Neuroprotective Natural Products' Regulatory Effects on Depression via Gut-Brain Axis Targeting Tryptophan

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: 5-HT; L-tryptophan; gastroprotective; gut–brain axis; metabolites; neuroprotective; phytochemicals; signaling pathways.

Figure 1

Three Integrated pathways of tryptophan metabolism. Tryptophan (Trp) is an essential amino acid obtained from dietary protein. The majority of Trp is metabolized alongside the kynurenine pathway to produce different molecules collectively referred to as kynurenines. The most widely studied fate of Trp is the downstream conversion to serotonin and melatonin. Trp availability is also altered by gut microbes generating either indole or its derivatives, tryptamine or serotonin, which can affect the gastrointestinal tract. TDO, tryptophan 2,3-dioxygenase; IDO, indoleamine 2,3-dioxygenase; Fmd, formamidase; KAT, kynurenine aminotransferase; KrA, kynureninase A; KMO, kynurenine hydroxylase (monooxygenase); KrB, kynureninase B; NAD, nicotinamide adenine dinucleotides; TpH, tryptophan hydroxylase; AAAD, aromatic amine acid decarboxylase; AANAT, arylakylamine-N-acetyltransferase; HIOMT, hydroxyindolo-O-methyltransferase; MAO, monoamine oxidase; AlDh, aldehyde dehydrogenase; TrpD, tryptophan decarboxylase; TNA, tryptophanase; SLT, sulfotransferase; TMO, tryptophan monooxygenase; IaaH, indoleacetamide hydrolase; IaaD, indoleacetate decarboxylase; Arat, aromatic amino acid aminotransferase; ID, indolepyruvate decarboxylase; ADhn, alcohol dehydrogenase; fldH, phenyllactate dehydrogenase; ILD, indolelactate dehydratase; ACD, acyl-CoA dehydrogenase.

Figure 2

GBA targeting tryptophan: Peripheral serotonin synthesis by enterochromaffin cells is stimulated by gut microbiota. 5-HT from the gut has various direct or indirect effects, such as gut motility and gut microbiota. This affects central serotoninergic pathways by moderating Trp and tryptamine availability. Gut microbiota affect the kynurenine pathway, which plays a critical role in inflammatory mechanisms and neuroendocrine functions. Dietary Trp can also be directly converted by the gut microbiota into AhR ligands and can help to perform many functions. Trp; tryptophan; Kyn, kynurenine; KynA, kynurenic acid; quinolinic acid; 3HANA, 3-hydroxyanthranilic acid; 3-HK, 3-hydroxykynurenine; 5-HTP, 5-hydroxytryptophan, 5-HT, 5-hydroxytryptamine; 5-HIAA, 5-hydroxyindole acetic acid; AhR, aryl hydrocarbon receptor; EC, enterochromaffin cells.

Figure 3

Structures of bioactive metabolites from natural products: Tryptophan—human breast milk, Moringa oleifera, and Nelumbo nucifera; theanine—Camellia sinensis; anonaine—Annona muricata; piperine—Piper nigrum; lycopene—Citrullus lanatus; 2-O-β-d-glucopyranosyl-l-ascorbic acid—Lycium barbarum.

Figure 4

Structures of bioactive metabolites from natural products: Anthocyanin—Rubus fruticosus; Catechin—Rhizophora mucronata; Chrysin—Matricaria chamomilla; Curcumin—Curcuma longa; Ellagic acid—Punica granatum; Eugenol—Syzygium aromaticum; Ferulic acid—Ferula foetida; Hesperidin—Citrus limon; Oleuropein—Olea europaea.

Figure 5

Structures of bioactive metabolites from natural products: Proanthocyanin—Cinnamomum zeylanicum; Rutin—Fagopyrum esculentum; Sanggenon G—Morus alba; Salidroside—Rhodiola rosea; Resveratrol—Polygonum cuspidatum; Astragaloside IV—Astragalus membranaceus; Carvacrol—Origanum vulgare; Limonene—Citrus sinensis.

Figure 6

Structures of bioactive metabolites from natural products: Asiaticoside—Centella asiatica; Bacoside—Bacopa monnieri; Ginkgolides B—Ginkgo biloba; Linalool—Lavandula angustifolia; Ginsenoside Rg5—Panax ginseng; Oleanolic acid—Pimenta pseudocaryophyllus; Hyperforin—Hypericum perforatum.

Figure 7

Metabolism of Trp by natural products and constituents via different signaling pathways: Trp is metabolized via the kynurenine pathway (95%), serotonin pathway (1%), and microbial pathway (3%). 1: anonaine, 2: anthocyanin, 3: asiaticoside, 4: astragaloside IV, 5: bacoside A, 6: carvacrol, 7: catechin, 8: chrysin, 9: curcumin, 10: ellagic acid, 11: eugenol, 12: ferulic acid, 13: ginkgolides B, 14: ginsenoside Rg5, 15: hesperidin, 16: hyperforin, 17: limonene, 18: linalool, 19: luteolin, 20: lycopene, 21: naringin, 22: oleanolic acid, 23: oleuropein, 24: omega-3 fatty acids, 25: piperine, 26: proanthocyanidins, 27: resveratrol, 28: rutin, 29: salidroside, 30: sanggenon G, 31: theanine, 32–35: tryptophan, 36: 2-O-β-d-glucopyranosyl-l-ascorbic acid, 37: Mimosa pudica, 38: Poria cocos, 39: Salvia officinalis, 40: Tagetes lucida, 41: Tualang honey.

Figure 8

Natural products with neuroprotective and gastroprotective effects on the regulation of the GBA targeting tryptophan and its metabolites through different pathways: Specific natural products and the derived compounds exhibit specific functions in the bidirectional communication of the gut and brain. 1: anonaine, 2: anthocyanin, 3: asiaticoside, 4: astragaloside IV, 5: bacoside A, 6: carvacrol, 7: catechin, 8: chrysin, 9: curcumin, 10: ellagic acid, 11: eugenol, 12: ferulic acid, 13: ginkgolides B, 14: ginsenoside Rg5, 15: hesperidin, 16: hyperforin, 17: limonene, 18: linalool, 19: luteolin, 20: lycopene, 21: naringin, 22: oleanolic acid, 23: oleuropein, 24: omega-3 fatty acids, 25: piperine, 26: proanthocyanidins, 27: resveratrol, 28: rutin, 29: salidroside, 30: sanggenon G, 31: theanine, 32–35: tryptophan, 36: 2-O-β-d-glucopyranosyl-l-ascorbic acid, 37: Mimosa pudica, 38: Poria cocos, 39: Salvia officinalis, 40: Tagetes lucida, 41: Tualang honey.