Tag: 2026

Association between myalgic encephalomyelitis/chronic fatigue syndrome and irritable bowel syndrome: a systematic review and meta-analysis

Abstract:

Background: Irritable bowel syndrome (IBS) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are chronic, debilitating disorders characterized by substantial symptom burden, impaired quality of life, and high healthcare utilization. IBS is a disorder of gut-brain interaction with a global prevalence ranging from 3.8% to 9.2%, while ME/CFS is defined by persistent, exertion-intolerant fatigue and multisystem dysfunction. Growing evidence suggests frequent co-occurrence of these conditions, implicating shared mechanisms such as immune dysregulation, autonomic imbalance, and altered gut-brain signaling. However, the magnitude of their association has not been comprehensively quantified.

Methods: We conducted a systematic review and meta-analysis by searching Embase, PubMed, Scopus, and Google Scholar databases from inception through February 2026. Eligible observational studies reporting associations or prevalence between IBS and ME/CFS were included. Random-effects meta-analyses were performed to pool odds ratios (ORs) and prevalence estimates. Heterogeneity was assessed using I2 statistics. We evaluated for publication bias and assessed for risk of bias.

Results: Twenty-two studies were included in the systematic review and 18 in the meta-analysis. Individuals with ME/CFS had significantly higher odds of IBS compared with controls (OR = 7.20; 95% CI: 2.77-18.76; I2 = 72.1%). The pooled prevalence of IBS among individuals with ME/CFS was 37% (95% CI: 23-54%), with substantial heterogeneity (I2 = 99.5%). Subgroup analysis revealed that diagnostic criteria significantly influenced prevalence (p < 0.0001), while meta-regression identified ME/CFS diagnostic criteria as a significant moderator.

Conclusion: IBS and ME/CFS are strongly associated, suggesting shared underlying mechanisms. These findings support integrated screening approaches and coordinated, multidisciplinary management to improve outcomes in affected patients.

Source: Rajabi N, Ramdass PVAK. Association between myalgic encephalomyelitis/chronic fatigue syndrome and irritable bowel syndrome: a systematic review and meta-analysis. Front Med (Lausanne). 2026 Jul 27;13:1881784. doi: 10.3389/fmed.2026.1881784. PMID: 42577233; PMCID: PMC13453825. https://pmc.ncbi.nlm.nih.gov/articles/PMC13453825/ (Full text)

Haptoglobin Phenotypes Stratify Post-Exertional Cognitive Dysfunction Associated with Altered Cerebral Oxygenation and Metabolic Signatures in Long COVID

Abstract:

Long COVID (LC) is a heterogeneous post-infectious syndrome characterized by persistent symptoms, yet the biological basis underlying its interindividual variability remains poorly understood. Given the clinical overlap between LC and myalgic encephalomyelitis (ME), and prior demonstration that haptoglobin (Hp) phenotypes modulate symptom severity in ME, we investigated whether Hp phenotypes similarly stratify post-exertional cognitive dysfunction in LC.
In this longitudinal observational study, 44 individuals with LC and 20 short-course COVID controls, who recovered rapidly from SARS-CoV-2 infection without persistent symptoms or sequelae, underwent Hp phenotyping alongside metabolomic and physiological profiling before and after a standardized 90 min passive post-exertional challenge. Hp phenotypes identified clinically distinct LC subgroups.
Compared with Hp1-1 individuals, Hp2 allele carriers exhibited greater fatigue, poorer physical function, and more severe post-exertional symptoms. Immediately following the challenge, Hp2-2 participants with LC showed significant cognitive decline, whereas Hp1-1 individuals demonstrated cognitive resilience and more favorable longitudinal cognitive trajectories.
This differential susceptibility was accompanied by higher post-exertional cerebral fractional tissue oxygen extraction in the right hemisphere in Hp1-1 individuals and by distinct metabolic signatures, with Hp2 allele carriers exhibiting lower post-exertional plasma concentrations of citric acid, isethionate, and glucosamine. Lower metabolite levels were associated with poorer cognitive performance.
These findings support Hp phenotypes as promising candidate biomarkers for biological stratification in Long COVID, pending validation in larger independent cohorts.

Source: Moezzi A, Elremaly W, Leveau C, Franco A, Nepotchatykh O, Armstrong CW, Moreau A. Haptoglobin Phenotypes Stratify Post-Exertional Cognitive Dysfunction Associated with Altered Cerebral Oxygenation and Metabolic Signatures in Long COVID. International Journal of Molecular Sciences. 2026; 27(15):7000. https://doi.org/10.3390/ijms27157000 https://www.mdpi.com/1422-0067/27/15/7000 (Full text)

Peripheral blood cytokines during early and post-acute stages of SARS-CoV-2 infection are associated with disease severity and long-term symptoms

Abstract:

Background: U.S. Veterans experience a high burden of COVID-19; characterizing immune responses associated with COVID-19 outcomes could help improve treatment. Changes in peripheral blood cytokines over time may predict both acute outcomes and long COVID symptoms.

Methods: Cytokine concentrations were quantified from peripheral blood collected 0-7 days (early) and 14-42 days (post-acute) after enrollment from SARS-CoV-2 positive participants in the EPIC3 study, a prospective, longitudinal cohort following U.S. Veterans. Responses were correlated with Veterans Affairs Severity Index for COVID-19 criteria and chronic symptoms with the modified Medical Research Council Dyspnea scale, Patient-Reported Outcomes Measurement Information System (PROMIS) Cognitive function, and PROMIS Fatigue scores 3 months after enrollment (60-135 days). Trends in cytokine concentration with COVID-19 severity were assessed. Odds of COVID-19 severity and long-term symptoms were estimated with logistic regression adjusted for sex, age, and morbidity. Longitudinal changes in cytokine concentration were examined for participants sampled during both time periods, by severity and long-term symptom group.

Results: Early HGF, IL-18, IL-1RA, IP-10, and VEGF-A and post-acute MIP-1α and VEGF-A concentrations trended positively with increasing COVID-19 severity (q-values < 0.05, Jonckheere-Terpstra trend test). Increases in EGF, MIP-1β, and RANTES concentration and decreases in MIP-1α concentration over time were associated with mild rather than moderate or severe disease. Increases in MIP-1β and RANTES concentration and decreases in Eotaxin concentration over time were associated with the absence of long-term symptoms.

Conclusions: Worse COVID-19 severity by 30 days was associated with higher early and post-acute period cytokine concentrations. Participants with long-term symptoms did not see resolution of cytokine responses over time.

Source: Mendall C, Li X, Pakanati V, Liu C, Wang T, Morelli D, Korpak A, Baraff A, Isaacs SN, Chang KM, Le E, Holodniy M, Sugimoto JD, Smith NL, Lee JS, Ross JM, Shah JA. Peripheral blood cytokines during early and post-acute stages of SARS-CoV-2 infection are associated with disease severity and long-term symptoms. Front Immunol. 2026 Jul 15;17:1870109. doi: 10.3389/fimmu.2026.1870109. PMID: 42528778; PMCID: PMC13415590. https://pmc.ncbi.nlm.nih.gov/articles/PMC13415590/ (Full text)

Altered TRPM3‐Dependent Cytosolic and Mitochondrial Calcium Influx in Natural Killer Cells of Post‐COVID‐19 Condition Patients

Abstract:

According to the World Health Organization (WHO), approximately 6% of COVID-19 cases develop serious long-term sequelae referred to as post-COVID-19 condition (PCC). Immunological disturbances such as persistent activation of immune cells and reduced cytotoxicity by natural killer (NK) cells are reported as key aspects in PCC.

Recently, electrophysiological studies by our group demonstrated impairment of transient receptor potential melastatin 3 (TRPM3) ion channels in NK cells from PCC patients. The significant reduction in TRPM3 channel function and reduced functional activity by NK cells warrants further investigation. Hence, using live cell calcium (Ca2+) imaging ex vivo, we examined the downstream impact of TRPM3 ion channel dysfunction on intracellular and mitochondrial Ca2+ mobilization in NK cells from N = 8 PCC patients, age and sex matched to N = 8 PCC healthy controls (HC).

Our findings provide new evidence of altered passive and TRPM3-mediated Ca2+ influx, significantly impacting cytoplasmic and mitochondrial Ca2+ mobilization in PCC. Passive cytosolic Ca2+ influx amplitude (p < 0.0001) was significantly reduced in PCC; however, passive mitochondrial Ca2+ mobilization (p < 0.0001) was significantly increased. Importantly, cytoplasmic and mitochondrial response rates (slope, p < 0.001) to pregnenolone sulphate stimulation were significantly reduced in PCC.

Consequently, TRPM3-dependent cytosolic (p < 0.001) and mitochondrial (p < 0.0005) Ca2+ mobilization were significantly reduced in PCC compared with HC. Altered ion channel Ca2+ signalling can severely impact both the immune system and bioenergetic processes, potentially leading to broader systemic dysregulations underpinning the pathomechanism of the PCC condition, and warrants further investigations.

Source: Magawa CT, Eaton-Fitch N, Muraki K, Marshall-Gradisnik S. Altered TRPM3-Dependent Cytosolic and Mitochondrial Calcium Influx in Natural Killer Cells of Post-COVID-19 Condition Patients. Eur J Immunol. 2026 Jul;56(7):e70240. doi: 10.1002/eji.70240. PMID: 42484498; PMCID: PMC13390657.  https://pmc.ncbi.nlm.nih.gov/articles/PMC13390657/ (Full text)

Central origin of fatigability in Myalgic encephalomyelitis/chronic fatigue syndrome revealed by multimodal neuroimaging

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating chronic disease characterized by physical and mental fatigue, post-exertional malaise, muscle pain, headaches, and unrefreshing sleep. Fatigability refers to a reduction of muscular force over time despite willed effort and has a central and a peripheral component. We studied whether fatigability in ME/CFS is related to central or peripheral mechanisms.

We recruited fifteen patients with ME/CFS and nineteen age- and sex-matched healthy volunteers (with seven females in each group). Participants performed a fatiguing grip force task, requiring them to maintain 50% of their maximum voluntary force during alternating 30 s blocks of grip and rest. We simultaneously recorded grip force, forearm muscle activity with electromyography, and brain activity with electroencephalography and functional magnetic resonance imaging. Fatigue onset was based on grip force performance and was set individually for each participant.

ME/CFS patients generated the same level of maximum voluntary force than healthy volunteers but developed fatigue much earlier. Healthy volunteers increased their muscle and brain activity from the beginning of the task until the onset of fatigue. Specifically, muscle activity shifted from high to low frequencies and brain activity increased steadily in cortical and subcortical areas. Then, muscle and brain activity declined slowly. In contrast, in ME/CFS, the muscles and brain activity only showed minimal fluctuations across all the task blocks.

The earlier onset of fatigue in ME/CFS is related to central mechanisms, as their brain did not increase its output to drive muscle activity like healthy volunteers did. While this is a small sample study, and caution should be taken regarding the generalizability of the results, the earlier onset of fatigue in ME/CFS was observed to be related to central mechanisms. The brain in ME/CFS participants did not increase its output to drive muscle activity like healthy volunteers did.

Source: Bedard P, Knutson KM, McGurrin PM, Vial F, Popa T, Horovitz SG, Hallett M, Nath A, Walitt B. Central origin of fatigability in Myalgic encephalomyelitis/chronic fatigue syndrome revealed by multimodal neuroimaging. Neuroimage Clin. 2026 Jul 28;51:104041. doi: 10.1016/j.nicl.2026.104041. Epub ahead of print. PMID: 42551185. https://www.sciencedirect.com/science/article/pii/S2213158226001002 (Full text)

School Difficulties and Long COVID in Children and Adolescents

Abstract:

Objective: Pediatric Long COVID (LC) is an infection-associated chronic condition following SARS-CoV-2 infection. While research has begun to elucidate clinical phenotypes, functional impacts are not well described.

Methods: Cross-sectional data from the NIH-funded Researching COVID to Enhance Recovery (RECOVER) pediatric observational cohort were analyzed to assess associations in school-age children (6 to 11 years) and adolescents (12 to 17 years) between LC and caregiver-reported school-related functional outcomes. LC was defined using RECOVER age group-specific symptom-based LC research indices. The primary outcome was worsening of child grades. Secondary outcomes included difficulty paying attention, limited fun with friends, and having an Individualized Education Program (IEP). Using age-stratified analyses, children with and without LC were matched based on age, sex, and dates of infection and enrollment, to estimate risk ratios (RRs) between LC and each outcome.

Results: The cohort included 1976 children (406 school-age, 1570 adolescent). About 18% of school-age children and 29% of adolescents with LC had reported worsened grades, compared to 7% and 11% without LC, respectively [school-age: adjusted RR 2.18 (95% CI: 1.15-4.11); adolescent: adjusted RR 2.39 (95% CI: 1.86-3.06)]. In both age groups, children with LC were more likely to have difficulty paying attention, limited fun with friends, and IEPs.

Conclusions: LC in school-age children and adolescents was negatively associated with functional school-related outcomes, including academic performance, attention, and peer interactions. As LC affects a substantial proportion of U.S. children, these findings highlight the urgent need to develop, provide, and evaluate school-related services for children and adolescents with LC.

Source: Reeder HT, Kleinman LC, Stockwell MS, Thaweethai T, Pant DB, Rhee KE, Jernigan TL, Snowden JN, Salisbury AL, Kinser PA, Milner JD, Tantisira KG, Warburton D, Mohandas S, Wood JC, Fitzgerald ML, Carmilani M, Krishnamoorthy A, Foulkes AS, Gross RS; RECOVER-Pediatrics Consortium. School Difficulties and Long COVID in Children and Adolescents. Acad Pediatr. 2026 Jul;26(5):103314. doi: 10.1016/j.acap.2026.103314. Epub 2026 Apr 3. PMID: 41936816; PMCID: PMC13386493. https://pmc.ncbi.nlm.nih.gov/articles/PMC13386493/ (Full text)

Microstructural alterations in brain tissue of ME/CFS and long COVID using diffusion tensor imaging and diffusion kurtosis imaging

Abstract:

Introduction: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and long COVID have overlapping symptoms, such as profound fatigue, cognitive impairment, post-exertional malaise, pain and sleep disturbances that are debilitating and reduce quality of life. While Magnetic Resonance Imaging (MRI) techniques, specifically Diffusion Tensor Imaging (DTI) and Diffusion Kurtosis Imaging (DKI), have been used to investigate brain tissue microstructure in ME/CFS or long COVID, no study has yet combined these modalities to directly compare tissue microstructural differences between people living with ME/CFS and long COVID.

Methods: We recruited 37 ME/CFS participants (Age: 43.56 ± 12.5), 19 long COVID participants (Age: 47.92 ± 13.3), and 27 healthy controls (Age: 37.9 ± 10.4). Data were acquired using a 3 Tesla (3T) Prisma MRI scanner. DTI and DKI metrics were determined using MRtrix v3.0.7 and Designer V2.0 software, respectively. Voxel-based statistical analysis of cohort differences was performed using the Statistical Parametric Mapping (SPM12) toolbox in MATLAB. Correlation analysis was performed between DTI, DKI metrics and clinical measures such as duration of illness, fatigue severity, SF36 domains and WHODAS domains.

Results: Compared with healthy controls, individuals with ME/CFS showed microstructural alterations in the cingulum, supplementary motor areas, and parts of the corpus callosum (all p < 0.05). Long COVID participants demonstrated microstructural alterations in regions including the fusiform and precentral gyrus and in major white matter tracks (all p < 0.05). Direct comparisons between ME/CFS and long COVID revealed difference in the left corona radiata (p = 0.001).

Conclusion: This study identifies distinct tissue microstructural alterations in ME/CFS and long COVID and offers a vital insight into the neuropathological basis of shared symptoms in both conditions.

Source: Singh TB, Marshall-Gradisnik S, Barnden L, Eaton-Fitch N, Huynh TH, Inderyas M, Thapaliya K. Microstructural alterations in brain tissue of ME/CFS and long COVID using diffusion tensor imaging and diffusion kurtosis imaging. Front Med (Lausanne). 2026 Jul 17;13:1824498. doi: 10.3389/fmed.2026.1824498. PMID: 42539798; PMCID: PMC13424405. https://pmc.ncbi.nlm.nih.gov/articles/PMC13424405/ (Full text)

Central noradrenergic deficiency in post-infectious chronic fatigue: Neurobehavioral correlates

Abstract:

Fatigue, brain fog and post-exertional malaise are major features of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome and post-acute sequelae of severe acute respiratory syndrome coronavirus 2. To date, no specific neurotransmitter abnormalities have been found in either condition. We examined the possibility of central catecholaminergic involvement and clinical correlates in post-infectious myalgic encephalomyelitis/chronic fatigue syndrome and post-acute sequelae of severe acute respiratory syndrome coronavirus 2 groups compared to healthy volunteers and, as positive controls, Parkinson’s disease patients.

In an observational, cross-sectional cohort study conducted at the National Institutes of Health Clinical Center we measured CSF levels of catecholamines and metabolites in the four groups and assessed correlations with neurobehavioral measures. CSF indices of the central Norepinephrine Pathway (norepinephrine + 3,4-dihydroxyphenylglycol + 3-methoxy-4-hydroxyphenylglycol) and Dopamine Pathway (dopamine + 3,4-dihydroxyphenylacetic acid + homovanillic acid) were measured and related to patient-recorded outcomes and physiological assessments.

Mean values for Norepinephrine Pathway activity (in pmol/mL) were lower in the post-infectious myalgic encephalomyelitis/chronic fatigue syndrome, post-acute sequelae of severe acute respiratory syndrome coronavirus 2, and Parkinson’s disease groups compared to the healthy volunteer cohort (post-infectious myalgic encephalomyelitis/chronic fatigue syndrome (-15.9, 95% confidence interval [-26.1, -5.7], P = 0.0006); post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (-9.62, [-17.9, -1.4], P = 0.015); Parkinson’s disease (-19.4, [-27.5, -11.3], P < 0.0001)).

Post-acute sequelae of severe acute respiratory syndrome coronavirus 2 participants with post-exertional malaise had evidence of central noradrenergic deficiency compared to healthy volunteers (-18.3 [-31.3, -5.3], P = 0.0018). The post-infectious myalgic encephalomyelitis/chronic fatigue syndrome and post-acute sequelae of severe acute respiratory syndrome coronavirus 2 groups did not differ from the healthy group in values for the Dopamine Pathway index. Across all participants, Norepinephrine Pathway activity correlated positively with handgrip duration and general health and negatively with fatigue.

We conclude that post-infectious myalgic encephalomyelitis/chronic fatigue syndrome and post-acute sequelae of severe acute respiratory syndrome coronavirus 2 feature a specific central neurotransmitter pattern involving noradrenergic but not dopaminergic deficiency. The noradrenergic abnormality is associated with major symptoms such as post-exertional malaise.

Source: Aregawi L, Walitt B, Sullivan P, Norato G, Benjamin RN, Goldstein DS. Central noradrenergic deficiency in post-infectious chronic fatigue: neurobehavioral correlates. Brain Commun. 2026 May 13;8(3):fcag173. doi: 10.1093/braincomms/fcag173. PMID: 42205163; PMCID: PMC13202209. https://pmc.ncbi.nlm.nih.gov/articles/PMC13202209/ (Full text)

Circulating extracellular vesicles-microRNAs as potential biomarkers for the identification of ME/CFS: differentiating fatigue-related conditions

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating, multi-systemic condition that has gained renewed global attention due to its clinical overlap with the growing population of long COVID patients. Despite ongoing efforts to characterize the disease, definitive diagnostic molecular markers are yet to be fully established, posing challenges in clinically differentiating from idiopathic chronic fatigue (ICF) and depression (Dep). This study aimed to identify circulating extracellular vesicles (EVs)-associated microRNAs (miRNAs) that serve as both diagnostic signatures and windows into the disease’s underlying pathophysiology.

Methods: Circulating EVs from ME/CFS (n = 6), ICF (n = 6), and depression (n = 8) patients were analyzed using flow cytometry, nano-tracking analysis, and comprehensive miRNA analysis. Differentially expressed miRNAs were analyzed using KEGG pathway enrichment to identify ME/CFS-specific signatures. Key candidate biomarkers were further validated in an additional healthy control (HC) cohort (n = 4).

Results: ME/CFS-EVs exhibited a unique subpopulation with high calcein intensity and larger diameters. Initial global miRNA profiling (Volcano plot) identified miR-21-5p, let-7f-5p, miR-26b-5p, and miR-20a-5p as significantly dysregulated EV-miRNAs in ME/CFS compared to ICF and Dep. To explore systemic pathophysiology, we identified a 114 EV-miRNA signature that achieved 87.0 ± 4.8% sensitivity and 93.7 ± 2.4% specificity within repeated cross-validation of the discovery cohort. After adjusting for covariates, 91 miRNAs remained significant; pathway analysis of the 62 up-regulated EV-miRNAs revealed significant enrichment in neuro-systemic axes, encompassing cellular structural integrity (focal adhesion), core signaling hubs (PI3K-Akt), and systemic homeostasis (such as insulin signaling and endocrine functions). Preliminary evaluation confirmed that these target EV-miRNAs remained at minimal or undetectable levels in the HC group.

Conclusions: A 62 EV-miRNA signature provides insight into the interconnected neuro-systemic pathways disrupted in ME/CFS, particularly those governing neuronal connectivity and cellular scaffolding. Within this candidate EV-miRNA signature, the top-ranked miRNAs-miR-21-5p, let-7f-5p, miR-26b-5p, and miR-20a-5p-emerge as potential candidate biomarkers whose specific elevation was not shared by HC. These findings establish a valuable framework for targeted diagnosis and enhance our understanding of the molecular pathways involved in synaptic and structural alterations in ME/CFS.

Source: Eguchi A, Kuratsune H, Nakatomi Y, Yasui T, Nakagawa R, Watanabe Y, Fukuda S. Circulating extracellular vesicles-microRNAs as potential biomarkers for the identification of ME/CFS: differentiating fatigue-related conditions. J Transl Med. 2026 Jul 27;24(1):979. doi: 10.1186/s12967-026-08695-w. PMID: 42533331. https://link.springer.com/article/10.1186/s12967-026-08695-w (Full text)

Guidance on Home-Based Care for People with Severe ME/CFS: A Transdisciplinary Expert Statement

Abstract:

in English, German

Background: Many patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) have significant care needs. However, post-exertional malaise-the defining feature of ME/CFS-means that even minor physical, orthostatic, cognitive, or sensory stressors can trigger a disproportionate worsening of symptoms. This results in specific requirements and significant challenges in home care. Care is still provided predominantly by family caregivers, who frequently lack adequate assistance and support. At the same time, there are significant gaps in knowledge, care infrastructure, and professional guidance for nurses and other healthcare professionals, as well as physicians involved in providing care.

Objective: The objective of this guide is to structure care measures in a way that prevents overexertion and promotes stability.

Methods: The guide is based on a compilation of practice-oriented measures that have proven effective from the perspective of patients and family caregivers. These were professionally categorized and further developed by experts in nursing science, physical therapy, general medicine and public health.

Results: The guide describes how to adapt key dimensions of care-from nutrition and personal hygiene to communication and managing emotional stress-to disease-specific exertion thresholds. Additionally, it outlines requirements for the caregiving relationship and the planning of home visits and discusses the application of palliative care principles.

Source: Hermisson J, Schreiner C, Weichselbaumer S, Werner M, Hackl V, Roth J, Leiss S, Maukner AC, Wojczewski S, Hainzl A, Hermisson S, Thonhofer K, Pleschberger S, Hoffmann K. Guidance on Home-Based Care for People with Severe ME/CFS: A Transdisciplinary Expert Statement. Wien Med Wochenschr. 2026 Jul 29. English. doi: 10.1007/s10354-026-01182-3. Epub ahead of print. PMID: 42525195. https://link.springer.com/article/10.1007/s10354-026-01182-3 (Full text)