Category: Pathophysiology

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)

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)

Dynamic microclot profiling: thromboelastography advances precision management in long COVID and myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) share overlapping symptoms, and emerging evidence implicates persistent fibrinoid microclots in their pathophysiology, contributing to impaired microcirculation. This review explores the role of microclots and evaluates thromboelastography (TEG) as a potential diagnostic tool.

A comprehensive literature review was conducted using major biomedical databases. Studies indicate microclots are prevalent in both conditions. Long COVID patients demonstrate a TEG profile of increased clot strength (maximum amplitude) and reduced fibrinolysis (LY30), suggesting a persistent hypercoagulable state. Despite its advantages in real-time assessment, TEG interpretation faces challenges from preanalytical variability and a lack of standardized protocols. Promising therapeutic trials, including anticoagulants (e.g., apixaban) and fibrinolytics (e.g., lumbrokinase), require further validation. Technological advancements like AI-driven TEG analysis and portable devices could improve diagnostic precision.

In conclusion, persistent microclots are a key pathophysiological feature. TEG provides a promising, novel approach for detecting coagulation abnormalities and could guide treatment, but requires standardization in future clinical trials. Future research should integrate multiomics biomarkers for precision therapeutics to improve patient outcomes.

Source: Saleem S, Hussain A, Haroon M, Raza A, Afzal U, Anwar MF, Imran S, Iqbal MU, Hajj F. Dynamic microclot profiling: thromboelastography advances precision management in long COVID and myalgic encephalomyelitis/chronic fatigue syndrome. Blood Coagul Fibrinolysis. 2026 Jun 11. doi: 10.1097/MBC.0000000000001439. Epub ahead of print. PMID: 42274123. https://pubmed.ncbi.nlm.nih.gov/42274123/

Immune remodeling and metabolic reprogramming in chronic fatigue: insights into GPCR signaling and epigenetic regulation

Abstract:

Inflammation-driven fatigue is a clinically significant feature of several chronic inflammatory conditions, including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), post-COVID condition, autoimmune disease, and cancer-related fatigue. Across these conditions, partially overlapping disturbances in immune regulation, cellular metabolism, and neuroimmune signaling may contribute to persistent fatigue, despite important differences in initiating context and biological substrate. Current evidence implicates mitochondrial dysfunction, altered glycolysis and fatty acid utilization, lactate- and succinate-associated signaling, metabolite-sensing G protein-coupled receptor (GPCR) pathways, epigenetic acylation, and immune remodeling in the maintenance of fatigue.

This narrative review synthesizes both shared and disease-context-specific mechanisms underlying inflammation-associated fatigue, with particular emphasis on immunometabolism, peripheral-central neuroimmune crosstalk, metabolite-GPCR signaling, and epigenetic regulation.

We highlight GPCR signaling as a potentially important regulatory interface in inflammatory and metabolic pathways relevant to fatigue, while recognizing that direct causal evidence in human fatigue syndromes remains limited.

The review also examines how metabolite-mediated epigenetic acylation may influence immune cell function and fatigue-related biology, although this association remains incompletely validated in fatigue-specific settings. By integrating metabolic dysregulation, neuroimmune signaling, and immune dysfunction, this review consolidates current knowledge on candidate biomarkers, mechanistic pathways, and emerging therapeutic targets in chronic inflammation-driven fatigue.

Overall, this review provides a multidimensional framework for understanding fatigue across inflammatory disorders and for guiding future mechanistic and translational research.

Source: Hu Z, Wang J, Ma S, Zhuang J, Shi J, Zhu Y. Immune remodeling and metabolic reprogramming in chronic fatigue: insights into GPCR signaling and epigenetic regulation. Front Immunol. 2026 May 15;17:1806420. doi: 10.3389/fimmu.2026.1806420. PMID: 42220511; PMCID: PMC13218923. https://pmc.ncbi.nlm.nih.gov/articles/PMC13218923/ (Full text)

Deficient TRPM3-linked mitochondrial Ca2+ influx in natural killer cells associated with myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Introduction: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multisystemic illness, commonly associated with dysregulation of the immune system including reduced cytotoxicity of natural killer (NK) cells and post-exertional neuroimmune exhaustion. Previously, transient receptor potential melastatin 3 (TRPM3) ion channel impairment associated with reduced Ca2+ mobilisation in NK cells from ME/CFS patients was reported. To further explore the pathomechanisms involved in ME/CFS, we investigated the downstream impact of TRPM3 ion channel dysfunction on mitochondrial Ca2+ mobilisation in NK cells.

Method: Fluorescence live-cell imaging was used to investigate Ca2+ mobilisation in NK cells of (N = 10) ME/CFS, classified using Canadian Consensus Criteria, and (N = 10) healthy control (HC) participants. Cytoplasmic and mitochondrial Ca2+ entry was determined using Fluo-8 AM and Rhod-2 AM Ca2+ indicators, respectively. The effect of TRPM3 modulation on Ca2+ mobilisation ex vivo, was examined using pregnenolone sulfate and ononetin to activate and inhibit the channel, respectively.

Results: Cytosolic Ca2+ influx amplitude and slope were significantly reduced (p < 0.001), with a significantly shorter T1/2 response (p = 0.001) in ME/CFS compared to HC. Ca2+ influx amplitude (p < 0.001) and slope (p < 0.041) into the mitochondria were significantly higher in ME/CFS compared to HC. TRPM3 activation triggered pronounced cytosolic response (P < 0.001) accompanied by mitochondrial Ca2+ increase in HC. TRPM3-dependent cytosolic and mitochondrial Ca2+ mobilisation (P < 0.015) were significantly reduced with a shorter T1/2 response (p < 0.02) in ME/CFS compared to HC.

Conclusion: The results demonstrate that altered TRPM3-mediated cytosolic Ca2+ influx may significantly impact Ca2+ mobilisation into the mitochondria of people with ME/CFS. Alterations that interfere with the optimal function of Ca2+ permeable channels may cumulatively impact downstream signalling, leading to detrimental cellular consequences. Collectively these findings provide an avenue for further studies on the physiological functions of TRPM3 ion channel and its role in ME/CFS.

Source: Magawa CT, Eaton-Fitch N, Muraki K, Marshall-Gradisnik S. Deficient TRPM3-linked mitochondrial Ca2+ influx in natural killer cells associated with myalgic encephalomyelitis/chronic fatigue syndrome. BMC Immunol. 2026 May 23. doi: 10.1186/s12865-026-00849-1. Epub ahead of print. PMID: 42177403. https://link.springer.com/article/10.1186/s12865-026-00849-1 (Full text)

Reframing ME/CFS: toward a unified mechanistic model of chronic post-infectious diseases

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe multisystem illness marked by post-exertional malaise (PEM), cognitive dysfunction, autonomic disturbance, and impaired physiological resilience. Historically, the absence of validated biomarkers, heterogeneous definitions, and limited investigative capacity have complicated mechanistic interpretation and contributed to the use of psychosocial and rehabilitative frameworks in clinical practice and in parts of the literature.

Main body: Advances in systems biology, accelerated by Long-COVID research, have transformed our understanding of post-infectious syndromes, implicating persistent immune dysregulation, mitochondrial and metabolic reprogramming, endothelial and microvascular dysfunction, abnormal coagulation, lipid-mediated signalling, extracellular vesicle communication, and viral protein-associated immune activation. This review charts the shift from early post-infectious observations through psychosocial dominance to contemporary biological frameworks, emphasising that pathology is state-dependent and revealed under physiological stress.

Conclusion: ME/CFS is thus reframed here as a disorder of impaired adaptive capacity within post-infectious disease biology.

Source: Watton P, Prusty BK. Reframing ME/CFS: toward a unified mechanistic model of chronic post-infectious diseases. J Transl Med. 2026 May 22. doi: 10.1186/s12967-026-08319-3. Epub ahead of print. PMID: 42174604. https://link.springer.com/article/10.1186/s12967-026-08319-3 (Full text available as PDF file)

3D Virtual Reality Performance Metrics as a Future Fatigue Biomarker in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disorder, characterized by symptoms such as post-exertional malaise (PEM) and cognitive impairments. This study assessed reaction time (RT) metrics in three-dimensional (3D) visual tasks with the aim of objectively quantifying the cognitive impairments in ME/CFS patients compared to controls.

Methods: A total of 120 participants (60 ME/CFS patients and 60 controls) were recruited at the Department of Ophthalmology, Universität of Erlangen-Nürnberg. RT was assessed using a virtual reality-oculomotor test system, presenting 3D stimuli at three disparity levels (275″, 550″, and 1100″) within three gaming repetitions (R1, R2, and R3). Mixed-effects models were used to evaluate group differences, with age and gender as covariates. Pairwise contrasts were calculated to assess changes across repetitions. Fatigue self-assessments were recorded by validated questionnaires, (FACIT Fatigue Scale, Chalder Fatigue Scale, Bell Score and Health Assessment Questionnaire), and their correlation with RT metrics was portrayed using a Spearman correlation matrix.

Results: Estimated means (EM-means) for RT were significantly prolonged in ME/CFS patients compared to controls at disparity 275″ (1969 ms vs. 1384 ms; p = 0.0001), 550″ (1409 vs. 1071 ms; p = 0.0012) and 1100″ (1126 ms vs. 891 ms; p = 0.00223). Age was a significant covariate (p < 0.001), while gender showed no effect. Both groups demonstrated improvements in RT over repetitions; however, ME/CFS patients showed a significantly lower improvement compared to controls, reaching significance in R3 (p = 0.0042). RT metrics did not correlate with patients’ self-assessment scores.

Conclusions: ME/CFS patients showed consistently slower RTs compared to controls, particularly in later, easier gaming repetitions, potentially reflecting the impact of fatigue.

Source: Ladek AM, Priebe L, Harrer T, Harrer E, Michelson G, Knauer TS, Dias-Nunes DX, Mardin CY, Bergua A, Hohberger B. 3D Virtual Reality Performance Metrics as a Future Fatigue Biomarker in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Biomedicines. 2026 Apr 9;14(4):855. doi: 10.3390/biomedicines14040855. PMID: 42072397. https://www.mdpi.com/2227-9059/14/4/855 (Full text)

 

Cardiopulmonary Exercise Testing Reveals Functional Limitations and Work Disability in Severe Post-COVID-19 and ME/CFS Patients

Abstract:

Background: Patients severely affected by post-COVID-19 condition (PCC) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) often experience long-term work incapacity, contributing to a growing economic burden. Organ-centered clinical diagnostics frequently fail to explain their work disability.

Objectives: We aimed to objectively assess physical work ability using cardiopulmonary exercise testing (CPET) in a cohort of long-standing and severely affected PCC patients. We hypothesized: (1) patients with ME/CFS exhibit lower peak oxygen uptake (VO₂peak [mL/min/kg]) and peak power output (PPO [W/kg]) than those without; (2) most patients demonstrate objective work disability, closely aligned with subjective perception of disability; (3) oxygen pulse (O2 pulse [mL/bpm]) is reduced in ME/CFS, independent of comorbidity.

Methods: The study was conducted in the Department of Sports Medicine, Prevention and Rehabilitation at Johannes Gutenberg-University Mainz (Mainz, Germany). Between July 31, 2023, and March 31, 2025, a total of 92 PCC patients with suspected occupational disease underwent symptom-limited CPET and completed the Canadian Consensus Criteria, Bell Disability Scale (Bell-Score), and DePaul Symptom Questionnaire (Post-Exertional Malaise) Short Form (DSQ-PEM).

Results: Nearly half of the patients (49%) met ME/CFS criteria and 79% screened positive on the DSQ-PEM. ME/CFS patients showed significantly lower VO₂peak (13.0 ± 3.1 vs. 15.4 ± 4.9, p = 0.012), PPO (0.9 ± 0.3 vs. 1.1 ± 0.5, p = 0.014), and O₂ pulse (7.7 ± 2.0 vs. 8.5 ± 1.9, p = 0.047) compared to those without ME/CFS. Overall, 66% of patients met objective thresholds for work disability (VO₂peak < 15 mL/min/kg or PPO < 1 W/kg). Forty-five patients (51%) had a Bell-Score ≤ 30 and 82% from those had VO₂peak < 15 and/or PPO < 1. VO₂peak and PPO significantly correlated with Bell-Score (r = 0.3, p = 0.005 and r = 0.3, p = 0.003) and were the lowest among patients on medical sick leave (13.3 ± 3.3 and 0.9 ± 0.3), compared to those in occupational reintegration (16.0 ± 3.9, p = 0.04 and 1.2 ± 0.5, p = 0.024) or currently working (18.0 ± 7.1, p = 0.036 and 1.2 ± 0.5, p = 0.015).

Conclusions: Severely affected PCC patients exhibit objective work disability, particularly those with ME/CFS. VO₂peak and PPO are associated with subjective disability and occupational status. Therefore, early integration of CPET into clinical and occupational evaluations can inform individualized therapy planning and return-to-work decisions.

Trial registration DRKS, DRKS00032394. Registered 28 July 2023, https://drks.de/search/de/trial/DRKS00032394.

Source: Tomaskovic A, Weber V, Ochmann DT, Hillen B, Neuberger EWI, Brahmer A, Lachtermann E, Lieb K, Simon P. Cardiopulmonary Exercise Testing Reveals Functional Limitations and Work Disability in Severe Post-COVID-19 and ME/CFS Patients. Sports Med Open. 2026 Apr 27;12(1):50. doi: 10.1186/s40798-026-00995-1. PMID: 42043742. https://link.springer.com/article/10.1186/s40798-026-00995-1 (Full text)