Tag: fatigue

Alterations in gut microbiota and associated metabolites in patients with chronic fatigue syndrome

Abstract:

To investigate differences in gut microbiota composition and short-chain fatty acids (SCFAs) metabolism between patients with Chronic Fatigue Syndrome (CFS) and Healthy Controls (HC), and to explore their associations with the CFS pathogenesis. This case-control study included 80 subjects, comprising 40 patients with CFS and 40 age- and sex-matched HC.

Fecal microbial community structure was analyzed using 16S rRNA gene high-throughput sequencing. Fecal SCFAs concentrations were quantified using Gas Chromatography-Mass Spectrometry (GC-MS). Spearman correlation analysis with false discovery rate (FDR) adjustment was performed to elucidate associations among gut microbiota, SCFAs, and clinical scores.

Compared to the HC group, the CFS group exhibited reduced gut microbiota α-diversity (e.g., ACE, Chao1, Shannon indices, all P < 0.01) and significantly altered β-diversity (ADONIS, P = 0.006). After FDR adjustment, fecal levels of acetate, butyrate, isobutyrate, and isovalerate remained significantly lower in the CFS group (all q < 0.05). Differential abundance analysis revealed a significant reduction in key taxa including the phylum Firmicutes (q = 0.010), class Verrucomicrobiae (q = 0.038), order Clostridiales (q = 0.043), and families Rikenellaceae (q = 0.011) and Ruminococcaceae (q = 0.049). Spearman correlation analysis solidified functional connections: key SCFA-producing taxa (e.g., Faecalibacterium, Subdoligranulum, Ruminococcaceae) were positively correlated with butyrate levels (r = 0.52-0.56, all q < 0.05).

Furthermore, reduced abundances of Rikenellaceae and Alistipes were associated with lower SF-36 scores (r = 0.26, q = 0.032) and higher fatigue scores (FSS/FS-14, r = – 0.28 to – 0.30, q < 0.05). Isovalerate levels were negatively correlated with FS-14 scores (r = – 0.307, q = 0.014). Among CFS patients, those with higher dietary fiber intake had significantly higher levels of acetate and isovalerate than those with lower intake (both q < 0.05).

Patients with CFS exhibit significant gut dysbiosis and abnormal SCFA metabolism. The reduction in key SCFA-producing taxa, their positive correlations with SCFAs levels, and the negative correlations of both with fatigue severity solidify a functional link between gut microbial depletion, reduced SCFAs, and clinical symptoms in CFS. Higher dietary fiber intake may partially ameliorate SCFAs metabolic disturbances in CFS patients.

Source: Cheng X, Wang W, Xu T, Wang Y, Zhen X, Man W, Gao S, Yin Y. Alterations in gut microbiota and associated metabolites in patients with chronic fatigue syndrome. Sci Rep. 2025 Dec 12;15(1):43681. doi: 10.1038/s41598-025-27564-y. PMID: 41387992; PMCID: PMC12700865. https://pmc.ncbi.nlm.nih.gov/articles/PMC12700865/ (Full text)

The association of fatigue and pain with cognitive test performance in patients with myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Objectives: Patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) typically perform worse on cognitive tasks compared to controls. The present study explored the independent associations of fatigue and pain symptoms with cognitive performance in a large sample of patients who met CDC criteria of CFS (n = 1375), of whom most also met NICE/ IOM criteria (n = 1072). Moreover, we tested the hypothesis that these associations become stronger with older age and longer symptom duration.

Methods: Questionnaires and diaries were employed assessing fatigue and pain severity, together with the impact of health problems on daily life (using the SF-36 ‘Physical Functioning’ and ‘Bodily Pain’ subscales). Cognitive outcomes consisted of speeded performance measures, namely the Symbol Digit Test, motor speed, simple and choice reaction time (RT), and response inhibition. Categorical regression with lasso penalization was employed to identify relevant correlates of cognitive performance.

Results: Fatigue severity remained as only correlate of response inhibition. For the other cognitive outcomes, fatigue severity consistently emerged together with contributions of pain severity, bodily pain and/or physical functioning. Restricting these analyses to those patients meeting NICE/IOM criteria revealed overall similar results. Age, not symptom duration, moderated several relationships, showing more pronounced associations between cognitive performance and pain severity, physical functioning, and bodily pain with older age.

Conclusions: This study highlights that a multidimensional nature of symptoms, including fatigue and pain severity, and the impact on daily-life functioning, relate to lower cognitive performance in patients with ME/CFS. Studies are needed to identify the direction and potential causality of these associations.

Source: Oosterman JM, van der Schaaf M, de Kleijn WPE, Kuut TA, Brazil IA, Knoop H. The association of fatigue and pain with cognitive test performance in patients with myalgic encephalomyelitis/chronic fatigue syndrome. J Psychosom Res. 2025 Oct 3;199:112401. doi: 10.1016/j.jpsychores.2025.112401. Epub ahead of print. PMID: 41101039. https://www.sciencedirect.com/science/article/pii/S0022399925003654 (Full text)

Understanding Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Physical Fatigue Through the Perspective of Immunosenescence

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating illness marked by persistent fatigue, yet its mechanisms remain unclear. Growing evidence implicates immunosenescence-the age-related decline in immune function-in the onset and persistence of fatigue.

Methods: This review synthesizes clinical and experimental data to examine how immunosenescence contributes to ME/CFS. We focus on chronic inflammation, senescent immune phenotypes, mitochondrial dysfunction, and neuroendocrine imbalance, with emphasis on maladaptive crosstalk among immune, muscular, neuroendocrine, and vascular systems.

Results: Aging immune cells drive chronic inflammation that impairs mitochondrial ATP production and promotes muscle catabolism. Concurrently, HPA-axis suppression and β2-adrenergic dysfunction amplify immune dysregulation and energy imbalance. Together, these processes illustrate how immunosenescence sustains pathological cross-organ signaling underlying systemic fatigue.

Conclusion: Immunosenescence provides a unifying framework linking immune, metabolic, and neuroendocrine dysfunction in ME/CFS. Recognizing cross-organ communication highlights its clinical relevance, suggesting biomarkers such as cytokines and exhaustion markers, and supports integrated therapeutic strategies targeting immune and metabolic networks.

Source: Luo Y, Xu H, Xiong S, Ke J. Understanding Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Physical Fatigue Through the Perspective of Immunosenescence. Compr Physiol. 2025 Oct;15(5):e70056. doi: 10.1002/cph4.70056. PMID: 41017304. https://pubmed.ncbi.nlm.nih.gov/41017304/

Exploration of Intersections and Divergences of Long COVID and Chronic Fatigue Syndrome

Abstract:

Background: Fatigue is the most common symptom of Long COVID (LC), defined by persistent or newly emerging symptoms that develop at least three months after an initial SARS-CoV-2 infection, in the absence of other identifiable cause. This study investigates the prevalence of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) as a potential comorbidity of LC.

Methods: The study enrolled 37 adult controls with no documented SARS-CoV-2 infection and 32 individuals with a history of infection, categorized as LC-yes (with LC symptoms) and LC-no (without LC symptoms). ME/CFS diagnosis was based on the International Consensus Criteria (ICC).

Results: Among LC-yes cases, the most frequently reported symptoms included post-exertional malaise (PEM); neurosensory, perceptual, or motor disturbances; cognitive impairment; sleep disturbances; pain; impaired thermoregulation; and flu-like symptoms, all occurring significantly more than in the LC-no or control groups. All individuals in the LC-yes group reported PEM. ME/CFS was diagnosed in three LC-yes cases (18.8%), one LC-no case (6.7%), and four control subjects (10.8%), with no statistically significant differences observed among groups. Experiencing more than six symptoms during acute infection, such as fatigue, loss of taste or smell, headache, fever, cough, myalgia, sore throat, shortness of breath, rhinorrhea, and diarrhea, was associated with a twofold higher risk of developing LC.

Conclusion: A substantial proportion of LC-yes individuals experienced PEM; neurosensory, perceptual, or motor disturbances; cognitive impairment; and sleep disturbances, with rates significantly exceeding those in the LC-no and control groups. Nevertheless, only a minority of LC-yes cases (18.8%) satisfied criteria for the ME/CFS, and the prevalence did not significantly differ from LC-no and controls. These findings suggest that while many symptoms of LC overlap with those of ME/CFS, only a subset of LC cases meet established ME/CFS diagnostic criteria.

Source: Kouyoumdjian JA, Yamamoto LA, Graca CR. Exploration of Intersections and Divergences of Long COVID and Chronic Fatigue Syndrome. Cureus. 2025 Aug 20;17(8):e90607. doi: 10.7759/cureus.90607. PMID: 40978825; PMCID: PMC12448662. https://pmc.ncbi.nlm.nih.gov/articles/PMC12448662/ (Full text)

Solriamfetol improves daily fatigue symptoms in adults with myalgic encephalomyelitis/chronic fatigue syndrome after 8 weeks of treatment

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a long-term illness with no treatment options that address the disease directly. Solriamfetol is a selective dual norepinephrine-dopamine reuptake inhibitor that promotes wakefulness in obstructive sleep apnea and narcolepsy.

Aims: This study evaluated the efficacy and safety of solriamfetol for fatigue symptoms in adults with ME/CFS over 8 weeks of treatment.

Methods: This was a phase 4, double-blind, randomized, placebo-controlled trial of solriamfetol in adults with ME/CFS. Eligible participants (N = 38) were randomly assigned to receive 75 mg (titrated to 150 mg as needed) solriamfetol or placebo. Participants completed a battery of assessments at weekly visits. The primary outcome was Fatigue Symptom Inventory (FSI) scores, and the secondary outcome measure was Behavioral Rating Inventory of Executive Function for Adults (BRIEF-A), at Weeks 6 and 8. T-tests assessed the differences in mean change from baseline between solriamfetol and placebo. Adverse events were monitored throughout the study.

Results: At Week 8 (p = 0.039), but not Week 6 (p = 0.270), solriamfetol improved FSI severity compared to placebo. On the BRIEF-A global executive composite, solriamfetol improved more than placebo at Week 8 (p = 0.012), driven by improved metacognition index (p = 0.004), but not behavioral regulation index (p = 0.574). Solriamfetol was well tolerated, with most common AEs being sleep loss and headaches.

Conclusions: Solriamfetol demonstrated good safety and efficacy in improving fatigue and executive functioning in patients with ME/CFS. As a dual norepinephrine-dopamine reuptake inhibitor and wakefulness-promoting factors, solriamfetol has the potential to improve fatigue symptoms of ME/CFS.

Clinical trial number: NCT04622293.

Source: Young JL, Powell RN, Powell A, Welling LLM, Granata L, Saal J. Solriamfetol improves daily fatigue symptoms in adults with myalgic encephalomyelitis/chronic fatigue syndrome after 8 weeks of treatment. J Psychopharmacol. 2025 Sep 16:2698811251368371. doi: 10.1177/02698811251368371. Epub ahead of print. PMID: 40958377. https://journals.sagepub.com/doi/10.1177/02698811251368371

Fatigue, interoplastic and nociplastic distress in myalgic encephalomyelitis/chronic fatigue syndrome, Gulf War Illness, and chronic idiopathic fatigue

Abstract:

Introduction: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Gulf War Illness (GWI) have similar profiles of pain (nociception), visceral interoception, and tenderness (central sensitization) that may be due to dysfunction of midbrain and medulla descending antinociceptive and antiinteroceptive mechanisms. If so, then dolorimetry, a proxy for tenderness, may be correlated with subjective symptoms. The relationship with fatigue was assessed in Chronic Idiopathic Fatigue (CIF).

Methods: Cohorts of ME/CFS, GWI, and sedentary control subjects completed questionnaires and had dolorimetry. Spearman correlations were calculated between central sensitization (dolorimetry), fatigue (Chalder Fatigue), pain (McGill Pain), interoception (Chronic Multisymptom Inventory), disability (SF36), psychological constructs, and other symptoms. Females were more tender than males and were thus analyzed separately.

Results: GWI and ME/CFS groups were more tender than controls for females (p < 0.0045) and males (p < 10-6). Receiver operating characteristics area under the curve for female ME/CFS (0.730) and GWI (0.792) and male ME/CFS (0.816) and GWI (0.831) were not optimal for diagnostic purposes. Pain and interoception were highly correlated. Dolorimetry correlated better with pain (Spearman R = -0.574 to -0.629) than interoception (R = -0.417 to -0.545) questionnaires. Dolorimetry correlated weakly with fatigue and disability (|R| < 0.42). CIF was defined by receiver operating characteristics with elevated fatigue, postexertional malaise, and reduced vitality. CIF had intermediate tenderness.

Discussion: The outcomes generate several hypotheses about ME/CFS and GWI pathophysiology. Disease pathologies may involve injury to midbrain and medulla regulatory pathways causing central sensitization with the loss of descending antiinteroceptive and antinociceptive inhibitory mechanisms and increased perceptions of widespread visceral complaints and pain. The diseases can be re-conceptualized as chronic disabling fatigue with heightened interoceptive and nociceptive symptoms. Variations in antiinteroceptive control may provoke unpredictable shifts in symptom spectrum and severity that contribute to exertional exhaustion and symptom exacerbation. Subjective criteria were found to define CIF prospectively.

Source: Chen E, Rudder T, Nwankwere C, Baraniuk JN. Fatigue, interoplastic and nociplastic distress in myalgic encephalomyelitis/chronic fatigue syndrome, Gulf War Illness, and chronic idiopathic fatigue. Front Neurosci. 2025 Aug 25;19:1530652. doi: 10.3389/fnins.2025.1530652. PMID: 40927423; PMCID: PMC12415031. https://pmc.ncbi.nlm.nih.gov/articles/PMC12415031/ (Full text)

Nutraceutical Supplementation Effects on Subjective Fatigue Symptoms in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Systematic Review

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating condition marked by severe, long-lasting fatigue and exhaustion that does not improve with rest. ME/CFS is reported in individuals of all ages and various racial, socioeconomic, and ethnic groups. This condition lacks standard treatment. Nutritional supplements and dietary interventions are often used to manage symptoms, but the efficacy of these interventions remains scarce in the current literature. This systematic review aims to evaluate and summarize recent evidence on nutrient supplementation and diet-based interventions in patients with ME/CFS sourced from clinical trial registries and article databases.

Registries improve the quality, integrity, and transparency of clinical trials by providing a standardized platform for reporting study design and results and, thus, reducing the biases related to selective reporting practices. Systematic reviews using these registries, therefore, are an efficient pathway to acquire current medical evidence for use in clinical decision-making and the development of practice guidance in various fields. ClinicalTrials.gov, Medline, PubMed, Cochrane, and Web of Science were systematically searched for interventional studies in which patients suffering from ME/CFS supplemented or altered their diet.

The results of this review showed several supplements that suggest improvement in patients’ symptomatology, including nicotinamide adenine dinucleotide (NADH), coenzyme Q10 (CoQ10), wasabi, and probiotics. However, many of these registered clinical trials did not employ the U.S. National Institutes of Health (NIH)’s National Institute of Neurological Disorders and Stroke (NINDS) suggested common data elements (CDEs). These standardized outcome-measuring tools allow the generalization and true comparison of the patient-reported outcomes.

Source: Brito EM, Bonifanti L, Patel R, Jimenez J, Junco J, Rozenfeld IR, Renesca V, Cheema AK. Nutraceutical Supplementation Effects on Subjective Fatigue Symptoms in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Systematic Review. Cureus. 2025 Jul 2;17(7):e87178. doi: 10.7759/cureus.87178. PMID: 40755709; PMCID: PMC12315604. https://pmc.ncbi.nlm.nih.gov/articles/PMC12315604/ (Full text)

Intelligent Eye Tracker Integrated with Cylindrical Capacitive Sensors for Chronic Fatigue Assessment

Abstract:

Fatigue negatively impacts health, safety, and productivity, yet current monitoring methods are often subjective, labor-intensive, and inaccurate. To address these challenges, this study presents a capacitive sensor-based eye tracker leveraging cylindrical carbon nanotube-paper composite (CCPC) sensors for chronic fatigue (CF) assessment.

Fabricated by novel wet-fracture and paper-rolling methods, CCPC sensors demonstrate superior proximity sensitivity with a small form factor. These one-dimensional sensors are seamlessly integrated into an eyeglass frame for noncontact monitoring of blink rates and eye closures. A 15-minute testing protocol, combining cognitive tasks and noise exposure, is designed to induce acute fatigue and identify CF. By analyzing changes in the digital markers against established fatigue indicators, CF is assessed with the aid of machine learning models for the evaluation of accuracy, sensitivity, and specificity.

This real-time, wearable monitoring platform provides an objective, effortless, and noncontact approach to fatigue assessment. With further testing and optimization, it holds the potential for user-friendly evaluation of acute fatigue or fatigue-associated diseases, such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Source: Li T, Park SH, Lee C, Kim S, Kwon Y, Kim H, Chung JH. Intelligent Eye Tracker Integrated with Cylindrical Capacitive Sensors for Chronic Fatigue Assessment. Adv Sens Res. 2025 Jul;4(7):e00027. doi: 10.1002/adsr.202500027. Epub 2025 May 22. PMID: 40662140; PMCID: PMC12259227. https://pmc.ncbi.nlm.nih.gov/articles/PMC12259227/ (Full text)

Brain and muscle chemistry in myalgic encephalitis/chronic fatigue syndrome (ME/CFS) and long COVID: a 7T magnetic resonance spectroscopy study

Abstract:

Myalgic encephalitis/chronic fatigue syndrome (ME/CFS) is a common debilitating medical condition, whose main symptoms – fatigue, post-exertional malaise and cognitive dysfunction – are also present in many cases of long COVID. Magnetic resonance spectroscopy (MRS) allows the insight into their pathophysiology through exploration of a range of biochemicals putatively relevant to aetiological processes, in particular mitochondrial dysfunction and energy metabolism.

24 patients with ME/CFS, 25 patients with long COVID and 24 healthy controls (HC) underwent brain (pregenual and dorsal anterior cingulate cortex, respectively, pgACC and dACC) and calf muscle MRS scanning at 7 Tesla, followed by a computerised cognitive assessment. Compared to HC, ME/CFS patients had elevated levels of lactate in both pgACC and dACC, while long COVID patients had lowered levels of total choline in dACC. By contrast, skeletal muscle metabolites at rest did not significantly differ between the groups.

The changes in lactate in ME/CFS are consistent with the presence of energetic stress and mitochondrial dysfunction. A reduction in total choline in long COVID is of interest in the context of the recently reported association between blood clots and ‘brain fog’, and earlier animal studies showing that choline might prevent intravascular coagulation.

Importantly, differences in findings between ME/CFS and long COVID suggest that the underlying neurobiological mechanisms, while leading to similar clinical presentations, may differ. An important implication is that patients with ME/CFS and those with fatigue in the course of long COVID should not be studied as a single group, at least until the mechanisms are better understood.

Source: Godlewska BR, Sylvester AL, Emir UE, Sharpley AL, Clarke WT, Williams SR, Gonçalves AJ, Raman B, Valkovič L, Cowen PJ. Brain and muscle chemistry in myalgic encephalitis/chronic fatigue syndrome (ME/CFS) and long COVID: a 7T magnetic resonance spectroscopy study. Mol Psychiatry. 2025 Jul 12. doi: 10.1038/s41380-025-03108-8. Epub ahead of print. PMID: 40652046. https://www.nature.com/articles/s41380-025-03108-8 (Full text)

The impact of leading questions on ME/CFS research: bias and stigma in study design

Abstract:

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex and often misunderstood illness, characterized by post-exertional malaise, unrefreshing sleep, and cognitive impairments.

Objective: To investigate how question phrasing in ME/CFS research may influence participant attributions of fatigue/energy problems and unintentionally reinforce psychosomatic assumptions.

Methods: A total of 2248 individuals with ME/CFS from an international sample completed a survey assessing fatigue-related attributions. We analyzed how question wording influenced whether participants attributed their symptoms to physical or psychosocial causes. Particular focus was given to a fatigue attribution item that framed causes in terms of ‘personal life’ or ‘environmental factors.’

Results: Participants were significantly more likely to attribute their fatigue/energy problems to psychosocial factors when prompted with psychosocial framing. Many respondents who previously indicated physical causes as the primary source of their symptoms shifted to psychosocial explanations in response to the differently phrased item. This shift was especially pronounced among participants reporting higher levels of psychological distress.

Conclusions: Leading or biased question phrasing may distort participant responses in ME/CFS research, potentially inflating psychosomatic interpretations of the illness. Researchers should critically examine survey language to avoid introducing unintended bias that could compromise research validity and reinforce stigma.

Source: Campolattara, A. T. T., Jason, L. A., & Tuzzolino, K. C. (2025). The impact of leading questions on ME/CFS research: bias and stigma in study design. Fatigue: Biomedicine, Health &amp; Behavior, 1–16. https://doi.org/10.1080/21641846.2025.2530338 https://www.tandfonline.com/doi/full/10.1080/21641846.2025.2530338