Tag: 2025

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)

Brain MRI findings in patients with post COVID-19 condition: frequency and longitudinal changes in a nationwide cohort study

Abstract:

Background: Prolonged neurological symptoms following COVID-19 are common, yet few longitudinal studies describe brain MRI findings in this patient group. The use of contrast enhanced sequences is particularly lacking. We address this knowledge gap by reporting the frequency and longitudinal changes in brain MRI findings among patients with post COVID-19 condition exhibiting neurological symptoms.

Methods: This prospective multicenter study included 140 adult patients referred for persistent neurological symptoms following COVID-19. Brain MRI was performed at both 6 and 12 months after infection onset, reporting white matter hyperintensities, cerebral microbleeds, and additional pathological findings including contrast enhancement. White matter hyperintensities were compared with a healthy control group.

Results: The prevalence of white matter hyperintensities was comparable to healthy controls, and microbleeds were found at rates comparable to population studies, with longitudinal changes being infrequent. Lesions consistent with inflammation or demyelination were present in 4% (5/120) of patients at 6 months. Cranial nerve enhancement was found in 7% (7/94) of patients, persisting up to 12 months, predominantly affecting the oculomotor nerve. However, enhancement occurred without clinically detected ocular muscle paresis.

Conclusion: Our findings indicate that brain MRI primarily serves to exclude differential diagnoses in post COVID-19 condition, with limited clinical benefit of repeated imaging in the absence of new symptoms. However, signs of long-term inflammatory processes can be observed, and detection is improved by contrast enhanced sequences.

Source: Furevik LL, Lapina O, Lindland ES, Høgestøl EA, Geier OM, Devik K, Farmen AH, Flemmen HØ, Harbo HF, Morsund ÅH, Novotny V, Ofte HK, Pedersen KO, Popperud TH, Ratajczak-Tretel B, Samsonsen C, Selnes P, Torkildsen Ø, Undseth RM, Aamodt AH, Beyer MK, Boldingh MI. Brain MRI findings in patients with post COVID-19 condition: frequency and longitudinal changes in a nationwide cohort study. Front Neurol. 2025 Nov 13;16:1662263. doi: 10.3389/fneur.2025.1662263. PMID: 41323230; PMCID: PMC12658414. https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2025.1662263/full (Full text)

Glymphatic System Dysregulation as a Key Contributor to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Defined by the World Health Organization as a neurological disorder, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disabling illness, affecting millions of people worldwide. First reported in the early nineteenth century, ME/CFS is uniquely characterized by a wide array of symptoms, including fatigue, brain fog, post-exertional malaise (PEM), sleep dysfunction, and orthostatic intolerance (OI). Despite decades of extensive research, there are no effective medical treatments or simple diagnostics for ME/CFS, with an estimated 90% of patients remaining undiagnosed.

The recently discovered glymphatic system, a lymphatic analog of the brain, is believed to be responsible for the removal of toxic metabolic wastes accumulated in the course of daily activities, primarily during sleep. A link between glymphatic dysfunction and some neurological disorders such as Alzheimer’s disease has already been established, raising the possibility of its involvement in ME/CFS. Accordingly, we believe the ME/CFS medical/scientific community will be interested in seriously considering GD an important contributor to its pathophysiology. If so, therapeutics that modulate glymphatic function may also benefit patients with ME/CFS.

Source: Nemat-Gorgani M, Jensen MA, Davis RW. Glymphatic System Dysregulation as a Key Contributor to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Int J Mol Sci. 2025 Nov 27;26(23):11524. doi: 10.3390/ijms262311524. PMID: 41373677. https://www.mdpi.com/1422-0067/26/23/11524 (Full text)

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): diagnosis and management

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has garnered substantial scientific and clinical interest, due to its rising global prevalence and significant pathophysiological overlap with post-acute COVID-19 syndrome (PACS). This review systematically elucidates the prevailing diagnostic criteria, summarizes recent advances in understanding the potential pathophysiological mechanisms, and evaluates pharmacological and non-pharmacological interventions, and symptom-based assessment and management strategies.

Methods: A comprehensive literature search was conducted across PubMed, Web of Science, Embase, and the Cochrane Library for articles published from inception to August 2025.

Results: Current diagnostic frameworks for ME/CFS rely primarily on clinical symptomatology and lack definitive biomarkers. Immune dysregulation, oxidative stress, mitochondrial dysfunction, and neuroinflammation are central to its pathology. Pharmacological management includes immunomodulatory treatments, antioxidant therapies, mitochondrial support, and neuroinflammation intervention. Non-pharmacological strategies such as cognitive behavioral therapy (CBT), graded exercise therapy (GET), activity pacing, and traditional Chinese medicine (TCM) complement biomedical approaches by alleviating symptom severity and promoting energy conservation.

Conclusion: Among these approaches, CBT serves as an adjunctive therapy for symptom management rather than a curative one, whereas GET is contraindicated due to its potential for harm. Comprehensive clinical assessment and management of ME/CFS requires being symptom oriented and the recognition of individual differences. Recommended directions for future research include developing biomarker-based diagnostic tools, optimizing combination therapies that target multiple pathophysiological pathways simultaneously, and integrating real-world data and digital health technologies for precise monitoring and management of ME/CFS.

Source: Fan J, Jiao J, Chang HQ, Zhong DL, Liu XB, Li J, Chen LM, Jin RJ, Wu X. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): diagnosis and management. J Transl Med. 2025 Dec 9. doi: 10.1186/s12967-025-07506-y. Epub ahead of print. PMID: 41366804. https://link.springer.com/article/10.1186/s12967-025-07506-y

A multidimensional immunological perspective on long COVID

Highlights:

  • Inflammaging may predispose to and be amplified by Long COVID.
  • SARS-CoV-2 may trigger autoantibodies disrupting neuroimmune balance.
  • Long COVID involves persistent immune system and autonomic dysregulation.
  • Biomarkers reflect immune and autonomic imbalance in Long COVID.
  • Biological clocks may help identify Long COVID vulnerability and guide care.

Abstract

Long COVID is a chronic condition that arises after SARS-CoV-2 infection and is characterized by persistent and often debilitating symptoms, such as fatigue, cognitive dysfunction (“brain fog”), dyspnea, and autonomic disturbances. Increasing evidence suggests that Long COVID shares key immunopathological mechanisms with autoimmune diseases, primarily sustained immune dysregulation.

In individuals with genetic or immunological susceptibility, SARS-CoV-2 infection can trigger the production of autoantibodies targeting cytokines, membrane receptors, and components of the autonomic nervous system (ANS), thereby disrupting neuroimmune homeostasis. This immune imbalance may impair anti-inflammatory regulatory pathways, such as the cholinergic anti-inflammatory pathway (CAP), and may contribute to a chronic state of inflammation and autoimmunity. One proposed contributor to this process is inflammaging – a chronic, low-grade inflammation associated with aging – which may not only predispose individuals to Long COVID but may also be amplified by the persistent immune activation seen in this condition.

In this perspective, we propose a conceptual framework in which inflammaging, immune-tolerance breakdown, and autonomic dysfunctions interact to sustain the pathophysiology of Long COVID. We discuss emerging biomarkers across these axes, including inflammatory cytokines, circulating autoantibodies, immune cell phenotypes, epigenetic modifications, and heart rate variability. Advances in inflammaging-related biomarkers and biological clocks may support early identification of individuals at higher risk for persistent immune and autonomic dysregulation, ultimately informing more precise diagnostic and therapeutic strategies for Long COVID.

Source: Giunta S, Giuliani A, Sabbatinelli J, Olivieri F. A multidimensional immunological perspective on long COVID. Cytokine Growth Factor Rev. 2025 Aug;84:1-11. doi: 10.1016/j.cytogfr.2025.07.001. Epub 2025 Jul 5. PMID: 40640033. https://pubmed.ncbi.nlm.nih.gov/40640033/

Exploring a genetic basis for the metabolic perturbations in ME/CFS using UK Biobank

Highlights:

  • ME/CFS shows distinct genetic influences on metabolic regulation.
  • Lipid and hormone-related pathways emerge as key areas of interest.
  • Many small genetic effects may collectively disrupt metabolic resilience in ME/CFS.

Summary:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a clinically heterogeneous disease lacking approved therapies. To assess genetic susceptibility towards a specific metabolic phenotype, we performed a genome-wide association study on plasma biomarker levels (mGWAS) in ME/CFS patients (n=875) and healthy controls (HCs) (n=36,033).
We identified 112 significant SNP–biomarker associations in ME/CFS, compared with 4,114 in HCs. Two SNPs specific to ME/CFS, mapping to HSD11B1 and SCGN, were associated to phospholipids in extra-large very low-density lipoproteins (VLDL) and total fatty acids respectively. Genetic effects of VLDL associations were among the least correlated between ME/CFS and HCs. Heterogeneity tests found differential effects for several lipid traits at ADAP1, NR1H3 and CD40, which are involved in immune regulation.
ME/CFS mGWAS summary statistics were decomposed to uncover shared genetic-metabolic patterns, where enrichment analysis highlighted pathways in lipid metabolism, neurotransmitter transport, and inflammation. These findings provide a genetic and molecular rationale for patient heterogeneity and suggest a polygenic predisposition in which many small-effect variants may jointly perturb metabolic mechanisms.
Source: Katherine Huang, Muhammad Muneeb, Natalie Thomas, Elena K. Schneider-Futschik, Paul R. Gooley, David B. Ascher, Christopher W. Armstrong. Exploring a genetic basis for the metabolic perturbations in ME/CFS using UK Biobank. iScience, 2025, 114316 ISSN 2589-0042, https://doi.org/10.1016/j.isci.2025.114316. https://www.sciencedirect.com/science/article/pii/S2589004225025775 (Full text available as PDF file)

Lingering echoes of SARS-CoV-2: mechanistic insights and management of long COVID syndrome

Abstract:

Throughout the world-wide COVID-19 pandemic, there has arisen a significant and a sustained public-health issue, whereby a significant proportion of individuals report persistent symptoms, well beyond the acute period of infection. The non-united array of chronic, multisystemic events, such as fatigue, cognitive deficit, respiratory dysfunction, cardiovascular abnormalities, and neuropsychiatric disorders characterize this sequela, which is referred to as LCS. LCS is much more than the starting viral insult, as it causes long-term complications that impact various organ systems.

The current review questions the pathophysiological mechanisms of LCS, including scrutinizing the importance of the dysregulation of immunity, the persistence of viral reservoirs, endothelial dysfunction, autonomic imbalance, and mitochondrial injury. We highlight the heterogeneity of the syndrome and the associated diagnostic and treatment difficulties. In addition, we stress the urgency of powerful biomarkers that will be used to diagnose LCS as early as possible and monitor it over time. Present treatment strategies, including pharmacologic therapy (immunomodulators, anticoagulants, antiviral medications, etc.) and non-pharmacologic treatment (rehabilitative programs, etc.) are discussed against the backdrop of recent clinical findings.

This review incorporates the recent literature and presents a review of potential treatment options that alleviate symptoms and improve the quality of life of LCS patients. Finally, this integrated synthesis can be used by both clinicians and researchers to gain practical information on the diagnosis, treatment, and future treatment directions of LCS.

Source: Yadav JP, Yadav S, Dubey NK, Yadav IP, Pathak P, Verma A. Lingering echoes of SARS-CoV-2: mechanistic insights and management of long COVID syndrome. Inflammopharmacology. 2025 Nov 30. doi: 10.1007/s10787-025-02062-9. Epub ahead of print. PMID: 41318861. https://pubmed.ncbi.nlm.nih.gov/41318861/

The lingering shadow of epidemics: post-acute sequelae across history

Significance:
Long COVID, a chronic multisystemic health condition, impacts hundreds of millions around the world. Long COVID has brought light to other related post-acute infection syndromes (PAIS) that are triggered by a wide array of pathogens. This opinion article highlights historical accounts of PAIS through the centuries and emphasizes the need for integrated approaches to understanding and treating PAIS.
Highlights:

  • New or persistent symptoms following COVID-19, known as ‘long COVID’, occur in an estimated 4–20% of pediatric and 10–20% of adult patients after acute infection with SARS-CoV-2. Long COVID is associated with dysregulation of both innate and adaptive immunity.
  • While long COVID is a relatively new clinical entity, post-acute infection syndromes (PAIS) have been well documented for over a century.
  • A wide variety of pathogens are associated with PAIS, including divergent classes of viruses, bacteria, and parasites. While each PAIS has a unique trigger and pathology, similarities in symptom profiles and immunological findings suggest these conditions may share features or involve overlapping biological mechanisms.
  • Despite being well described in the literature, PAIS remain understudied relative to their high disease burden. Patients often face stigma and psychologization from medical professionals when disease biomarkers are not readily apparent, exemplified by the historic dismissal of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Abstract:
The SARS-CoV-2 pandemic has drawn global attention to post-acute infection syndromes (PAIS), with millions affected by post-acute sequelae of COVID-19 (PASC, or Long COVID). While Long COVID is newly defined, PAIS have been described for over a century following epidemic infections. Multiple pathogens – including influenza, Epstein-Barr virus, and Borrelia burgdorferi, among others – can precipitate persistent, poorly understood symptoms. Chronic illnesses such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) have long been linked to infectious triggers. This recurring association highlights critical knowledge gaps and underscores the need for systematic investigation. Unlike prior pandemics, the current era offers advanced technologies and analytic tools to address these gaps. Defining the biology of Long COVID may yield broader insights into host–pathogen interactions and mechanisms of chronic illness.
Source: Miller CM, Moen JK, Iwasaki A. The lingering shadow of epidemics: post-acute sequelae across history. Trends Immunol. 2025 Dec 4:S1471-4906(25)00267-4. doi: 10.1016/j.it.2025.10.010. Epub ahead of print. PMID: 41350176. https://www.cell.com/trends/immunology/fulltext/S1471-4906(25)00267-4 (Full text)

Identification of Novel Reproducible Combinatorial Genetic Risk Factors for Myalgic Encephalomyelitis in the DecodeME Patient Cohort and Commonalities with Long COVID

Abstract:

Background: Myalgic encephalomyelitis (also known as ME/CFS or simply ME) has severely impacted the lives of tens of millions of people globally, but the disease currently has no accurate diagnostic tools or effective treatments. Identifying the biological causes of ME has proven challenging due to its wide range of symptoms and affected organs, and the lack of reproducible genetic associations across ME populations. This has prolonged misunderstanding, lack of awareness, and denial of the disease, further harming patients.

Methods: We used the PrecisionLife combinatorial analytics platform to identify disease signatures (i.e., combinations of 1-4 SNP-genotypes) that are significantly enriched in two cohorts of ME participants from DecodeME relative to controls from UK Biobank (UKB). We tested whether the number of these signatures possessed by an individual is significantly associated with increased prevalence of ME in a third disjoint cohort of DecodeME participants. We characterized a number of drug repurposing opportunities for a set of candidate core genes whose disease signatures had the strongest association with ME and which were linked to different mechanisms. We then tested gene overlap between the ME signatures identified and previous studies in long COVID, using two independent approaches to explore these shared genetic commonalities.

Results: We identified 22,411 reproducible disease signatures, comprising combinations of 7,555 unique SNPs, that are consistently associated with increased prevalence of ME in three disjoint patient cohorts. The count of reproducible signatures was significantly associated with increased prevalence of ME (p = 4×10-21), and participants with a top 10% signature count had an odds ratio of disease 1.64 times greater than participants with a bottom 10% signature count, confirming that these genetic signatures increase susceptibility for developing ME. These disease signatures map to 2,311 genes. We identified substantial overlap between the genes found by this combinatorial analysis and previous studies. We found that the 259 candidate core genes most strongly associated with ME are enriched in disease mechanisms including neurological dysregulation, inflammation, cellular stress responses and calcium signaling. We demonstrated that 76 out of 180 genes previously linked to long COVID in UKB and the US All of Us cohorts are also significantly associated with ME in the DecodeME cohort. These findings allowed identification of many existing and novel repurposing opportunities, including candidates linked to several genes with shared etiology for long COVID.

Conclusion: These findings provide further evidence that ME is a complex multisystemic condition where the risk of developing the disease has a very clear genetic and biological basis. They give a substantially deeper level of insight into the genetic risk factors and mechanisms involved in ME. The discovery of so many multiply reproducible genetic associations implies that ME is highly polygenic, which has important consequences for its future study and the delivery of clinical care to patients. The striking overlap in genes and mechanisms between long COVID and ME (76 / 180 long COVID genes tested) suggests the potential for development of novel or repurposed drug therapies that could be used to successfully treat either condition. However, although they share significant genetic commonalities, long COVID and ME appear to be best considered as partially overlapping but different diseases.

Source: Lu J, Sun W, Li S, Qu Y, Liu T, Guo S, Feng C, Yang T. Assessment of symptoms in myalgic encephalomyelitis/chronic fatigue syndrome: a comparative study of existing scales. Front Neurol. 2025 Nov 18;16:1618272. doi: 10.3389/fneur.2025.1618272. PMCID: PMC12668935. https://pmc.ncbi.nlm.nih.gov/articles/PMC12668935/ (Full text available as PDF file)

Assessment of symptoms in myalgic encephalomyelitis/chronic fatigue syndrome: a comparative study of existing scales

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multifaceted disorder characterized by persistent fatigue, post-exertional malaise (PEM), cognitive dysfunction, sleep disturbance, pain, psychological distress, orthostatic intolerance, and impaired multidimensional health status and functioning. In the absence of reliable biomarkers, standardized symptom assessment is essential for accurate diagnosis and comparability across studies.

This narrative literature review synthesized studies identified through PubMed and Web of Science up to June 2024, covering assessment instruments across major ME/CFS symptom domains. Tools were evaluated for their psychometric validity, clinical applicability, and key limitations.

Overall, existing scales demonstrate acceptable reliability but vary in sensitivity and disease specificity. Harmonized, multidimensional, and digitally or objectively validated measures are needed to improve diagnostic precision, longitudinal monitoring, and clinical translation in ME/CFS.

Source: Lu J, Sun W, Li S, Qu Y, Liu T, Guo S, Feng C, Yang T. Assessment of symptoms in myalgic encephalomyelitis/chronic fatigue syndrome: a comparative study of existing scales. Front Neurol. 2025 Nov 18;16:1618272. doi: 10.3389/fneur.2025.1618272. PMID: 41341517; PMCID: PMC12668935. https://pmc.ncbi.nlm.nih.gov/articles/PMC12668935/ (Full text)