Kynurenines in the Pathogenesis of Multiple Sclerosis: Therapeutic Perspectives

Biernacki, Tamás; Sandi, Dániel; Bencsik, Krisztina; Vécsei, László

doi:10.3390/cells9061564

Cited by 40 publications

(48 citation statements)

References 294 publications

(364 reference statements)

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“…An increasing amount of evidence supports the involvement of kynurenine metabolites and antigen presenting cells expressing IDO1 in neuroinflammatory diseases such as MS ( 13 ). In this study, we found nominally lower levels of KYNA and higher levels of 3HAA in MS patients.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, other microbiota-related metabolites, such as tryptophan and kynurenine metabolites have been shown to have immunomodulatory properties influencing several inflammatory diseases, including MS. Tryptophan can be metabolized both peripherally and in the CNS into neuroactive kynurenines and aryl hydrocarbon receptor (AHR) ligands that are able to modulate local and distant host functions involving inflammation, neurotransmission and complex immune responses. Gut microbiota are also capable of producing these neuroactive kynurenine metabolites making it interesting in relation to SCFAs ( 13 ).…”

Section: Introductionmentioning

confidence: 99%

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Serum Short-Chain Fatty Acids and Associations With Inflammation in Newly Diagnosed Patients With Multiple Sclerosis and Healthy Controls

et al. 2021

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Multiple sclerosis (MS) is a chronic immune-mediated disease characterized by demyelination and neuroaxonal damage in the central nervous system. The etiology is complex and is still not fully understood. Accumulating evidence suggests that our gut microbiota and its metabolites influence the MS pathogenesis. Short-chain fatty acids (SCFAs), such as acetate, propionate and butyrate, are metabolites produced by gut microbiota through fermentation of indigestible carbohydrates. SCFAs and kynurenine metabolites have been shown to have important immunomodulatory properties, and propionate supplementation in MS patients has been associated with long-term clinical improvement. However, the underlying mechanisms of action and its importance in MS remain incompletely understood. We analyzed serum levels of SCFAs and performed targeted metabolomics in relation to biomarkers of inflammation, and clinical and MRI measures in newly diagnosed patients with relapsing-remitting MS before their first disease modifying therapy and healthy controls (HCs). We demonstrated that serum acetate levels were nominally reduced in MS patients compared with HCs. The ratios of acetate/butyrate and acetate/(propionate + butyrate) were significantly lower in MS patients in a multivariate analysis (orthogonal partial least squares discriminant analysis; OPLS-DA). The mentioned ratios and acetate levels correlated negatively with the pro-inflammatory biomarker IFNG, indicating an inverse relation between acetate and inflammation. In contrast, the proportion of butyrate was found higher in MS patients in the multivariate analysis, and both butyrate and valerate correlated positively with proinflammatory cytokines (IFNG and TNF), suggesting complex bidirectional regulatory properties of SCFAs. Branched SCFAs were inversely correlated with clinical disability, at a nominal significance level. Otherwise SCFAs did not correlate with clinical variables or MRI measures. There were signs of an alteration of the kynurenine pathway in MS, and butyrate was positively correlated with the immunomodulatory metabolite 3-hydroxyanthranilic acid. Other variables that influenced the separation between MS and HCs were NfL, ARG1 and IL1R1, D-ribose 5-phosphate, pantothenic acid and D-glucuronic acid. In conclusion, we provide novel results in this rapidly evolving field, emphasizing the complexity of the interactions between SCFAs and inflammation; therefore, further studies are required to clarify these issues before supplementation of SCFAs can be widely recommended.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Serum Short-Chain Fatty Acids and Associations With Inflammation in Newly Diagnosed Patients With Multiple Sclerosis and Healthy Controls

et al. 2021

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“…The kynurenine pathway ( Figure 2 ) is responsible for processing >90% of the Trp in humans, producing kynurenine and niacin as the major metabolites. The build-up of these and other metabolites of this pathway can lead to multiple pathological conditions, such as AIDS-related dementia, multiple sclerosis, and ischemic brain injury [ 46 , 47 , 48 , 49 , 50 ], although the molecular mechanisms are not fully clear.…”

Section: Metabolism Of Trpmentioning

confidence: 99%

“…Perhaps the most enigmatic aspect of Trp metabolism that has defied a clear molecular explanation for years is its intersection with various normal and pathological conditions, such as cancer, multiple sclerosis, transplantation, peripheral and CNS disorders, and recently in SARS-CoV-2 infection [ 47 , 48 , 49 , 50 , 109 , 110 , 111 ]. For the sake of brevity, the focus in this review is on selected branches of immune regulation, a key character in which is indole 2,3-dioxygenase (IDO), the rate-limiting first enzyme in the kynurenine pathway of Trp degradation ( Figure 2 ).…”

Section: Intersection Between Trp Degradation and Immunitymentioning

confidence: 99%

The Uniqueness of Tryptophan in Biology: Properties, Metabolism, Interactions and Localization in Proteins

Barik

2020

IJMS

121

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Tryptophan (Trp) holds a unique place in biology for a multitude of reasons. It is the largest of all twenty amino acids in the translational toolbox. Its side chain is indole, which is aromatic with a binuclear ring structure, whereas those of Phe, Tyr, and His are single-ring aromatics. In part due to these elaborate structural features, the biosynthetic pathway of Trp is the most complex and the most energy-consuming among all amino acids. Essential in the animal diet, Trp is also the least abundant amino acid in the cell, and one of the rarest in the proteome. In most eukaryotes, Trp is the only amino acid besides Met, which is coded for by a single codon, namely UGG. Due to the large and hydrophobic π-electron surface area, its aromatic side chain interacts with multiple other side chains in the protein, befitting its strategic locations in the protein structure. Finally, several Trp derivatives, namely tryptophylquinone, oxitriptan, serotonin, melatonin, and tryptophol, have specialized functions. Overall, Trp is a scarce and precious amino acid in the cell, such that nature uses it parsimoniously, for multiple but selective functions. Here, the various aspects of the uniqueness of Trp are presented in molecular terms.

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“…In addition to the aforementioned research articles, this Special Issue of Cells also published three review articles that cover different research topics in MS. Forsthuber and colleagues [ 6 ] summarized the role of memory CD4+ T cells in autoimmune diseases, with specific focus on MS and EAE. Vecsei and colleagues [ 7 ] discussed the importance of kynurenines in the pathogenesis of MS. Last but not least, we [ 8 ] provided a comprehensive review on the role of granulocyte-macrophage colony-stimulating factor (GM-CSF) in mediating neuroinflammation, and discussed the potential of targeting GM-CSF in the treatment of MS.…”

mentioning

confidence: 99%