Tag: 2026

Elevated serum levels of interleukin-11 and matrix metalloproteinase-9 in myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease of unknown etiology associated with chronic severe fatigue and neurological symptoms, including dizziness, sleep disturbances, cognitive impairment and pain. There are no reliable blood biomarkers available for ME/CFS, possibly due to the lack of specific pathogenesis, even though Epstein-Barr Virus (EBV) has been suspected.

We quantified the levels of interleukin-11 (IL-11) in the serum of female ME/CFS patients (n = 40; mean age 51 years) and age- and gender-matched healthy control subjects (n = 38; mean age 43), as well as matrix metalloproteinase-9 (MMP-9) in ME/CFS patients (n = 18; mean age 57 years old) and healthy control subjects (n = 18; mean age 53 years old), using an enzyme-linked immunosorbent assay (ELISA). We hypothesized that mast cells (MC) stimulated by EBV may be involved.

MC are unique tissue immune cells that have been implicated in ME/CFS. MC were grown from human umbilical cord blood CD34+ stem cells in vitro and incubated with recombinant (rEBV) protein, following which the release of MMP-9 was assayed in the cell culture supernatant media by ELISA. There was a significant increase in serum levels of IL-11 and MMP-9 in ME/CFS patients compared to control subjects. MCs stimulated by rEBV protein released a high amount of MMP-9 compared to control cells.

In conclusion, IL-11, MMP-9 and MCs may be involved in ME/CFS individuals.

Source: Chinnappan B, Kempuraj D, Aenlle KK, Middleton A, Day KS, Kothuru SP, Joshi RS, Klimas NG, Theoharides TC. Elevated serum levels of interleukin-11 and matrix metalloproteinase-9 in myalgic encephalomyelitis/chronic fatigue syndrome. Front Immunol. 2026 Jun 5;17:1827700. doi: 10.3389/fimmu.2026.1827700. PMID: 42327760; PMCID: PMC13278969. https://pmc.ncbi.nlm.nih.gov/articles/PMC13278969/ (Full text)

Tryptophan Metabolism and Aryl-Hydrocarbon Receptor Agonists in the Gut Microbiome of People With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic disease with unknown biological basis and no cure. Microbiome dysbiosis has been reported in people with ME/CFS but its relevance to pathophysiology is unknown. Gut microbes are an important source of tryptophan metabolites that activate the aryl hydrocarbon receptor (AHR), a regulator of homeostatic and inflammatory genes. Dysregulated activation of AHR contributes to pathophysiology of several neuroimmune and chronic diseases but its role in ME/CFS has not been investigated. The purpose of this study was to investigate the production of tryptophan metabolites and AHR agonists by gut microbes of people with ME/CFS.

We found lower diversity and altered microbiome community structure in people with ME/CFS and changes in the subcommunity of microbes that correlated with tryptophan metabolites. Using targeted metabolomics we identified nine metabolites elevated in the stool of people with ME/CFS, including three AHR agonists. Stool ex vivo cultures were tested for their capacity to activate AHR in a reporter cell line and by qPCR. AHR activation did not differ between people with ME/CFS and controls, however, we detected elevated agonist activity in people with neurocognitive symptoms, regardless of underlying disease.

These findings are consistent with previous work revealing changes in the gut microbiome of people with ME/CFS and adds further support to alterations in tryptophan metabolism associated with the disease. Altered AHR activity by gut microbial metabolites may be a common mechanism contributing to neurocognitive symptoms in diseases including ME/CFS.

Source: Esteban DJ, Conrad B, Cullinan A, Luong S, Albaum J, Wilk V. Tryptophan Metabolism and Aryl-Hydrocarbon Receptor Agonists in the Gut Microbiome of People With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Microbiologyopen. 2026 Jun;15(3):e70333. doi: 10.1002/mbo3.70333. PMID: 42325052. https://onlinelibrary.wiley.com/doi/10.1002/mbo3.70333 (Full text)

Gastrointestinal symptoms correlate with core clinical features and systemic inflammation in myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisystem illness marked by fatigue, cognitive impairment, and post-exertional malaise. Gastrointestinal (GI) symptoms are frequently reported, yet their relationship to central features of the illness and biological correlates remains poorly understood.

Objectives: We aimed to characterize GI symptom burden in ME/CFS and evaluate its associations with core clinical features and specific immune and inflammatory markers, with attention to potential gut-related contributions to disease expression.

Methods: GI symptoms and 49 additional symptoms across nine domains were assessed in 116 ME/CFS patients and 80 matched controls. Plasma C-reactive protein (CRP) and antibodies against dietary and microbial antigens were measured as indicators of systemic inflammation and putative gut-derived antigen exposure.

Results: ME/CFS patients reported significantly elevated GI symptom frequency and severity compared with controls, with 53% of ME/CFS patients versus 8% of controls reporting a prior diagnosis of irritable bowel syndrome. GI symptom burden correlated with fatigue, cognitive difficulties, flu-like symptoms, pain, sleep disturbances, neurological complaints, and sensory sensitivities, independent of illness duration. CRP levels were higher in patients with greater GI symptoms and correlated with GI, fatigue, musculoskeletal pain, and flu-like symptom burden. Patients with greater flu-like symptom expression exhibited higher IgM responses to dietary gliadin and bacterial lipopolysaccharide. These associations were not detected in controls.

Conclusions: GI symptoms are a prominent, clinically relevant dimension of ME/CFS, associated with broader symptom burden and inflammatory heterogeneity. These findings highlight the relevance of gut-related and immune processes in ME/CFS and underscore the value of incorporating GI symptom assessment in translational studies to help refine mechanistic understanding and improve therapeutic stratification. https://link.springer.com/article/10.1186/s12967-026-08442-1 (Full text available as PDF file)

Systems neuroendocrinology in ME/CFS and long COVID: a chronobiological framework for hormone-based research

Abstract:

Hormonal dysregulation is increasingly reported in ME/CFS and Long COVID, yet the broader role of neuroendocrine disruption in these conditions remains underexplored. While changes in steroid, peptide, and neuropeptide hormones have been identified, these findings are often considered in isolation and without attention to their timing or integration within broader physiological systems. The hypothalamic-pituitary axes regulate endocrine, immune, autonomic, nervous, and metabolic functions, systems commonly affected in both conditions, yet their circadian and menstrual dynamics are rarely investigated.

In this review, we examine the evidence for neuroendocrine dysfunction in ME/CFS and Long COVID, focusing on hormone output, functional assays, receptor expression, and the coordination of endocrine biorhythms. Sex hormone signalling emerges as a key area of vulnerability, particularly given the female predominance in both conditions and the complexity of reproductive hormone regulation.

We argue that accurate hormone measurement and time-structured sampling, including circadian and menstrual rhythms, are essential for detecting meaningful biological differences. By embedding chronobiology-aware, dense-sampling strategies and integrating multi-omic analyses into multi-system study designs, we outline a framework for investigating dynamic endocrine mechanisms underlying symptom variability and multisystem dysfunction, which may ultimately support the development of more targeted, personalised interventions.

Source: Thomas N, Huang K, Schneider-Futschik EK, Pollack B, Tal MC, Fineberg D, Wang X, Gurvich C, Pretorius R, Bergquist J, Armstrong CW. Systems neuroendocrinology in ME/CFS and long COVID: a chronobiological framework for hormone-based research. Front Neuroendocrinol. 2026 Jun 19:101268. doi: 10.1016/j.yfrne.2026.101268. Epub ahead of print. PMID: 42320559. https://www.sciencedirect.com/science/article/abs/pii/S0091302226000385 (Full text)

Self-management support needs for individuals with Myalgic Encephalomyelitis and their next of kin – a qualitative study

Abstract:

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, disabling condition with limited evidence-based treatment options. Self-management support is recommended to improve people’s coping and quality of life, yet little is known about whether the provided self-management support meet individuals with ME/CFS and their next of kins needs. The aim of this study was to explore the self-management support needs of individuals with ME/CFS and their next of kin, and to identify barriers and facilitators to effective self-management support in order to inform improvements to existing self-management interventions.

Methods: We conducted an exploratory descriptive qualitative study using a combination of semi-structured individual and focus group interviews with a total of 16 participants (12 individuals with ME/CFS and four next of kin) in Norway. Data were analysed thematically within a constructivist framework.

Results: We identified three main themes. Theme one was named “Individualised and accessible support”, focusing on the importance of timing, readiness, and flexible delivery formats (digital, hybrid, modular). The second theme was named “Continuity and validation”, emphasising current gaps in follow-up care for individuals with ME/CFS and experiences of stigma. The third main theme was named “The role of peer support and practical strategies”, highlighting the value of peer interaction, sharing experiences, and adaptive tools (e.g., pacing, symptom tracking). Overall, the participants described that existing self‑management support was poorly aligned with their physical and cognitive limitations, lacked consistent and structured follow‑up, and often conveyed contradictory guidance on activity management.

Conclusions: Self-management support for individuals with ME/CFS should be integrated into standardised care pathways, delivered in phased and modular formats, and include structured follow-up. Digital and hybrid solutions can enhance accessibility. Including peer-led components and family involvement may foster empowerment and reduce isolation. Training healthcare professionals in ME-sensitive communication and developing national guidelines are critical to improving service quality and reducing stigma.

Source: Grønning K, Lysfjord LE, Røstad AKH. Self-management support needs for individuals with Myalgic Encephalomyelitis and their next of kin – a qualitative study. BMC Health Serv Res. 2026 Jun 15. doi: 10.1186/s12913-026-14962-9. Epub ahead of print. PMID: 42298601. https://link.springer.com/article/10.1186/s12913-026-14962-9 (Full text available as PDF file)

ME/CFS and/or Long Covid in Aotearoa New Zealand: results from a food insecurity survey

Abstract:

Background: Various chronic health conditions are associated with household vulnerability to food insecurity. There is limited evidence regarding the prevalence of food insecurity or the experiences and challenges related to nutrition and food access among people living with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long Covid (LC) in Aotearoa New Zealand.

Methods: Adults were recruited between June and September 2025 from online communities, support networks and primary care providers to complete an anonymous, online survey. Food insecurity was defined as ‘sometimes’ or ‘never’ being able to afford to eat properly, or ‘sometimes’ or ‘always’ having food run out, eating less, eating less variety due to cost, relying on others for food or using food grants/banks. Descriptive results were reported as percentages; multivariable risk ratios were estimated from generalised linear models. Quotes from open-ended questions were used to illustrate the quantitative findings.

Results: Among 333 respondents, half (50%) had experienced food insecurity in the past 12 months. There was an inverse-J shape association between food insecurity and disease severity. Younger respondents were more likely to face food insecurity than older respondents. Beyond financial constraints, reported challenges to adequate nutrition included physical limitations affecting going shopping, receiving online deliveries and preparing meals.

Conclusion: Findings support the need to recognise ME/CFS and LC as disabilities for the purposes of social service and income support provision, which could relieve some of the financial pressures on patients. We also recommend that GPs routinely screen for food insecurity among people with ME/CFS or LC.

Source: Dey, K., Butler, J., Riordan Crichton, T., Jeffreys, I., & Jeffreys, M. (2026). ME/CFS and/or Long Covid in Aotearoa New Zealand: results from a food insecurity survey. Fatigue: Biomedicine, Health & Behavior, 1–15. https://doi.org/10.1080/21641846.2026.2688051 https://www.tandfonline.com/doi/full/10.1080/21641846.2026.2688051 (Full text)

Stigmatisation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) – a scoping review

Abstract:
Objective: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a severe chronic, multi-systemic disease characterised by post-exertional malaise (PEM), cognitive impairments and pain. There is no curative treatment yet. Stigmatisation is prevalent in several chronic illnesses, impacting patients’ quality of life and health outcomes. This review aims to examine the types and effects of stigmatisation experienced by individuals with ME/CFS.
Methods: This scoping review followed the PRISMA-ScR guidelines. A systematic literature search was  executed across six electronic databases, complemented by citation searching. The screening was performed independently by two researchers.
Results: We included 44 studies in this review. The most commonly assessed type of stigma was  perceived stigma (n = 7); however, the majority of studies (n = 33) did not specify the type of stigma assessed. Our findings showed that not only individuals with ME/CFS can be affected by stigmatisation, but also people in their social circles such as friends and family members. Stigmatisation was reported in various areas of life, but the most frequently identified issue were stigmatising experiences by healthcare professionals such as physicians. Stigmatisation was found to contribute to poorer health outcomes, delays in diagnosis, and broader personal and societal consequences.
Conclusion: Individuals with ME/CFS can be profoundly affected by stigmatisation. Further research  should investigate experiences of children and (very) severely ill patients. Research is also needed to develop strategies to reduce stigmatisation in healthcare and other settings and to improve the quality  of care for individuals with ME/CFS.
Note: ©American Psychological Association, 2026. This paper is not the copy of record and may not exactly replicate the authoritative document published in the APA journal. The final article is available, upon publication, at: [ARTICLE DOI] Stigmatisation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) – a scoping review
Source: Patricia Vester, Stefanos Boudouroglou-Walter, Chantal Wieting, Prof. Dr. Jonas Schreyögg, Niklas Dammann, Annemarie Feißel, Dr. Katharina Piontek, PD Dr. Christine Blome. Stigmatisation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) – a scoping review. https://www.researchgate.net/publication/406829675_Stigmatisation_in_Myalgic_EncephalomyelitisChronic_Fatigue_Syndrome_MECFS_-_a_scoping_review (Full text)

Raman Spectroscopy Combined with Machine Learning Reveals Myalgic Encephalomyelitis–Associated Biomolecular Signatures at Rest and After Standardized Stress

Abstract:

Myalgic encephalomyelitis (ME) is characterized by profound fatigue, post-exertional malaise (PEM), and cognitive dysfunction. Despite its clinical significance, the pathophysiology of PEM and disease heterogeneity remain unclear, and no validated biomarkers are available for rapid diagnosis or monitoring. We aimed to develop a screening approach combining label-free Raman spectroscopy (RS) and machine learning modeling (ML) to detect biomolecular changes in blood plasma and differentiate patients with ME from sedentary healthy controls.
Blood plasma was collected from 115 patients with ME and 45 controls at rest (T0) and 90 min after a standardized, non-invasive stress test designed to induce PEM. Plasma samples were analyzed by RS, and ML models were developed independently at each time point to differentiate patients with ME and controls.
The RS-ML models identified spectral features consistent with contributions from proteins, lipids, and low-molecular-weight metabolites. At T0 and T90, the area under the receiver operating characteristic curve, accuracy, specificity and sensitivity were 0.85 and 0.83, 79% and 84%, 82% and 90%, and 73% and 69%, respectively. RS-ML provides a rapid, low-cost approach to detect ME-associated biomolecular signatures in plasma and capture biochemical alterations associated with standardized stress.
Source: Heidarifard M, Moezzi A, Dallaire F, Ember K, Elremaly W, Caraus I, Franco A, Leblond F, Moreau A, Dehaes M. Raman Spectroscopy Combined with Machine Learning Reveals Myalgic Encephalomyelitis–Associated Biomolecular Signatures at Rest and After Standardized Stress. International Journal of Molecular Sciences. 2026; 27(11):4937. https://doi.org/10.3390/ijms27114937 https://www.mdpi.com/1422-0067/27/11/4937 (Full text)

Two-timepoint multidomain follow-up of post-COVID condition and ME/CFS: overlapping autonomic, small-fiber, and cognitive changes

Abstract:

Background: Post-COVID condition (PCC) and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) show marked clinical overlap, suggesting a shared post-infectious pathophysiology. This study aims to characterize the longitudinal change of autonomic function, small-fiber integrity, cognitive performance, and clinical symptoms in PCC and ME/CFS, and to determine whether trajectories differ between diagnostic groups.

Methods: Thirty-eight participants (21 PCC, 17 ME/CFS) underwent two standardized evaluations separated by a median of 31 months. Assessments included comprehensive autonomic testing, small-fiber evaluation, and an extensive neuropsychological battery.

Results: ME/CFS showed longer disease duration than PCC at baseline (median 42 vs. 12 months), while the interval between evaluations was comparable (31 vs. 30 months). Baseline profiles were largely overlapping, although ME/CFS showed nominally higher QST warm detection thresholds (p = 0.034), greater autonomic symptom burden (p = 0.038), and lower hemodynamic scores (p = 0.019), none surviving FDR correction. Cross-domain analyses linked small-fiber symptoms with autonomic symptom burden (Rho = 0.65, pFDR = 0.002) and fatigue (Rho = 0.55, pFDR = 0.018), while fatigue was negatively associated with processing speed (Rho = – 0.57, pFDR = 0.004), attention (Rho = – 0.49, pFDR = 0.018), and executive function (Rho = – 0.44, pFDR = 0.047). Rank-transformed mixed-effects models identified FDR-corrected Time effects, with increases in CHEPs (pFDR < 0.001) and verbal memory (pFDR = 0.010), and decreases in processing speed (pFDR = 0.006) and QST cold thresholds (pFDR = 0.038).

Conclusions: PCC and ME/CFS showed broadly overlapping multidomain profiles, with particularly similar profiles at follow-up. This suggests that, among individuals with persistent symptoms, PCC may increasingly resemble longer-standing ME/CFS across autonomic, small-fiber/sensory, and cognitive domains. These findings are consistent with overlapping post-infectious mechanisms, but do not establish identical disease trajectories or definitive disease convergence.

Source: Azcue N, Barranco C, Tijero-Merino B, Acera M, Fernández-Valle T, Lafuente JV, Gabilondo I, Ruiz-Lopez M, Del Pino R, Gómez-Esteban JC. Two-timepoint multidomain follow-up of post-COVID condition and ME/CFS: overlapping autonomic, small-fiber, and cognitive changes. J Transl Med. 2026 Jun 12. doi: 10.1186/s12967-026-08321-9. Epub ahead of print. PMID: 42286686. https://link.springer.com/article/10.1186/s12967-026-08321-9 (Full study available as PDF file)

Irisin Signaling Resistance in Myalgic Encephalomyelitis: A Proposed Mechanistic Framework for Post-Exertional Malaise Involving the TSP-1-HSP90α-αvβ5 Axis

Abstract:

Myalgic Encephalomyelitis (ME) is a chronic, multisystem disease characterized by systemic metabolic dysfunction and post-exertional malaise (PEM). In this study, we investigated the dysregulation of irisin, an exercise-induced myokine, and its potential antagonism by thrombospondin-1 (TSP-1).

In a cross-sectional study (92 ME patients vs. 44 sedentary healthy controls), plasma irisin and TSP-1 levels were measured at baseline and after a 90 min mechanical stress challenge applied to induce PEM. ME patients exhibited significantly lower baseline irisin (p < 0.05) and a blunted exertional response (p < 0.05). Paradoxically, baseline irisin was an independent predictor of fatigue severity (β = 0.728, p = 0.018), with moderate-to-severe patients showing elevated levels of both irisin and TSP-1 (p < 0.05), suggesting a compensatory but ineffective response. Functional cellular dielectric spectroscopy indicated that TSP-1 inhibits irisin signaling in a concentration-dependent manner. Irisin signaling was markedly reduced by both αvβ5 blockade and HSP90α inhibition in this experimental system, consistent with a diminished ability to counteract TSP-1.

Collectively, these findings support a model in which dysregulation of the irisin-TSP-1 axis contributes to metabolic dysfunction in ME. Elevated circulating TSP-1 levels are associated with symptom severity and are linked to impaired irisin signaling in an HSP90α- and αvβ5-dependent context. This interaction is consistent with defective metabolic adaptation and highlights a potential therapeutic target that warrants further validation to restore energy homeostasis.

Source: Souma B, Elremaly W, Akoume MY, Elbakry M, Godbout C, Moreau A. Irisin Signaling Resistance in Myalgic Encephalomyelitis: A Proposed Mechanistic Framework for Post-Exertional Malaise Involving the TSP-1-HSP90α-αvβ5 Axis. Int J Mol Sci. 2026 May 26;27(11):4770. doi: 10.3390/ijms27114770. PMID: 42278300. https://www.mdpi.com/1422-0067/27/11/4770 (Full text)