The Cogence Clinical Pearls Series

Migraines, Dysbiosis, and Food Sensitivities

What the research says…

The immunology research suggests an important connection between digestive dysfunction and migraines. This includes influences of both intestinal infection and antibody-mediated food responses. The papers listed below demonstrate 1) that calcitonin gene-related peptide (CGRP) upregulates migraine circuitry, 2) that plasma CGRP levels were elevated during intestinal sepsis, and 3) that both plasma CGRP levels and enteric neuronal CGRP levels were elevated during the development of intestinal antibody-mediated food reactions. Enteric neurons are the neurons of the intestinal tract’s semi-autonomous nervous system.

Application…

CGRP can activate migraine circuitry. Both intestinal infection (dysbiosis) and antibody reactions to foods (food sensitivities) can drive up CGRP levels. So, it’s essential that patients with migraines be evaluated for dysbiosis and food sensitivities. Persistent work, including consistent patient compliance for at least three months if not longer, is essential to turning the tide toward success in managing tough chronic migraine cases.

This study suggests that migraine circuitry is strongly upregulated in the presence of elevated CGRP levels.

CGRP and its receptors provide new insights into migraine pathophysiology.
Ho, T. W. et al. Nat. Rev. Neurol. 6, 573–582 (2010).

Abstract
Over the past 300 years, the migraine field has been dominated by two main theories-the vascular theory and the central neuronal theory. The success of vasoconstrictors such as ergotamine and the triptans in treating acute migraine bolstered the vascular theory, but evidence is now emerging that vasodilatation is neither necessary nor sufficient to induce a migraine attack. Attention is now turning to the core migraine circuits in the brain, which include the trigeminal ganglia, trigeminal nucleus, medullary modulatory regions, pons, periaqueductal gray matter, hypothalamus and thalamus. Migraine triggers are likely to reflect a disturbance in overall balance of the circuits involved in the modulation of sensory activity, particularly those with relevance to the head. In this Review, we consider the evidence pointing towards a neuronal mechanism in migraine development, highlighting the role of calcitonin gene-related peptide (CGRP), which is found in small to medium-sized neurons in the trigeminal ganglion. CGRP is released during migraine attacks and can trigger migraine in patients, and CGRP receptor antagonists can abort migraine. We also examine whether other drugs, such as triptans, might exert their antimigraine effects via their actions on the neuronal circuit as opposed to the intracranial vasculature.

These studies show that CGRP is elevated in response to intestinal infection and in the presence of immunological reactions to food antigens…

In this first study, researchers found that plasma CGRP levels went up 177% (a nearly three-fold increase) at the peak, ten hours after the induction of intestinal sepsis, and that the source of the CGRP elevation was the small intestine. It’s interesting to consider the thematic similarity between this mouse model and the increased systemic LPS burden that occurs with chronic dysbiosis.

The small intestine plays an important role in upregulating CGRP during sepsis.
Zhou M, Arthur AJ, Ba ZF, Chaudry IH, Wang P. Am J Physiol Regulatory Integrative Comp Physiol 280: R382–R388, 2001.

Abstract
Although studies have indicated that calcitonin gene-related peptide (CGRP), a potent vasodilatory peptide, is upregulated after endotoxic shock, it remains controversial whether this peptide increases during sepsis and, if so, whether the gut is a significant source of CGRP under such conditions. To study this, polymicrobial sepsis was induced by cecal ligation and puncture (CLP) followed by fluid resuscitation. Plasma levels of CGRP were measured at 2, 5, and 10 h after CLP (i.e., early, hyperdynamic sepsis) and at 20 h after CLP (late, hypodynamic sepsis). The results indicate that plasma CGRP did not increase at 2–5 h but increased by 177% at 10 h after CLP (P < 0.05). At 20 h after the onset of sepsis, however, the elevated plasma CGRP returned to the sham level. To determine the source of the increased plasma CGRP, the liver, spleen, small intestine, lungs, and heart were harvested, and tissue CGRP was assayed at 10 h after CLP in additional animals. Only the small intestine showed a significant increase in tissue levels of CGRP (by 129%, P < 0.05). Determination of portal vs. systemic levels of CGRP indicates that portal CGRP was 65.7 +/- 22.7% higher than the systemic level at 10 h after CLP, whereas portal CGRP in sham-operated rats was only 4.9 +/- 2.1% higher. Immunohistochemistry examination revealed that CGRP-positive stainings increased in the intestinal tissue but not in the liver at 10 h after the onset of sepsis. The distribution of CGRP stainings was associated with intestinal nerve fibers. These results, taken together, demonstrate that upregulation of CGRP occurs transiently during the progression of sepsis (at the late phase of the hyperdynamic sepsis), and the gut appears to be a major source of such an increase in circulating levels of this peptide.

In this study, researchers again found that CGRP levels were upregulated in plasma, not just in enteric nervous system neurons, reflecting a systemic elevation. It’s also important to note the juxtaposition of CGRP-reactive nerve fibers with mast cells in the intestines of food allergic mice. 

Enhancement of CGRP sensory afferent innervation in the gut during the development of food allergy in an experimental murine model.
Lee J, Yamamoto T, Hayashi S, Kuramoto H, Kadowaki M. Biochem Biophys Res Commun. 2013 Jan 18;430(3):895-900.

Abstract
Recent advances in neuroscience and immunology have revealed a bidirectional interaction between the nervous and immune systems. Therefore, the gastrointestinal tract may be modulated by neuro-immune interactions, but little information about this interaction is available. Intrinsic and extrinsic primary afferent neurons play an important role in this interaction because of their abilities to sense, process and transmit various information in the intestinal microenvironment. Calcitonin gene-related peptide (CGRP) is exclusively contained in intrinsic and extrinsic primary afferent neurons in the mouse intestine. Therefore, we investigated CGRP-immunoreactive nerve fibers in the colonic mucosa of mice induced to develop food allergy. CGRP-immunoreactive nerve fibers were specifically increased with the development of food allergy, and the fibers were juxtaposed to mucosal mast cells in the colonic mucosa of food allergy mice. Denervation of the extrinsic afferent neurons using neonatal capsaicin treatment did not affect the development of food allergy or the density and distribution of CGRP-immunoreactive nerve fibers in the colonic mucosa of food allergy mice. Furthermore, the mRNA and plasma level of CGRP was increased in food allergy mice. These results suggest that the activation of intrinsic primary afferent neurons in the intestine contributes to the development and pathology of food allergy.