Tag: energy metabolism

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)

A map of metabolic phenotypes in patients with myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease usually presenting after infection. Emerging evidence supports that energy metabolism is affected in ME/CFS, but a unifying metabolic phenotype has not been firmly established. We performed global metabolomics, lipidomics, and hormone measurements, and we used exploratory data analyses to compare serum from 83 patients with ME/CFS and 35 healthy controls.

Some changes were common in the patient group, and these were compatible with effects of elevated energy strain and altered utilization of fatty acids and amino acids as catabolic fuels. In addition, a set of heterogeneous effects reflected specific changes in 3 subsets of patients, and 2 of these expressed characteristic contexts of deregulated energy metabolism. The biological relevance of these metabolic phenotypes (metabotypes) was supported by clinical data and independent blood analyses.

In summary, we report a map of common and context-dependent metabolic changes in ME/CFS, and some of them presented possible associations with clinical patient profiles. We suggest that elevated energy strain may result from exertion-triggered tissue hypoxia and lead to systemic metabolic adaptation and compensation. Through various mechanisms, such metabolic dysfunction represents a likely mediator of key symptoms in ME/CFS and possibly a target for supportive intervention.

Source: Hoel F, Hoel A, Pettersen IK, Rekeland IG, Risa K, Alme K, Sørland K, Fosså A, Lien K, Herder I, Thürmer HL, Gotaas ME, Schäfer C, Berge RK, Sommerfelt K, Marti HP, Dahl O, Mella O, Fluge Ø, Tronstad KJ. A map of metabolic phenotypes in patients with myalgic encephalomyelitis/chronic fatigue syndrome. JCI Insight. 2021 Aug 23;6(16):149217. doi: 10.1172/jci.insight.149217. PMID: 34423789. https://pubmed.ncbi.nlm.nih.gov/34423789/

Human Herpesvirus-6 Reactivation, Mitochondrial Fragmentation, and the Coordination of Antiviral and Metabolic Phenotypes in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multifactorial disorder with many possible triggers. Human herpesvirus (HHV)–6 and HHV-7 are two infectious triggers for which evidence has been growing. To understand possible causative role of HHV-6 in ME/CFS, metabolic and antiviral phenotypes of U2-OS cells were studied with and without chromosomally integrated HHV-6 and with or without virus reactivation using the histone deacetylase inhibitor trichostatin-A. Proteomic analysis was conducted by pulsed stable isotope labeling by amino acids in cell culture analysis.

Antiviral properties that were induced by HHV-6 transactivation were studied in virus-naive A549 cells challenged by infection with influenza-A (H1N1) or HSV-1. Mitochondria were fragmented and 1-carbon metabolism, dUTPase, and thymidylate synthase were strongly induced by HHV-6 reactivation, whereas superoxide dismutase 2 and proteins required for mitochondrial oxidation of fatty acid, amino acid, and glucose metabolism, including pyruvate dehydrogenase, were strongly inhibited. Adoptive transfer of U2-OS cell supernatants after reactivation of HHV-6A led to an antiviral state in A549 cells that prevented superinfection with influenza-A and HSV-1. Adoptive transfer of serum from 10 patients with ME/CFS produced a similar fragmentation of mitochondria and the associated antiviral state in the A549 cell assay.

In conclusion, HHV-6 reactivation in ME/CFS patients activates a multisystem, proinflammatory, cell danger response that protects against certain RNA and DNA virus infections but comes at the cost of mitochondrial fragmentation and severely compromised energy metabolism.

Source: Philipp Schreiner, Thomas Harrer, Carmen Scheibenbogen, Stephanie Lamer, Andreas Schlosser, Robert K. Naviaux and Bhupesh K. Prusty. Human Herpesvirus-6 Reactivation, Mitochondrial Fragmentation, and the Coordination of Antiviral and Metabolic Phenotypes in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. ImmunoHorizons April 1, 2020, 4 (4) 201-215; DOI: https://doi.org/10.4049/immunohorizons.2000006 https://www.immunohorizons.org/content/4/4/201  (Full text)

CD24 Expression and B Cell Maturation Shows a Novel Link With Energy Metabolism: Potential Implications for Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

CD24 expression on pro-B cells plays a role in B cell selection and development in the bone marrow. We previously detected higher CD24 expression and frequency within IgD+ naïve and memory B cells in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) compared with age-matched healthy controls (HC). Here, we investigated the relationship between CD24 expression and B cell maturation.

In vitro stimulation of isolated B cells in response to conventional agonists were used to follow the dynamics of CD24 positivity during proliferation and differentiation (or maturation). The relationship between CD24 expression to cycles of proliferation and metabolism in purified B cells from HC was also investigated using phospho-flow (phosphorylation of AMPK-pAMPK), 1proton nuclear magnetic resonance and Mitotracker Far-red (Mitochondrial mass-MM).

In vitro, in the absence of stimulation, there was an increased percentage of CD24+ viable B cells in ME/CFS patients compared to HC (p < 0.05) following 5 days culture. Following stimulation with B cell agonists, percentage of CD24+B cells in both naïve and memory B cell populations decreased. P < 0.01). There was a negative relationship between percentage of CD24+B cells with MM (R2 = 0.76; p < 0.01), which was subsequently lost over sequential cycles of proliferation.

There was a significant correlation between CD24 expression on B cells and the usage of glucose and secretion of lactate in vitro. Short term ligation of the B cell receptor with anti-IgM antibody significantly reduced the viability of CD24+ memory B cells compared to those cross-linked by anti-IgD or anti-IgG antibody. A clear difference was found between naïve and memory B cells with respect to CD24 expression and pAMPK, most notably a strong positive association in IgD+IgM+ memory B cells.

In vitro findings confirmed dysregulation of CD24-expressing B cells from ME/CFS patients previously suggested by immunophenotype studies of B cells from peripheral blood. CD24-negative B cells underwent productive proliferation whereas CD24+ B cells were either unresponsive or susceptible to cell death upon BCR-engagement alone. We suggest that CD24 expression may reflect variations in energy metabolism on different B cell subsets.

Source: Mensah FFK, Armstrong CW, Reddy V, Bansal AS, Berkovitz S, Leandro MJ, Cambridge G. CD24 Expression and B Cell Maturation Shows a Novel Link With Energy Metabolism: Potential Implications for Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Front Immunol. 2018 Oct 22;9:2421. doi: 10.3389/fimmu.2018.02421. eCollection 2018. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6204382/ (Full article)

Chronic fatigue syndrome patients have alterations in their oral microbiome composition and function

Abstract:

Host-microbe interactions have been implicated in the pathogenesis of chronic fatigue syndrome (CFS), but whether the oral microbiome is altered in CFS patients is unknown. We explored alterations of the oral microbiome in Chinese Han CFS patients using 16S rRNA gene sequencing and alterations in the functional potential of the oral microbiome using PICRUSt.

We found that Shannon and Simpson diversity indices were not different in CFS patients compared to healthy controls, but the overall oral microbiome composition was different (MANOVA, p < 0.01). CFS patients had a higher relative abundance of Fusobacteria compared with healthy controls. Further, the genera Leptotrichia, Prevotella, and Fusobacterium were enriched and Haemophilus, Veillonella, and Porphyromonas were depleted in CFS patients compared to healthy controls. Functional analysis from inferred metagenomes showed that bacterial genera altered in CFS patients were primarily associated with amino acid and energy metabolism.

Our findings demonstrate that the oral microbiome in CFS patients is different from healthy controls, and these differences lead to shifts in functional pathways with implications for CFS pathogenesis. These findings increase our understanding of the relationship between the oral microbiota and CFS, which will advance our understanding of CFS pathogenesis and may contribute to future improvements in treatment and diagnosis.

Source: Wang T, Yu L, Xu C, Pan K, Mo M, Duan M, Zhang Y, Xiong H. Chronic fatigue syndrome patients have alterations in their oral microbiome composition and function. PLoS One. 2018 Sep 11;13(9):e0203503. doi:
10.1371/journal.pone.0203503. eCollection 2018. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0203503 (Full article)

Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome

Abstract:

Myalgic encephalopathy/chronic fatigue syndrome (ME/CFS) is a debilitating disease of unknown etiology, with hallmark symptoms including postexertional malaise and poor recovery. Metabolic dysfunction is a plausible contributing factor.

We hypothesized that changes in serum amino acids may disclose specific defects in energy metabolism in ME/CFS. Analysis in 200 ME/CFS patients and 102 healthy individuals showed a specific reduction of amino acids that fuel oxidative metabolism via the TCA cycle, mainly in female ME/CFS patients. Serum 3-methylhistidine, a marker of endogenous protein catabolism, was significantly increased in male patients.

The amino acid pattern suggested functional impairment of pyruvate dehydrogenase (PDH), supported by increased mRNA expression of the inhibitory PDH kinases 1, 2, and 4; sirtuin 4; and PPARδ in peripheral blood mononuclear cells from both sexes. Myoblasts grown in presence of serum from patients with severe ME/CFS showed metabolic adaptations, including increased mitochondrial respiration and excessive lactate secretion. The amino acid changes could not be explained by symptom severity, disease duration, age, BMI, or physical activity level among patients.

These findings are in agreement with the clinical disease presentation of ME/CFS, with inadequate ATP generation by oxidative phosphorylation and excessive lactate generation upon exertion.

 

Source: Fluge Ø, Mella O, Bruland O, Risa K, Dyrstad SE, Alme K, Rekeland IG, Sapkota D, Røsland GV, Fosså A, Ktoridou-Valen I, Lunde S, Sørland K, Lien K, Herder I, Thürmer H, Gotaas ME, Baranowska KA, Bohnen LM, Schäfer C, McCann A, Sommerfelt K, Helgeland L, Ueland PM, Dahl O, Tronstad KJ. Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome. JCI Insight. 2016 Dec 22;1(21):e89376. doi: 10.1172/jci.insight.89376. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161229/ (Full article)

 

The assessment of the energy metabolism in patients with chronic fatigue syndrome by serum fluorescence emission

Abstract:

CONTEXT: Chronic fatigue syndrome (CFS) is a debilitating fatigue illness that has unknown etiology and lacks an objective diagnostic marker.

OBJECTIVE: To examine the metabolic component of CFS to determine if practitioners can use serum NAD(P)H concentration measurements to monitor metabolism and fatigue status in patients with CFS.

DESIGN: The research team conducted a case-control study, comparing a group of patients who were diagnosed with CFS with a control group of healthy subjects. The team obtained venous blood samples from fasting patients to examine the serum NAD(P)H concentrations.

SETTING: The study occurred at the Riordan Clinic in Witchita, Kansas.

PARTICIPANTS: The study included 44 CFS patients at the Riordan Clinic and 30 healthy control participants. The CFS patients presented a spectrum of symptoms that had existed for at least 6 months: new, unexplained, persistent, or relapsing chronic fatigue that bed rest did not resolve and that was severe enough to reduce daily activity significantly by 50% in conjunction with headache, muscle pain, pain in multiple joints, and unrefreshing sleep. In the control group, the research team enrolled subjects without diagnosis of disease or injury.

OUTCOME MEASURES: The research team determined levels of serum reduced nicotinamide adenine dinucleotides (NADH and NAD[P]H) by measuring serum fluorescence emission at 450 nm. The team then conducted sensitivity and specificity analyses. Results NAD(P)H concentrations in serum of CFS participants averaged 8.0 ± 1.4 (standard deviation [SD]) nmol/mL, while those in the healthy controls averaged 10.8 ± 0.8 (SD) nmol/mL, a statistically significant difference. Using a cut-off concentration of 9.5 nmol/mL, the research team attained a sensitivity of 0.73 and a specificity of 1.0. An analysis of receiver-operator characteristics yielded an area under the curve of 0.9. The research team compared serum NAD(P)H to several endocrine and metabolic lab parameters. Serum NAD(P)H was directly correlated with serum CoQ10 levels and inversely correlated with urine hydroxyhemopyrrolin-2-one levels.

CONCLUSIONS: Based on these findings, the research team proposed using serum NAD(P)H, measured as an intrinsic serum-fluorescence emission, to monitor metabolism and fatigue status in patients with CFS. Following patients NAD(P)H levels over time may aid in selecting therapeutic strategies and monitoring treatment outcomes.

 

Source: Mikirova N, Casciari J, Hunninghake R. The assessment of the energy metabolism in patients with chronic fatigue syndrome by serum fluorescence emission. Altern Ther Health Med. 2012 Jan-Feb;18(1):36-40. https://www.ncbi.nlm.nih.gov/pubmed/22516851