Tag: kynurenic acid

A Thesis on Immune Differences in Chronic Fatigue Syndrome, Fibromyalgia and Healthy Controls

Abstract:

Background: Chronic Fatigue Syndrome (CFS) and Fibromyalgia (FM) are debilitating disorders that significantly affect the daily lives of those suffering from them, as well as their loved ones. Both conditions have overlapping clinical features that resemble inflammatory disorders, and overlapping symptoms, such as depression, suggest central nervous system (CNS) involvement. The role of the immune system’s soluble messengers in the pathogenesis of CFS and FM has been under investigation, but so far the results are inconclusive. In addition, there is growing evidence that the kynurenine pathway is involved in the pathology of diseases related to the CNS, yet the role of each metabolite is not clear. The relationship between kynurenine metabolism and CFS and FM has not been extensively explored. Few studies have simultaneously examined the immunological status in both CFS and FM, making this thesis the first to comprehensively evaluate the potential distinct immunological differences between the two disorders.

Objective: The objective of this study was to compare the CFS and FM with healthy controls, regarding the levels of several soluble blood markers related to the immune system. The markers chosen were:

  • The inflammatory marker high-sensitive CRP (hsCRP)
  • The following cytokines and chemokines: Interferon (IFN)-γ, Interleukin (IL)-1β, IL1ra, IL-4, IL-6, IL-8, IL-10, IL-17, Interferon gamma-induced protein (IP)-10, Monocyte Chemoattractant Protein (MCP)-1, Transforming Growth Factor (TGF)-β1, TGF-β2, TGF-β3 and Tumour Necrosis Factor (TNF)-α
  • The metabolites and their ratios of the kynurenine pathway: Tryptophan (Try), kynurenine (Kyn), kynurenic acid (KA), 3-hydroxykykynurenine (HK), anthranilic acid (AA), xanthurenic acid (XA), 3-hydroxyanthranilic acid (HAA), quinolinic acid (QA) and picolinic acid (Pic).

Method: The population consisted of three groups: CFS patients (n = 49), FM patients (n = 58), and healthy controls (n = 54). All participants were females aged 18–60. Patients were recruited from a specialised university hospital clinic and controls were recruited by advertisement among the staff and students at the hospital and university.

Plasma levels of hsCRP were analysed at the hospital. The cytokines and chemokines IFN-γ, IL-1β, IL-1ra, xii IL-4, IL-6, IL-8, IL-10, IL-17, IP-10, MCP-1, TGF-β1, TGF-β2, TGF-β3, and TNF-α were analysed by multiplex. Kynurenine metabolites were analysed by LC-MS/MS.

Linear regression models of log-transformed data for hsCRP and the kynurenine metabolites were conducted for comparison of the three groups CFS, FM and controls. The Kruskal-Wallis test was used to analyse differences of cytokines between the three groups. Main findings were controlled for age, body mass index (BMI), and symptoms of anxiety and depression.

Results: hsCRP levels were significantly higher for both the CFS and FM groups compared to healthy controls when adjusting for age and BMI (p = .006). There was no difference between the two patient groups. Level of hsCRP was affected by BMI (p < .001) but not age.

MCP-1 was significantly increased in both patient groups compared to healthy controls (p < .001). IL-1β, Il-4, IL-6, TNF-α, TGF-β1, TGF-β2, TGF-β3 (all p < .001), IL-10 (p = .003) and IL17 (p = .002) all were significantly lower in the patient groups compared to healthy controls. IFN-γ was significantly lower in the FM group (p < .001). For IL-8, IP-10 and IL1ra there were no significant difference.

QA differed between CFS and FM patients (p = .036) and was related to higher levels of BMI (p = .002). The KA/QA ratio was lower for CFS patients compared to healthy controls (p = .016). The KA/HK ratio was lower for FM patients compared to healthy controls, and this lower ratio was associated with increased symptoms of pain (p = .002). The kynurenine aminotransferase II (KAT II) enzymatic activity given by XA/HK was lower for FM patients compared to healthy controls (p = .013). In addition, BMI was negatively associated with enhanced KAT II enzymatic activity (p = .039).

Symptoms of anxiety and depression were not associated with any of the immune markers studied.

Conclusion: In our material hsCRP and MCP-1 are increased in patients both with CFS and with FM, while several other cytokines are either similar or significantly lower in patients than controls. Our study also indicates associations between kynurenine metabolism and CFS and FM. Kynurenine also is associated with single symptoms such as fatigue and pain. Forthcoming studies indicating interactions and causative effects, or restoration of the inflammatory status, may place cytokines and kynurenine metabolites as a target for treatment as well as prevention of these conditions in the future.

Source: Groven, Nina. A Thesis on Immune Differences in Chronic Fatigue Syndrome, Fibromyalgia and Healthy Controls. PhD Thesis [Norwegian University of Science and Technology] https://ntnuopen.ntnu.no/ntnu-xmlui/handle/11250/3072207 (Full text available as PDF file)

On the question of infectious aetiologies for multiple sclerosis, schizophrenia and the chronic fatigue syndrome and their treatment with antibiotics

Abstract:

Close similarities in the courses of multiple sclerosis and schizophrenia laid the theoretical ground for attempting to find a common infectious aetiology for the two diseases. Chlamydia pneumoniae, which belongs to the rickettsial family of microorganisms has been linked to both diseases. It is postulated that since rickettsial microorganisms are ubiquitous in human populations they and the human species normally live in peaceful coexistence. In rare cases, for unknown reasons, varieties of them may become aggressive and pathogenic.

The kynurenic acid hypothesis of schizophrenia has attracted much attention. It also seems to have initiated a paradigmatic shift from the hitherto prevailing serological research approach to one which focuses on immunological factors.

An open clinical pilot study in which, during 2006, eight female and five male patients with psychotic symptoms were treated with a combination of antibiotics is presented, to which, in the beginning of 2007 two female patients suffering from severe and long standing chronic fatigue syndrome were added. On one year follow-up, six out of the eight female patients showed stable excellent treatment results, whereas two were rated as showing significant treatment results. Four of the five men who entered the study were suffering from chronic schizophrenia, whereas the fifth, was a case of severe acute catatonic schizophrenia.

Two of the male patients showed significant treatment results, whereas three of them were rated as having had a slight to moderate improvement. No less than three of the women had suffered their first episode of psychosis after giving birth to their first (and only) child. This finding, as these women all responded excellently to treatment with antibiotics, indicates that post partum psychosis could be regarded as an infectious complication of childbirth of, as to the causative agent, unknown aetiology. High priority ought therefore be given to initiate controlled clinical trials with antibiotic treatment of this serious condition. The otherwise promising results of the pilot study seem to warrant further and controlled clinical trials with treatment with antibiotics of patients with psychotic symptoms.

As the second patient with psychotic symptoms to enter the study, had a long standing history of chronic fatigue, where an initial treatment with the antidepressant fluoxetine had only worsened her condition, whereas ninety days of treatment with antibiotics, combined with vitamin B injections, effected a complete recovery, the author decided, when two patients with long standing and incapacitating chronic fatigue syndromes sought the clinic in February and March 2007, to include them in the study. The first of them, after sixty days of treatment with antibiotics showed excellent treatment results on follow-up one year later, whereas the second, who also took the combination of antibiotics for sixty days, was rated as having shown a significant improvement.

Comment in: Hypotheses concerning rickettsial microorganisms, autoimmune diseases and new treatment strategies. [Med Hypotheses. 2010]

 

Source: Frykholm BO. On the question of infectious aetiologies for multiple sclerosis, schizophrenia and the chronic fatigue syndrome and their treatment with antibiotics. Med Hypotheses. 2009 Jun;72(6):736-9. doi: 10.1016/j.mehy.2008.11.045. Epub 2009 Mar 6. https://www.ncbi.nlm.nih.gov/pubmed/19269110