AAN 2026 | The gut-brain axis in the pathophysiology of pediatric migraine

Really for a very long time, I think the gut-brain axis was first really identified within migraine in 400 BC by Hippocrates when he described this idea of headache happening from vapors rising from the stomach. And really over the next thousand years, we identified clinically that headache could occur, but it was also associated with nausea, vomiting, a lot of GI and abdominal symptoms. And so it was really not only until the 1990s, early 2000s, where we thought of nausea and vomiting as a clinical consequence of migraine. But then we started doing more functional MRIs and really starting to understand the pathophysiology and the different brain portions that were involved in migraine. And what we really kind of more modernly understood is that the hypothalamus is very active before migraine starts. And oftentimes people will start to associate nausea and vomiting even before the headache pain starts. So this idea that there’s much more actually happening between the gut and the brain when it comes to migraine. And really over the last kind of 10 to five years in pediatric migraine, really in the last one to two years, there’s been a lot of investigating going into how is the gut itself potentially having an interplay within the migraine pathophysiology. And so there have been some recent studies that are coming out that show that this could kind of be at play with four different big aspects. One is with the gut microbiome. So looking in patients with pediatric migraine, is the organism that lives around and in their gut different than patients who don’t have migraine? And there have been a handful of studies to show that it does tend to be different. It tends to be different in the diversity of the organisms that live there, but also potentially in the specific organisms that live there as well. And so it does look like there are some differences here and maybe some therapeutic options that we can look at and study more. There’s also a lot of questions when it comes to pediatric patients with migraine. There are studies that are starting to show that they have increased gut inflammation. So there was one study that looked at elevated levels of calprotectin in pediatric patients with migraine. Another one that showed that there was an increased mast cell density in the duodenum. And so if we have this increased intestinal inflammation, one would start to wonder if there could be translocation of certain peptides that are important in the pain cascade that may actually translocate from the gut and go actually to trigger and propagate migraine attack frequency. I think one area that needs a lot more studying is really around the potential role of things like CGRP or calcitonin gene-related peptide. There are two isoforms in our body. The alpha isoform is found in our peripheral and our central nervous system, but the beta isoform is found all throughout our GI system. And so there’s a lot of hypothesizing around this idea of how is this specific protein and peptide connected to each other in this gut and the brain. And how could those potentially think about therapeutic interventions as well. So, I think, from my talk, what I’m really excited about and excited to learn more about is that we have known that the gut-brain axis is intimately tied within migraine, and we see this clinically. This is coming from our patients, it’s coming from caring for people who have migraine. And really, in the last handful of years, we’re starting to understand and be able to study this in a more meaningful way, in a more granular way, to understand if there may be some therapeutic targets that could be helpful for our patients and new areas that we might be able to expand on.

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