Microbiota, Tryptophan and Aryl Hydrocarbon Receptors as the Target Triad in Parkinson's Disease-A Narrative Review

Abstract

In the era of a steadily increasing lifespan, neurodegenerative diseases among the elderly present a significant therapeutic and socio-economic challenge. A properly balanced diet and microbiome diversity have been receiving increasing attention as targets for therapeutic interventions in neurodegeneration. Microbiota may affect cognitive function, neuronal survival and death, and gut dysbiosis was identified in Parkinson's disease (PD). Tryptophan (Trp), an essential amino acid, is degraded by microbiota and hosts numerous compounds with immune- and neuromodulating properties. This broad narrative review presents data supporting the concept that microbiota, the Trp-kynurenine (KYN) pathway and aryl hydrocarbon receptors (AhRs) form a triad involved in PD. A disturbed gut-brain axis allows the bidirectional spread of pro-inflammatory molecules and α-synuclein, which may contribute to the development/progression of the disease. We suggest that the peripheral levels of kynurenines and AhR ligands are strongly linked to the Trp metabolism in the gut and should be studied together with the composition of the microbiota. Such an approach can clearly delineate the sub-populations of PD patients manifesting with a disturbed microbiota-Trp-KYN-brain triad, who would benefit from modifications in the Trp metabolism. Analyses of the microbiome, Trp-KYN pathway metabolites and AhR signaling may shed light on the mechanisms of intestinal distress and identify new targets for the diagnosis and treatment in early-stage PD. Therapeutic interventions based on the combination of a well-defined food regimen, Trp and probiotics seem of potential benefit and require further experimental and clinical research.

Keywords: Parkinson’s disease; aging; aryl hydrocarbon receptor; diet; individualized therapy; kynurenine; microbial–intestinal–brain axis; microbiota; probiotics; tryptophan.

Figure 1

A schematic overview of tryptophan metabolic pathways. Kynurenine, serotonin and indole pathways are the primary routes of host Trp metabolism and its commensal bacteria. Kynurenine pathway: IDO, indoleamine 2,3-dioxygenase; TDO, tryptophan 2,3-dioxygenase; KAT I–IV, kynurenine aminotransferase I–IV; KMO, kynurenine 3-monooxygenase; KYNU, kynureninase; 3HAAO, 3-hydroxyanthranilate 3,4-dioxygenase; ACMSD, α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase.

Figure 2

Tryptophan metabolites generated in the gut, periphery and brain. In red—AhR ligands; in italics—metabolites penetrating through the blood–brain barrier. Tryptophan (Trp) and kynurenine (KYN) are also easily transported into the brain. Kynurenines are produced in all three compartments, in contrast to indoles, which are synthesized only in the gut. In the brain, Trp comes from ingested proteins, and KYN originates from Trp metabolism in the gut and peripheral organs and from the conversion of Trp in situ. Other brain kynurenines are produced locally within the brain.

Figure 3

Microbiota, tryptophan (Trp), aryl hydrocarbon receptor (AhR) triad and the microbiota–gut–brain axis. Dysbiosis may affect Trp metabolism in the gut and the production of AhR ligands. Ensuing pro-inflammatory environment impacts intestinal enterocytes, and cytokines and chemokines evoke inflammation in situ. Furthermore, when absorbed into the systemic circulation, inflammatory molecules affect peripheral organs and the brain. Deficiency of Trp and AhR ligands further exacerbates inflammation. This, together with the disturbed metabolic conversion of Trp and shift from neuroprotective to neurotoxic kynurenines, will contribute to cytotoxicity.