Int. J. Mol. Sci. 2021, 22, 10134. https://doi.org/10.3390/ijms221810134 www.mdpi.com/journal/ijms Review Kynurenine Pathway of Tryptophan Metabolism in Migraine and Functional Gastrointestinal Disorders Michal Fila 1 , Jan Chojnacki 2 , Elzbieta Pawlowska 3 , Joanna Szczepanska 4 , Cezary Chojnacki 2 and Janusz Blasiak 5, * 1 Department of Developmental Neurology and Epileptology, Polish Mother’s Memorial Hospital Research Institute, 93‐338 Lodz, Poland; michal.fila@iczmp.edu.pl 2 Department of Clinical Nutrition and Gastroenterological Diagnostics, Medical University of Lodz, 90‐647 Lodz, Poland; jan.chojnacki@umed.lodz.pl (J.C.); cezary.chojnacki@umed.lodz.pl (C.C.) 3 Department of Orthodontics, Medical University of Lodz, 92‐217 Lodz, Poland; elzbieta.pawlowska@umed.lodz.pl 4 Department of Pediatric Dentistry, Medical University of Lodz, 92‐216 Lodz, Poland; joanna.szczepanska@umed.lodz.pl 5 Department of Molecular Genetics, Faculty of Biology and Environmental Protection, University of Lodz, 90‐236 Lodz, Poland * Correspondence: janusz.blasiak@biol.uni.lodz.pl Abstract: Migraine, the leading cause of disability in the population aged below 50, is associated with functional gastrointestinal (GI) disorders (FGIDs) such as functional nausea, cyclic vomiting syndrome, and irritable bowel syndrome (IBS). Conversely, changes in intestinal GI transit may cause diarrhea or constipation and are a component of the autonomic symptoms associated with pre‐ and post‐dorsal phases of migraine attack. These mutual relationships provoke a question on a common trigger in migraine and FGIDs. The kynurenine (L‐kyn) pathway (KP) is the major route for L‐tryptophan (L‐Trp) metabolism and transforms L‐Trp into several neuroactive compounds. Changes in KP were reported in both migraine and FGIDs. Migraine was largely untreatable, but several drugs approved lately by the FDA, including monoclonal antibodies for calcitonin gene‐ related peptide (CGRP) and its receptor, create a hope for a breakthrough in migraine treatment. Derivatives of L‐kyn were efficient in pain relief with a mechanism including CGRP inhibition. KP products are important ligands to the aryl hydrocarbon receptor (AhR), whose activation is impli‐ cated in the pathogenesis of GI and migraine. Toll‐like receptors (TLRs) may play a role in migraine and IBS pathogeneses, and KP metabolites detected downstream of TLR activation may be an IBS marker. The TLR4 signaling was observed in initiating and maintaining migraine‐like behavior through myeloid differentiation primary response gene 88 (MyD88) in the mouse. The aim of this review is to justify the view that KP modulation may provide common triggers for migraine and FGIDs with the involvement of TLR, AhR, and MyD88 activation. Keywords: tryptophan metabolism; migraine; kynurenines; functional gastrointestinal diseases; ir‐ ritable bowel syndrome; aryl hydrocarbon receptor; toll‐like receptors 1. Introduction Functional disorders of the gastrointestinal (GI) tract are frequently associated with neurological diseases, including migraine, and are a serious diagnostic problem due to nonspecific syndromes (reviewed in [1,2]). Migraine is bidirectionally comorbid with sev‐ eral other disorders, including neurological, psychiatric, cardio‐ and cerebrovascular, GI, metaboloendocrine, and immunological diseases [3]. Each of these comorbid diseases shares some mechanism of pathogenesis with migraine and can contribute to the activa‐ tion of the trigeminovascular system along with the neuroendocrine hypothalamic sys‐ tem, the causative mechanisms in migraine [4]. This reflects the gut–brain axis, a network Citation: Fila, M.; Chojnacki, J.; Pawlowska, E.; Szczepanska, J.; Chojnacki, C.; Blasiak, J. Kynurenine Pathway of Tryptophan Metabolism in Migraine and Functional Gastrointestinal Disorders. Int. J. Mol. Sci. 2021, 22, 10134. https:// doi.org/10.3390/ijms221810134 Academic Editors: Zsuzsanna Helyes and Roberto De Giorgio Received: 17 August 2021 Accepted: 18 September 2021 Published: 20 September 2021 Publisher’s Note: MDPI stays neu‐ tral with regard to jurisdictional claims in published maps and institu‐ tional affiliations. Copyright: © 2021 by the authors. Li‐ censee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and con‐ ditions of the Creative Commons At‐ tribution (CC BY) license (http://crea‐ tivecommons.org/licenses/by/4.0/).