Gut-Brain Axis and Neuroinflammation: The Role of Gut Permeability and the Kynurenine Pathway in Neurological Disorders

Abstract

The increasing prevalence of neurological disorders such as Alzheimer's, Parkinson's, and multiple sclerosis presents a significant global health challenge. Despite extensive research, the precise mechanisms underlying these conditions remain elusive, with current treatments primarily addressing symptoms rather than root causes. Emerging evidence suggests that gut permeability and the kynurenine pathway are involved in the pathogenesis of these neurological conditions, offering promising targets for novel therapeutic and preventive strategies. Gut permeability refers to the intestinal lining's ability to selectively allow essential nutrients into the bloodstream while blocking harmful substances. Various factors, including poor diet, stress, infections, and genetic predispositions, can compromise gut integrity, leading to increased permeability. This condition facilitates the translocation of toxins and bacteria into systemic circulation, triggering widespread inflammation that impacts neurological health via the gut-brain axis. The gut-brain axis (GBA) is a complex communication network between the gut and the central nervous system. Dysbiosis, an imbalance in the gut microbiota, can increase gut permeability and systemic inflammation, exacerbating neuroinflammation-a key factor in neurological disorders. The kynurenine pathway, the primary route for tryptophan metabolism, is significantly implicated in this process. Dysregulation of the kynurenine pathway in the context of inflammation leads to the production of neurotoxic metabolites, such as quinolinic acid, which contribute to neuronal damage and the progression of neurological disorders. This narrative review highlights the potential and progress in understanding these mechanisms. Interventions targeting the kynurenine pathway and maintaining a balanced gut microbiota through diet, probiotics, and lifestyle modifications show promise in reducing neuroinflammation and supporting brain health. In addition, pharmacological approaches aimed at modulating the kynurenine pathway directly, such as inhibitors of indoleamine 2,3-dioxygenase, offer potential avenues for new treatments. Understanding and targeting these interconnected pathways are crucial for developing effective strategies to prevent and manage neurological disorders.

Keywords: Dysbiosis; Gut permeability; Gut–brain axis; Kynurenine pathway; Neuroinflammation; Neurological disorders; Probiotic.

Fig. 1

The molecular composition of the tight junction (TJ). TJs are constituted by the transmembrane proteins occludin, claudins, and junctional adhesion molecule 1 (JAM-1), which seal the paracellular space and connect TJ to the actin cytoskeleton via interaction with proteins from the zona occludens (ZO) family. (With kind permission from Springer Science + Business Media: Histochem. Cell Biol., Tight junctions and the modulation of barrier function in disease, 130(1), 2008, 55, Förster, C., Copyright 2008)

Fig. 2

a General transport pathways: Paracellular, transcellular, and transcytosis. b Transcellular membrane transport: Transport across the apical cell membrane can be via (1) passive transport, which can be via (I) simple diffusion and (II) facilitated diffusion. Facilitated diffusion can, in turn, be either channel-mediated facilitated diffusion or carrier-mediated facilitated diffusion. (2) Active transport, which can be (I) primary active transport and (II) secondary active transport. c Endocytosis/transcytosis: Transport in vesicles that can be via (1) phagocytosis, via specialised cells of the reticuloendothelial system, e.g. neutrophils and macrophages, (2) pinocytosis: Nonspecific internalisation of extracellular fluid (ECF); any dissolved solutes that happen to be in the ECF also internalised and (3) receptor-mediated endocytosis/transcytosis, a highly selective type of endocytosis/transcytosis, by which cells take up specific ligands (Laurent et al. 2016)

Fig. 3

The tryptophan-kynurenine metabolic pathway. TRP tryptophan; IDO indoleamine 2,3-dioxygenase; TDO tryptophan 2,3-dioxygenase; N-fKYN N-formyl-kynurenine; AA anthranilate acid; KYNU kynureninase; KYN kynurenine; KAT kynurenine aminotransferase; KYNA kynerunic acid; KMO kynurenine 3-monooxygenase; 3-HK 3-hydroxykynurenine; HAAH 3-hydroxyanthranilic acid 3,4-hydroxylase; 3-HAA 3-hydroxyanthranilic acid; HAAO 3-hydroxyanthranilicacid 3,4-dioxygenase; AMS 2-aminomuconic-6-semialdehyde; ACMSD 2-amino-3-carboxymuconate-6-semialdehydedecarboxylase; ACMS 2-amino-3-carboxymuconate-6-semialdehyde; AMSD 2-aminomuconic-6-semialdehyde dehydrogenase; QUIN quinolinic acid; QPRT quinolinate phosphoribosyltransferase; PIC picolinic acid; NAD +  nicotinamide adenine dinucleotide