Tag: kynurenine pathways

Tryptophan Metabolites, Cytokines, and Fatty Acid Binding Protein 2 in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) differ for triggers, mode of start, associated symptoms, evolution, and biochemical traits. Therefore, serious attempts are underway to partition them into subgroups useful for a personalized medicine approach to the disease. Here, we investigated clinical and biochemical traits in 40 ME/CFS patients and 40 sex- and age-matched healthy controls. Particularly, we analyzed serum levels of some cytokines, Fatty Acid Binding Protein 2 (FAPB-2), tryptophan, and some of its metabolites via serotonin and kynurenine.
ME/CFS patients were heterogeneous for genetic background, trigger, start mode, symptoms, and evolution. ME/CFS patients had higher levels of IL-17A (p = 0.018), FABP-2 (p = 0.002), and 3-hydroxykynurenine (p = 0.037) and lower levels of kynurenine (p = 0.012) and serotonin (p = 0.045) than controls. Changes in kynurenine and 3-hydroxykynurenine were associated with increased kynurenic acid/kynurenine and 3-hydroxykynurenine/kynurenine ratios, indirect measures of kynurenine aminotransferases and kynurenine 3-monooxygenase enzymatic activities, respectively. No correlation was found among cytokines, FABP-2, and tryptophan metabolites, suggesting that inflammation, anomalies of the intestinal barrier, and changes of tryptophan metabolism may be independently associated with the pathogenesis of the disease.
Interestingly, patients with the start of the disease after infection showed lower levels of kynurenine (p = 0.034) than those not starting after an infection. Changes in tryptophan metabolites and increased IL-17A levels in ME/CFS could both be compatible with anomalies in the sphere of energy metabolism. Overall, clinical traits together with serum biomarkers related to inflammation, intestine function, and tryptophan metabolism deserve to be further considered for the development of personalized medicine strategies for ME/CFS.
Source: Manuela Simonato, Stefano Dall’Acqua, Caterina Zilli, Stefania Sut, Romano Tenconi, Nicoletta Gallo, Paolo Sfriso, Leonardo Sartori, Francesco Cavallin, Ugo Fiocco, Paola Cogo, Paolo Agostinis, Anna Aldovini, Daniela Bruttomesso, Renzo Marcolongo, Stefano Comai, and Aldo Baritussio. Tryptophan Metabolites, Cytokines, and Fatty Acid Binding Protein 2 in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Biomedicines 2021, 9(11), 1724; https://doi.org/10.3390/biomedicines9111724 (registering DOI) https://www.mdpi.com/2227-9059/9/11/1724/htm (Full text)

Kynurenine Clinical Trial for ME / CFS

Open Medicine Foundation is excited to announce its support of an initiation of a clinical trial to understand potential disturbances in the tryptophan metabolism and to test the benefits of treating people with Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME / CFS) with Kynurenine. Kynurenine is naturally produced in the body, is a key metabolite in the tryptophan metabolism, and serves several roles in the immune system and inflammation. The Kynurenine clinical trial will be conducted at the ME / CFS Collaborative Research Center at Uppsala University under the supervision of Dr. Jonas Bergquist. OMF has provided support to initiate the study in a randomized, double-blind, placebo-controlled, crossover study. The purpose of the study is to evaluate whether kynurenine is directly connected to ME / CFS patient symptom severity.

Read more HERE.

Kynurenine metabolites and ratios differ between Chronic Fatigue Syndrome, Fibromyalgia, and healthy controls

Abstract:

Background: There is growing evidence that the kynurenine pathway is involved in the pathology of diseases related to the central nervous system (CNS), because of the neuroprotective or neurotoxic properties of certain metabolites, yet the role of each metabolite is not clear. The pathology of Chronic Fatigue Syndrome (CFS) and Fibromyalgia (FM) is currently under investigation, and the overlapping symptoms such as depression suggest that the CNS may be involved. These symptoms may be driven by enhanced neurotoxicity and/or diminished neuroprotection. However, the kynurenine metabolite status has not been well studied in these two possible related disorders of CFS and FM. The objective of this study was to investigate the metabolites and ratios of the kynurenine pathway in CFS and FM compared to healthy controls and examine the possible correlations with symptoms of anxiety and depression.

Method: In this study, females aged 18-60 were included: 49 CFS patients; 57 FM patients; and 54 healthy controls. Blood plasma was analysed for the following metabolites involved in the kynurenine pathway: Tryptophan, kynurenine, kynurenic acid (KA), 3-hydroxykykynurenine (HK), anthranilic acid, xanthurenic acid (XA), 3-hydroxyanthranilic acid, quinolinic acid (QA) and picolinic acid. The concentrations of these metabolites, as well as the ratios of different metabolites indicating enzymatic activity, were compared between the groups. Findings were controlled for age, body mass index (BMI), and symptoms of anxiety and depression.

Results: QA differed between CFS and FM patients (β = .144, p = .036) and was related to higher levels of BMI (β = .017, p = .002). The neuroprotective ratio given by KA/QA was lower for CFS patients compared to healthy controls (β = -.211, p = .016). The neuroprotective ratio given by KA/HK was lower for FM patients compared to healthy controls, and this lower neuroprotective ratio was associated with increased symptoms of pain. The kynurenine aminotransferase II (KAT II) enzymatic activity given by XA/HK was lower for FM patients compared to healthy controls (β = -.236, p = .013). In addition, BMI was negatively associated with enhanced KAT II enzymatic activity (β = -.015, p = .039). Symptoms of anxiety and depression were not associated with the metabolites or ratios studied.

Conclusion: Our study indicates associations between kynurenine metabolism and CFS and FM as well as characteristic symptoms like fatigue and pain. Forthcoming studies indicating a causative effect may place kynurenine metabolites as a target for treatment as well as prevention of these conditions in the future.

Source: Groven N, Reitan SK, Fors EA, Guzey IC. Kynurenine metabolites and ratios differ between Chronic Fatigue Syndrome, Fibromyalgia, and healthy controls. Psychoneuroendocrinology. 2021 May 27;131:105287. doi: 10.1016/j.psyneuen.2021.105287. Epub ahead of print. PMID: 34090138. https://pubmed.ncbi.nlm.nih.gov/34090138/

Persistent fatigue induced by interferon-alpha: a novel, inflammation-based, proxy model of chronic fatigue syndrome

Abstract:

The role of immune or infective triggers in the pathogenesis of Chronic Fatigue Syndrome (CFS) is not yet fully understood. Barriers to obtaining immune measures at baseline (i.e., before the trigger) in CFS and post-infective fatigue model cohorts have prevented the study of pre-existing immune dysfunction and subsequent immune changes in response to the trigger. This study presents interferon-alpha (IFN-α)-induced persistent fatigue as a model of CFS. IFN-α, which is used in the treatment of chronic Hepatitis C Virus (HCV) infection, induces a persistent fatigue in some individuals, which does not abate post-treatment, that is, once there is no longer immune activation. This model allows for the assessment of patients before and during exposure to the immune trigger, and afterwards when the original trigger is no longer present.

Fifty-five patients undergoing IFN-α treatment for chronic HCV were assessed at baseline, during the 6-12 months of IFN-α treatment, and at six-months post-treatment. Measures of fatigue, cytokines and kynurenine pathway metabolites were obtained. Fifty-four CFS patients and 57 healthy volunteers completed the same measures at a one-off assessment, which were compared with post-treatment follow-up measures from the HCV patients. Eighteen patients undergoing IFN-α treatment (33%) were subsequently defined as having ‘persistent fatigue’ (the proposed model for CFS), if their levels of fatigue were higher six-months post-treatment than at baseline; the other 67% were considered ‘resolved fatigue’.

Patients who went on to develop persistent fatigue experienced a greater increase in fatigue symptoms over the first four weeks of IFN-α, compared with patients who did not (Δ Treatment Week (TW)-0 vs. TW4; PF: 7.1 ± 1.5 vs. RF: 4.0 ± 0.8, p = 0.046). Moreover, there was a trend towards increased baseline interleukin (IL)-6, and significantly higher baseline IL-10 levels, as well as higher levels of these cytokines in response to IFN-α treatment, alongside concurrent increases in fatigue. Levels increased to more than double those of the other patients by Treatment Week (TW)4 (p =  0.011 for IL-6 and p = 0.001 for IL-10).

There was no evidence of an association between persistent fatigue and peripheral inflammation six-months post-treatment, nor did we observe peripheral inflammation in the CFS cohort. While there were changes in kynurenine metabolites in response to IFN-α, there was no association with persistent fatigue. CFS patients had lower levels of the ratio of kynurenine to tryptophan and 3-hydroxykynurenine than controls. Future studies are needed to elucidate the mechanisms behind the initial exaggerated response of the immune system in those who go on to experience persistent fatigue even if the immune trigger is no longer present, and the change from acute to chronic fatigue in the absence of continued peripheral immune activation.

Source: Russell A, Hepgul N, Nikkheslat N, Borsini A, Zajkowska Z, Moll N, Forton D, Agarwal K, Chalder T, Mondelli V, Hotopf M, Cleare A, Murphy,  G, Foster G, Wong T, Schütze GA, Schwarz MJ, Harrison N, Zunszain PA, Pariante CM. Persistent fatigue induced by interferon-alpha: a novel, inflammation-based, proxy model of chronic fatigue syndrome. Psychoneuroendocrinology. 2018 Dec 14. pii: S0306-4530(18)30196-3.  doi: 10.1016/j.psyneuen.2018.11.032. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/30567628

The Many Neuroprogressive Actions of Tryptophan Catabolites (TRYCATs) that may be Associated with the Pathophysiology of Neuro-Immune Disorders

Abstract:

Many, if not all, chronic medical, neurodegenerative and neuroprogressive illnesses are characterised by chronic immune activation, oxidative and nitrosative stress (O&NS) and systemic inflammation. These factors, notably elevated pro-inflammatory cytokines, activate indoleamine 2,3-dioxygenase (IDO) leading to an upregulated tryptophan catabolite (TRYCAT) pathway of tryptophan degradation in the periphery and in the brain. In such conditions the TRYCAT pathway becomes the predominant system for tryptophan degradation in all body compartments.

In this paper we review the pathways whereby TRYCATs may play a role in neuro-inflammatory and neuroprogressive disease. Thus chronic activation of the TRYCAT pathway leads to the production of a range of neuroactive, neuroprotective and neurotoxic TRYCATs. Some TRYCATs such as quinolinic acid act as potent neurotoxins which inhibit ATP production by mitochondria, provoke increases in O&NS, disrupt neuron glial communication and blood brain barrier integrity, induce apoptosis of glial cells, directly damage neurons and function as a N-methyl D-aspartate (NMDA) receptor agonist.

Other TRYCATs such as kynurenic acid function as antagonists of NMDA, α- amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and kainate receptors and act to regulate levels of glutamate and dopamine.

The neuroprotective functions of this TRYCAT are likely exercised via engagement with alpha7 nicotinic acetylcholine and aryl hydrocarbon receptors but the neuroprotective effects stemming from elevated kynurenic acid levels come at the price of severely compromised neurocognitive function and emotional processing. Other TRYCATS also possess neurotoxic or neuroprotective properties via pro-oxidant and antioxidant effects.

Here we discuss the involvement of the above mentioned TRYCAT pathways in schizophrenia, Alzheimer’s disease and chronic fatigue syndrome.

Source: Morris G, Carvalho AF, Anderson G, Galecki P, Maes M. The Many Neuroprogressive Actions of Tryptophan Catabolites (TRYCATs) that may be Associated with the Pathophysiology of Neuro-Immune Disorders. Curr Pharm Des. 2016;22(8):963-77. https://www.ncbi.nlm.nih.gov/pubmed/26667000

 

Kynurenine Pathway Pathologies: do Nicotinamide and Other Pathway Co-Factors have a Therapeutic Role in Reduction of Symptom Severity, Including Chronic Fatigue Syndrome (CFS) and Fibromyalgia (FM)

Abstract:

The definition of dual tryptophan pathways has increased the understanding of the mind-body, body-mind dichotomy. The serotonergic pathway highlights the primary (endogenous) psychiatric disorders. The up-regulation of the kynurenine pathway by physical illnesses can cause neuropathic and immunological disorders1 associated with secondary neuropsychiatric symptoms.

Tryptophan and nicotinamide deficiencies fall within the protein energy malnutrition (PEM) spectrum. They can arise if the kynurenine pathway is stressed by primary or secondary inflammatory conditions and the consequent imbalance of available catabolic/anabolic substrates may adversely influence convalescent phase efficiency. The replacement of depleted or reduced NAD+ levels and other cofactors can perhaps improve the clinical management of these disorders.

Chronic fatigue syndrome (CFS) and fibromyalgia (FM) appear to meet the criteria of a tryptophan-kynurenine pathway disorder with potential neuroimmunological sequelae. Aspects of some of the putative precipitating factors have been previously outlined.2,3 An analysis of the areas of metabolic dysfunction will focus on future directions for research and management.

 

Source: Blankfield A. Kynurenine Pathway Pathologies: do Nicotinamide and Other Pathway Co-Factors have a Therapeutic Role in Reduction of Symptom Severity, Including Chronic Fatigue Syndrome (CFS) and Fibromyalgia (FM). Int J Tryptophan Res. 2013 Jul 21;6(Suppl 1):39-45. doi: 10.4137/IJTR.S11193. Print 2013. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3729338/ (Full article)

 

A Brief Historic Overview of Clinical Disorders Associated with Tryptophan: The Relevance to Chronic Fatigue Syndrome (CFS) and Fibromyalgia (FM)

Abstract:

Last century there was a short burst of interest in the tryptophan related disorders of pellagra and related abnormalities that are usually presented in infancy.1,2 Nutritional physiologists recognized that a severe human dietary deficiency of either tryptophan or the B group vitamins could result in central nervous system (CNS) sequelae such as ataxia, cognitive dysfunction and dysphoria, accompanied by skin hyperpigmentation.3,4 The current paper will focus on the emerging role of tryptophan in chronic fatigue syndrome (CFS) and fibromyalgia (FM).

 

Source: Blankfield A. A Brief Historic Overview of Clinical Disorders Associated with Tryptophan: The Relevance to Chronic Fatigue Syndrome (CFS) and Fibromyalgia (FM). Int J Tryptophan Res. 2012;5:27-32. doi: 10.4137/IJTR.S10085. Epub 2012 Sep 17. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3460668/ (Full article)

 

Kynurenine pathway Hypothesis: The nature of the chronic Fatigue syndrome (cFs) Revisited

Moderate physicians consider CFS to be missed diagnoses of uncommon illnesses with atypical features. Hartnup (heterozygotes), Lyme and Whipples—like diseases are examples of conditions which fit these clinical ambiguities. The detractors claim it is non-existent. The protractors complain CFS is excluded from standard medical texts. A broad overview of medical literature and support group newsletters, render these opposing views substantially incorrect.

The patient presents with a confounding array of neurological, mental, gastrointestinal, musculoskeletal and perhaps dermatological and visual signs and symptoms. Episodic night sweats can also be reported. Lack of energy, concentration and mobility, limit lifestyle. These symptom constellations evolve and fluctuate in a seemingly random order and can become entrenched. Alcohol intake, protracted steroid therapy and overt or latent infections usually aggravate the course of CFS.

You can read the rest of this article here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3195222/

 

Source: Blankfield A. Kynurenine pathway Hypothesis: The nature of the Chronic Fatigue Syndrome (CFS) Revisited. Int J Tryptophan Res. 2011;4:47-8. doi: 10.4137/IJTR.S7898. Epub 2011 Jul 31. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3195222/ (Full article)