episode includes educational content intended for medical professionals but may be interesting to some patients as well.

In this presentation by Dr. Gretchen Tietjen, we learn about the association between migraine and IBS, as well as other GI disorders. Dr. Tietjen summarizes the role of the brain-gut-microbiota axis and explains the impact of early life stress on the gastrointestinal system.

This episode is brought to you in part by our generous sponsors Amgen and Novartis.

Dr. Gretchen Tietjen: This is Dr. Gretchen Tietjen, at the University of Toledo, and my presentation is on migraine, irritable bowel syndrome, and the brain-gut-microbiota axis. I am a neurologist, not a GI specialist, but otherwise I have nothing pertinent to disclose as it pertains to this presentation.

So I’m going to go over the three educational objectives of the talk. One is to describe the association of migraine and irritable bowel syndrome, as well as some other GI disorders; to summarize the role of the brain-gut-microbiota in migraine and in irritable bowel syndrome; and then to summarize the impact of early life stress on the brain-gut-microbiota axis and the implications this may have for the treatment of migraine and irritable bowel syndrome.

Now, migraine has been linked to a number of different GI disorders. These include infant colic. Mothers with migraine have been known to have an increased prevalence of colic in their children. Gastroparesis is known to occur during migraine but also potentially in the interictal period. People with celiac disease — there may be a higher prevalence of celiac disease in persons with migraine. Inflammatory bowel disease — persons with that condition may have a higher prevalence of migraine. And then there has been a link between irritable bowel syndrome and migraine, and I’ll describe the epidemiology of that.

But first I wanted to just state that there’s a number of similarities between irritable bowel syndrome and migraine. For instance, both have similar prevalence of about 14 percent, at least in the United States. They affect predominantly females over males. Both have frequent family history. They have fluctuations in the natural disease course, in migraine and in IBS. Both conditions can be triggered particularly by stimuli such as stress. Neither have a well-defined organic cause. And both conditions have similarities in their comorbidities, particularly the psychiatric comorbidities.

So what is the epidemiology of migraine and irritable bowel syndrome? Well, a study from 2014 was in a population-based retrospective cohort of 14,000 migraineurs and 56,000 persons without migraine. And the incidence of IBS was — well, I think it’s actually the prevalence of IBS was twofold greater in the migraine cohort compared to the non-migraine controls, and it was about 3.4-fold higher in the subgroup of migraineurs that were under the age of 30, compared to the control group of similar age. 

Also, a recent literature review shows that the prevalence of irritable bowel syndrome in migraine can range anywhere from 25 percent to 50 percent, and if you compare this to what’s been found in control groups, it’s been anywhere from 4 to 19 percent. So that would be an odds ratio of about 2.7.

Now, this figure is from a study I presented about 10 years ago, and we refer to these groups of migraineurs as “comorbidity constellations.” What we did is took patients diagnosed with migraine in specialized headache clinics across the United States and Canada and did a cluster analysis on their comorbidities. We found that there was group that had a relative absence of comorbid conditions, there was another group of migraineurs that had multiple different pain conditions, and then there was a group that had predominantly metabolic and psychiatric conditions. The largest group was that with the pain conditions.

So the thought is, Well, what ties these patients together? Why do some people end up with no comorbidities, others end up with multiple pain conditions, and others end up with metabolic conditions? 

Well, one of the things that may be occurring is something that’s been referred to as central sensitization. So these would be the central-sensitivity syndromes. And central sensitization is a condition of chronic pain with a persistent state of high reactivity and lower pain thresholds, so you have sort of an amplification of the pain. And two of the main characteristics of it are something that’s referred to as hyperalgesia, where a painful stimulus causes heightened pain, and allodynia, where a nonpainful stimulus actually can be perceived as painful.

It’s thought that one of things that occurs in central sensitization is enhancement of nociceptive neuronal pathways, and this may be due to reduced inhibition or increased membrane excitability, somatosensory plasticity, increased synaptic efficiency. There may be a bunch of different things that lead to this enhancement of the nociceptive pathways.

Just to go over that a little bit further is that when you have — in sort of normal sensitization, you have this somatosensory system that sort of acts in parallel, where if you have a low-intensity stimulus stimulating these low-threshold mechanoreceptors, it’s perceived as touch. If you have a high-intensity stimulus, that’s going to activate the nociceptors, and that will be perceived as pain. And there’s not a lot of convergence of these two symptoms. They don’t functionally intersect with each other.

With the induction of central sensitization in the somatosensory pathways, you will have a central amplification that enhances the pain response to noxious stimuli. And so the stimuli cause higher degree of pain, longer duration of pain, larger spatial extent of the pain. But something else happens in addition to it. You now have what was normally sort of ineffective synapses now start to be recruited in. And so input through the low-intensity stimuli, they are now going to activate the pain circuit, and they will be perceived as pain, and that’s what we refer to as allodynia. So a nonpainful stimulus is perceived as being painful.

So what do we know about the pathophysiology of irritable bowel syndrome? Well, it likely is multifactorial. It may be a biopsychosocial disorder. Psychological stress likely plays a role in causing abnormal stress responsiveness and through HPA axis dysregulation and also altered nociceptive pathways. Food intolerance may play a role. There may be a genetic component. It may be a condition related to visceral hypersensitivity due to central and peripheral mechanisms and also an interplay of the enteric nervous system, the spinal cord, and the central nervous system. It’s also possible that injury or gastroenteritis-related changes in the intestinal microbiota plays a role, causing some changes in the immune system within the intestine and also increased inflammation.

So what about a shared pathophysiology between migraine and irritable bowel syndrome? Well, one may be central sensitization. Another component that might be linking these two conditions is increased inflammation. And then a third would be alteration in both conditions of the brain-gut-microbiota axis so that there’s increased gut permeability, interstitial dysbiosis — that means sort of a maladaptation of the microbiome or an imbalance of the microbiome. There can be altered levels of inflammatory cells and mediators, including lipopolysaccharides. And then both conditions may be linked because of alterations in brain function through the brain-gut-microbiota axis.

Now, I’m going to go over the brain-gut-microbiome axis in some detail because it’s becoming sort of a axis or a connectome that has got an increased relevance as it pertains to different diseases throughout the body. One thing that’s interesting is that there’s more microbial cells within the human body than human cells, and more than 99 percent of the genes in humans are actually microbial. When you think of the intestinal surface, there can be up to 100 trillion microorganisms. Now, gut colonization begins at birth, but a lot of it is influenced over the course of our lives by diet.

Now, when it comes to the gut, the gut has its own nervous system, the enteric nervous system, which contains between 200 and 600 million neurons. It’s thought that it derived from neural crest cells migrating along the vagus nerves, sort of tying the gut then to the central nervous system. And enteric nervous system cells, they secrete a number of neurotransmitters that are important in migraines, including serotonin and CGRP. The enterochromaffin cells actually release more than 90 percent of the serotonin that’s in the body, and the lymphoid tissues in the gut house up to 80 percent of the body’s immune cells.

So the brain interacts with the gut. If there’s stress and release of inflammatory cytokines, those can act at the pituitary and activate HPA axis and release of cortisol from the adrenals. That in turn has an anti-inflammatory effect on the GI immune system, which in turn causes an increase in corticotropin-releasing hormone. The central nervous system, the enteric nervous system, they communicate along the vagal pathways and the autonomic pathways, and the autonomic nervous system can actually stimulate the release of serotonin into the gut lumen from the enterochromaffin cells.

Now, the gut may also interact with the brain by transmitting sensory information to the nucleus tractus solitarius along the vagal nerve. The vagal nerve also transmits changes due to GI mast cell activation, and the enterochromaffin cells communicate with the central nervous system via the vagal afferent nerve fibers.

Now, when it comes to the interaction of the gut with the gut microbiome, any change in gut function may causes changes in the gut microbial behavior. Also, with the gut microbiome, the microbiota can communicate with the gut — neuronal, glial, endocrine, and immune cells — via metabolites that they release. The microbiota can also influence development and function of the enteric nervous system and the immune system in the gut, and the synthesis of serotonin from enterochromaffin cells is modulated by substances that are produced by Clostridiales, such as the small-chain fatty acids and the secondary bioacids. And these are dependent on the availability of dietary tryptophan.

Now, the brain can interact with the gut microbiome via regulation of the autonomic nervous system, and lastly the gut microbiome can interact with the brain, vagal nerves, spinal nerves, and autonomic nervous system both through direct pathways and also through indirect pathways. And by indirect pathways, we mean the microbial release of neurotransmitters and neuroactive metabolites. There may be release of substances that will change the immune and inflammatory cytokines that can then activate the pituitary, for instance, and lead to a release of cortisol. Also, short-chain fatty acids from the diet can act on afferent vagal and spinal nerve endings.

Inflammation and increased gut permeability and neuroimmune modulation in the GI tract could play a role in migraine pathogenesis. And there’s been other studies that suggest that the brain-gut-microbiome, particularly the gut microbiota, if out of balance, can contribute to migraine. So I just want to go over a few of these.

One study that was done that was published just this year showed that gut microbiota dysbiosis — we call that microbial imbalance — contributes to chronicity of migraine-like pain by upregulating TNFα levels in the trigeminal nociceptive system. So having problems within the gut have been related to upregulation of TNFα and may be directly related to migraine.

Now, there was a small study, 30 women that were hospitalized with irritable bowel syndrome; and out of that group, the women with migraine tended to have more severe intestinal dysbiosis, and they were also persons more likely to complain of food allergies, anxiety, fibromyalgia, and chronic pelvic pain, all also associated with irritable bowel syndrome and with migraine.

Now, another study of 105 women with migraine and without aura, they were evaluated for dysbiosis. And those that showed evidence of dysbiosis, they also showed a number of changes, including increase in the thickness of the intima-media of the carotid. They had elevated glycosylated hemoglobin levels. They had more severe migraines, longer duration of migraines. They also had elevated levels of tumor necrosis factor-alpha, and they had higher body-mass indices. So this suggests that young females with migraine may have significant alterations in their gut microbiota, that those are women that may experience early atherosclerosis.

Now, I want to just discuss a little bit about IBS pathophysiology, which some of the abnormalities seen in IBS occur at several different levels of the brain-gut-microbiota axis. There’s abnormalities of the microbiota, of the gut epithelium and the barriers, and so the leaky gut. There’s abnormalities of the neuroendocrine system, the immune system, brain structure and function. There’s abnormal stress response, abnormal pain modulation, and also some brain conditions, including changes in cognition and affect.

These two figures sort of summarize the brain-gut-microbiome axis but also represent a model of the interactions that occur with irritable bowel syndrome at the level of the brain, the gut, and the microbiota.

Now, going back to our comorbidity groups, particularly Group 2 with the pain conditions. One of the things we looked at in this study is that all persons in the study filled out something called the Childhood Trauma Questionnaire that quantitated abuse and neglect in childhood when answered by adults. And one of the things that we found was that if we used Group 1, which had an absence of comorbidities, as a reference group and then looked at, through logistic regression analysis, whether there was a greater amount of abuse in Group 2 and Group 3 compared to Group 1, we found that there was for all types of abuse and neglect. And the comorbidity groups were actually quite similar. But as it pertains to the discussion of migraine and irritable bowel syndrome, physical abuse, sexual abuse, emotional abuse, physical neglect, and emotional neglect all were associated with migraine in a way that was not seen in the group without comorbidities.

So what do we know about childhood maltreatment and irritable bowel disease and in migraine? Well, irritable bowel syndrome has been associated with a history of childhood sexual abuse. The data on the relationship of irritable bowel and childhood emotional and physical abuse tended to be inconsistent between studies. 

Migraine is associated with all types of abuse, emotional more than sexual more than physical, and some of the pathophysiological brain changes that occur with abuse have been described in another presentation that I gave at this symposium. But there’s also depressed serotonin levels, excessive norepinephrine responsivity, and alterations in the communication of the brain-gut-microbiota axis, and HPA dysregulation, so there’s abnormalities in cortisol regulation. So there tends to be, in persons that have undergone abuse, first sort of cortisol hypersecretion in response to stress, but then later there is a hyposecretion. And also corticotropin-releasing hormone secreted from the hypothalamus is associated with colonic dysmotility.

So, in closing, what are some possible treatments? So if the theory is that migraine and irritable bowel both stem from central sensitivity, underlying inflammation, dysregulation of the HPA axis, and dysregulation of the brain-gut-microbiota axis, that maybe there are some treatments that might be beneficial in preventing exacerbations of both these conditions. And these might include an elimination diet after a person undergoes testing for food allergens, use of probiotics and prebiotics, also using a vegan diet or going to an anti-inflammatory diet of high omega-3, low omega-6. Biofeedback and cognitive behavioral therapy have both also been used successfully in some patients with migraine and irritable bowel syndrome.

So I think there’s a lot more to be learned about these connections, and this is really only a start. I hope it will spur some people on to further research in this area. So, anyway, thank you very much, and I appreciate your interest.

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Voice-over: Thank you for tuning in to Spotlight on Migraine. For more information on migraine disease, please visit MigraineDisorders.org.

*The contents of this podcast are intended for general informational purposes only and do not constitute professional medical advice, diagnosis, or treatment. Always seek the advice of a physician or other qualified health provider with any questions you may have regarding a medical condition. The speaker does not recommend or endorse any specific course of treatment, products, procedures, opinions, or other information that may be mentioned. Reliance on any information provided by this content is solely at your own risk.