Tag: review

Micronutrition as a Therapeutic Strategy for Mitochondrial Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Fibromyalgia: A Narrative Review

Abstract:

Fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are chronic multisystem disorders characterized by persistent fatigue, pain, cognitive dysfunction, sleep disturbances, and reduced quality of life. Increasing evidence implicates mitochondrial dysfunction, oxidative and nitrosative stress, immune dysregulation, and altered redox and nicotinamide adenine dinucleotide (NAD+) metabolism as interconnected mechanisms contributing to fatigue, although the strength of evidence varies across these pathways. Micronutrients are essential components of mitochondrial bioenergetics, antioxidant defense, and immune-metabolic regulation.

This narrative review critically examines the mechanistic and clinical evidence supporting mitochondrial-oriented micronutritional interventions in fibromyalgia and ME/CFS, including NAD+ precursors, B-complex vitamins, magnesium, coenzyme Q10, alpha-lipoic acid, GlyNAC, L-carnitine, pyrroloquinoline quinone, taurine, and creatine. Mechanistic plausibility is distinguished from clinical efficacy, as disease-specific randomized controlled evidence remains limited for several interventions. We further discuss biomarkers, metabolic phenotyping, and precision nutrition within a systems-based micronutrition framework.

Finally, we present the rationale for a future randomized, double-blind, placebo-controlled trial in fibromyalgia patients with clinically significant fatigue, which is planned for 2027, subject to ethics approval and prospective registration, as a strategy for future clinical validation.

Source: Abanades S, Fernández I, Capdevila N, Cardona F. Micronutrition as a Therapeutic Strategy for Mitochondrial Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Fibromyalgia: A Narrative Review. Nutrients. 2026 Aug 19;18(16):2702. doi: 10.3390/nu18162702. PMID: 42654282. https://www.mdpi.com/2072-6643/18/16/2702 (Full text)

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)

Low-Dose Ionizing Radiation and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Review of Recent Evidence and Future Research Directions Toward the Elucidation of a Metabolic, Immunologic, and Signaling Cascade

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an idiopathic, multisystem disorder marked by debilitating fatigue, post-exertional malaise, cognitive dysfunction and neuroinflammation. Its etiology remains unclear, yet emerging evidence implicates a complex interplay between immune dysregulation, metabolic impairment, mitochondrial bioenergetics, and environmental stressors such as viral infection or low-dose ionizing radiation (LDIR). To develop treatments for ME/CFS, it is essential to identify suitable targets for therapy.

In this narrative review, we discuss recent findings on the overlap of ME/CFS with LDIR effects and examine potential mechanistic links that may arise from LDIR-induced bystander effects (RIBEs). We highlight potential candidate biomarkers that bridge these domains: mitochondrial respiratory dysfunction, altered ornithine transport via SLC25A15 (ORNT1), possible roles of CD38 in the context of immunity and NAD+ depletion, cyclin D1-dependent metabolic reprogramming and modulation of gene expression, and α-synuclein as a potential neuroinflammatory damage-associated molecular pattern (DAMP).

While the involvement of these biomarkers in ME/CFS is yet to be confirmed experimentally, evidence from in vitro studies of irradiated cells, exosome profiling, and patient samples suggests that RIBEs can, in theory, produce prominent cellular ME/CFS phenotypes through associated mechanisms, including those exhibiting oxidative stress, impaired ATP production, and immune modulation.

We propose a hypothetical, exploratory model wherein LDIR initiates or contributes to adaptive metabolic shifts (including CD38 upregulation and cyclin D1 stabilization) that, coupled with persistent bystander signaling, could potentially culminate in chronic fatigue and neurocognitive symptoms in some reported ME/CFS cases.

Finally, we outline a research agenda encompassing the establishment of standardized diagnostic criteria, multi-omics profiling of patient cohorts, exosome analysis, functional mitochondrial assays, and targeted therapeutic trials focusing on possible anti-CD38 antibodies and NAD+ precursor therapy. By integrating recent findings in low-dose radiation biology with ME/CFS pathophysiology, this review aims to promote interdisciplinary investigations that may uncover mechanistic insights and novel biomarkers for diagnosis and treatment of ME/CFS. We further review steps in a proposed model taking us from low-dose radiation exposure to a number of possible targets.

Source: Rusin A, Cocchetto A, Mothersill C. Low-Dose Ionizing Radiation and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Review of Recent Evidence and Future Research Directions Toward the Elucidation of a Metabolic, Immunologic, and Signaling Cascade. Int J Mol Sci. 2026 Jul 22;27(14):6535. doi: 10.3390/ijms27146535. PMID: 42511874; PMCID: PMC13411118. https://pmc.ncbi.nlm.nih.gov/articles/PMC13411118/ (Full text)

Pacing and energy management with digital tools for conditions with chronic fatigue: What we know so far in ME/CFS and Long COVID

Introduction:

Why pacing matters in conditions with post‑exertional symptom exacerbation

‘Pacing’, or ‘energy management’, is a structured approach to regulating one’s physical, cognitive, and emotional activities to remain within limits imposed by chronic illnesses such as fibromyalgia, cancer, ME/CFS, and Long COVID [1,2]. Pacing ostensibly prevents post‑exertional symptom exacerbation, notably post‑exertional malaise (PEM), the worsening of fatigue, pain, cognitive dysfunction, and other symptoms following even modest activity. Across the literature, pacing is heterogeneously described as strategies that include activity planning, routine‑setting, pre‑emptive rest, breaking tasks into smaller components, monitoring energy fluctuations, and intentionally avoiding activity “push‑crash” cycles that commonly drive clinical deterioration [3]. In addition to heterogenous implementation, evidence of efficacy is also varied [3–9]. In this article, we will focus on ME/CFS and Long COVID as use case examples.

Historically, pacing emerged as an energy management method encouraging individuals to do as much as they can within their limits, rather than pushing through symptoms or following externally prescribed exercise. The central principle is that of the “energy envelope” [1], which asks individuals to identify the threshold at which activity begins to provoke symptoms and then remain inside that envelope as consistently as possible.

While definitions vary across clinicians, researchers, and patient groups, a consistent theme in both our systematic review and the scoping review is that pacing is individualised and requires ongoing adjustment as symptoms fluctuate [3,7]. Importantly, pacing is now the only management strategy recommended by the 2021 NICE guidelines for ME/CFS [10], underscoring its centrality in clinical care despite the concerning lack of evidence for efficacy. As Long COVID research evolved, pacing increasingly became recognised as a pragmatic, do no harm approach for a condition characterised by varied symptomology, unpredictable recovery patterns, and vulnerability to overexertion [8,11].

Source: Sanal-Hayes NEM, Hayes LD, Mclaughlin M, Sculthorpe NF (2026) Pacing and energy management with digital tools for conditions with chronic fatigue: What we know so far in ME/CFS and Long COVID. PLOS Digit Health 5(7): e0001586. https://doi.org/10.1371/journal.pdig.0001586 https://journals.plos.org/digitalhealth/article?id=10.1371/journal.pdig.0001586 (Full text)

Biomarkers of post-acute infection syndrome: a systematic literature review

Abstract:

Background: Post-acute infection syndrome (PAIS) remained underrecognized before the COVID-19 pandemic, which further increased exposure by introducing a novel global cause. The global burden of post-acute COVID syndrome (PACS) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) alone is estimated at several tens of millions affected worldwide. Biomarker discovery is central to improving PAIS diagnosis and may provide therapeutic targets. This review summarizes current knowledge on biomarkers for PAIS, including PACS and ME/CFS.

Methods: A systematic literature search was conducted in PubMed and Web of Science. Inclusion criteria were: (1) studies including PAIS patients; (2) reporting laboratory or omics biomarkers; and (3) investigating biomarkers or pathomechanisms of PAIS. Although Guillain-Barré syndrome (GBS) is not PAIS, we have included it as a separate mechanistic comparator due to its prevalence in search results and its clinical and immunological similarities to PAIS.

Results: A total of 142 studies analyzing PAIS biomarkers were included. GBS was analyzed separately and later compared with the other results. Overall, the reviewed studies employed heterogeneous approaches. While similar types of data were frequently investigated, analytical methods varied and often focused only on a subset of molecules. The results indicate that amino acid, energy, and lipid metabolism, microbiome, mitochondrial stress, and miRNA networks are affected. All pathways are connected via NF-κB.

Discussion: PAIS is a multisystem disorder rooted in persistent immune activation, metabolic reprogramming, and systemic inflammation, driven not by active viral infection, but by dysregulated host responses. The NF-κB pathway serves as a unifying hub, connecting molecular, cellular, and clinical phenotypes. Our framework enables a shift from symptom-based to mechanism-based classification, paving the way for biologically grounded interventions.

Conclusion: This review synthesizes a broad spectrum of biomarkers in PAIS, integrating findings across pathogens and molecular levels rather than restricting to individual conditions or symptom clusters. This study highlights the differences and commonalities among pathogens and diseases that lead to post-acute sequelae, fills a critical knowledge gap, and provides a foundation for future research and clinical practice. Future studies incorporating multi-omics approaches, longitudinal designs, and larger patient cohorts are needed to validate specific biomarkers and advance the understanding of PAIS.

Source: Wendt K, Schieck M, Gille C, Marschollek M, Illig T, Wolff D, Nee S. Biomarkers of post-acute infection syndrome: a systematic literature review. Front Immunol. 2026 Jun 30;17:1741761. doi: 10.3389/fimmu.2026.1741761. PMID: 42454043; PMCID: PMC13365053. https://pmc.ncbi.nlm.nih.gov/articles/PMC13365053/ (Full text)

Therapeutic plasma exchange and immunomodulatory strategies in post-infectious syndromes: A review of immune dysregulation in PTLDS, long COVID, ME/CFS, and PANS/PANDAS

Abstract:

Post-infectious syndromes including post-treatment Lyme disease syndrome (PTLDS), long COVID, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and pediatric acute-onset neuropsychiatric syndrome (PANS)/pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) share overlapping clinical phenotypes characterized by fatigue, cognitive dysfunction, sleep disturbance, and neuropsychiatric symptoms. Increasing evidence suggests that immune dysregulation-including persistent inflammation, autoantibody production, and cellular immune dysfunction-may underlie these conditions.

This narrative review synthesizes peer-reviewed literature describing immune abnormalities across these syndromes and evaluates the rationale for immunomodulatory therapies, including intravenous immunoglobulin (IVIG), rituximab, and therapeutic plasma exchange (TPE). Evidence supporting immune-targeted treatment strategies is strongest in subsets of patients with identifiable immunologic abnormalities. Notably, the phase III RituxME trial in ME/CFS and a phase II trial of TPE in post-COVID condition both failed to demonstrate efficacy in unselected populations, reinforcing the importance of biomarker-guided patient stratification. TPE functions by removing circulating immune complexes, autoantibodies, and inflammatory mediators, and observational data suggest benefit in patients with demonstrable autoantibody burden. Further controlled studies incorporating immunologic phenotyping and early intervention are needed to define the therapeutic role of immune-directed interventions across these conditions.

Source: Kaplan G. Therapeutic plasma exchange and immunomodulatory strategies in post-infectious syndromes: A review of immune dysregulation in PTLDS, long COVID, ME/CFS, and PANS/PANDAS. Transfus Apher Sci. 2026 Jun 26;65(4):104482. doi: 10.1016/j.transci.2026.104482. Epub ahead of print. PMID: 42391726.  https://pubmed.ncbi.nlm.nih.gov/42391726/

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)

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)

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)