Citation: Liaqat, H.; Parveen, A.; Kim, S.Y. Neuroprotective Natural Products’ Regulatory Effects on Depression via Gut–Brain Axis Targeting Tryptophan. Nutrients 2022, 14, 3270. https://doi.org/10.3390/ nu14163270 Academic Editor: Rosa Casas Received: 21 July 2022 Accepted: 8 August 2022 Published: 10 August 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). nutrients Review Neuroprotective Natural Products’ Regulatory Effects on Depression via Gut–Brain Axis Targeting Tryptophan Humna Liaqat 1 , Amna Parveen 2, * and Sun Yeou Kim 2, * 1 Department of Animal Science, Biotechnical Faculty, University of Ljubljana, Groblje 3, 1230 Domzale, Slovenia 2 College of Pharmacy, Gachon University Medical Campus, No. 191, Hambakmoero, Yeonsu-gu, Incheon 21936, Korea * Correspondence: amnaparvin@gmail.com or amnaparvin@gachon.ac.kr (A.P.); sunnykim@gachon.ac.kr (S.Y.K.) Abstract: L-tryptophan (Trp) contributes to regulating bilateral communication of the gut–brain axis. It undergoes three major metabolic pathways, which lead to formation of kynurenine, serotonin (5-HT), and indole derivatives (under the control of the microbiota). Metabolites from the principal Trp pathway, kynurenic acid and quinolinic acid, exhibit neuroprotective activity, while picolinic acid exhibits antioxidant activity, and 5-HT modulates appetite, sleep cycle, and pain. Abnormality in Trp plays crucial roles in diseases, including depression, colitis, ulcer, and gut microbiota-related dysfunctions. To address these diseases, the use of natural products could be a favorable alternative because they are a rich source of compounds that can modulate the activity of Trp and combat various diseases through modulating different signaling pathways, including the gut microbiota, kynurenine pathway, and serotonin pathway. Alterations in the signaling cascade pathways via different phytochemicals may help us explore the deep relationships of the gut–brain axis to study neuroprotection. This review highlights the roles of natural products and their metabolites targeting Trp in different diseases. Additionally, the role of Trp metabolites in the regulation of neuroprotective and gastroprotective activities is discussed. This study compiles the literature on novel, potent neuroprotective agents and their action mechanisms in the gut–brain axis and proposes prospective future studies to identify more pharmaceuticals based on signaling pathways targeting Trp. Keywords: L-tryptophan; 5-HT; metabolites; phytochemicals; gut–brain axis; neuroprotective; gastroprotective; signaling pathways 1. Introduction The gut–brain axis (GBA) is a two-directional communication system between the gastrointestinal tract (GIT) and the brain. It links the emotional and cognitive centers of the brain with peripheral control and function of the GIT. Cross-communication between the gut and the brain via complex functions of neuronal, hormonal, and immune reflexes [1] is constant. This bidirectional system drives sensory signals from the gut to the central nervous system (CNS) and vice versa, thereby directing the regulation of reflex action and mood states. In turn, signals from both directions may influence motor, secretory, and immunological functions of the gut [2]. Various studies have revealed that alterations in the gut microbiota affect the GBA, which is regulated via L-tryptophan (Trp) metabolism [3–5]. L-tryptophan and its metabo- lites exhibit neuroprotective and gastroprotective activities against psychiatric disorders, such as depression, and GIT dysfunction in different diseases [6,7]. Recently, different studies have reported the regulatory roles of microbiota and their modification via di- etary supplements, diet, and naturally derived agents in GBA communication [5,8]. These studies found that the gut microbiota, CNS, enteric nervous system, sympathetic and parasympathetic nervous systems, neuroendocrine system, and neuroimmune pathways Nutrients 2022, 14, 3270. https://doi.org/10.3390/nu14163270 https://www.mdpi.com/journal/nutrients