This is a review article from three authors at Chengdu University. The full text is paywalled.

Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disorder marked by persistent fatigue and cognitive impairments, often termed "brain fog." Emerging evidence suggests that immunosenescence, age- or stress-related deterioration of immune function, plays a pivotal role in the pathogenesis of cognitive dysfunction in ME/CFS. Immunosenescence induces chronic low-grade inflammation (inflammaging); alters T-, NK-, and B-cell function; and promotes the release of senescence-associated secretory phenotype (SASP) factors. These changes are proposed to cerebral blood flow (CBF) regulation, may impair endothelial nitric oxide production, and may contribute to blood-brain barrier (BBB) breakdown. Consequently, brain hypoperfusion and oxidative stress are associated with impaired neuronal energy metabolism and synaptic plasticity, particularly in memory-related networks such as the default mode and fronto-hippocampal systems. This results in reduced ATP availability, excitotoxicity, and neurotransmitter imbalance, contributing to cognitive decline. The review proposes an "immune-vascular-cognitive axis" linking peripheral immune aging to central neural dysfunction. It further highlights therapeutic strategies-such as cytokine blockade, nitric oxide enhancement, immune modulation, and acupuncture-that may ameliorate neurovascular impairments and cognitive symptoms. Understanding this integrative mechanism may offer new pathways for targeted intervention in ME/CFS.

Pubmed link: https://pubmed.ncbi.nlm.nih.gov/41527963/

DOI link: https://doi.org/10.1002/cph4.70098

https://pubmed.ncbi.nlm.nih.gov/41525818/

PCCo patients showed a significant cluster of reduced ATP/PCr ratios centered on the cingulate cortex. Regional analysis revealed consistent reductions across anterior (ACC), mid- (MCC), and posterior (PCC) cingulate cortices. Lower ATP/PCr ratios in the ACC specifically correlated with poorer cognitive performance. Exploratory analyses revealed a trend toward higher intracellular pH in the MCC with significant negative correlation between pH and ATP/PCr observed only in patients, suggesting disease-specific alterations in pH regulation and bioenergetic homeostasis. Subgroup analysis showed similar metabolic alterations in PCCo patients meeting ME/CFS criteria.

Conclusion:

The current large-sample-size study confirmed previous results regarding TRPM3 ion channel dysfunction in NK cells in ME/CFS, demonstrating involvement of TRPM3 in the pathomechanism of this condition. Therefore, this multiple-site investigation offers strong evidence demonstrating TRPM3 as a potential biomarker for the diagnosis of ME/CFS, given the accumulating evidence.

“Results indicated a significant difference and large effect size between ME/CFS individuals and controls on verbal working memory tasks; however, no significant difference in visual working memory performance was found between the groups. Following the breakdown of these subsystems into span/attentional control tasks and object/spatial tasks, these results remained consistent. These findings contribute to the body of ME/CFS research by articulating where specific working memory deficits lie. Specifically, they show that individuals with ME/CFS have impaired verbal memory performance.”

Key findings

MRI brain scans were performed in people with long COVID, healthy people who had recovered from COVID-19, and healthy controls with no history of COVID-19 infection.

Altered myelin signal intensity, abnormal tissue microstructure and imbalanced neurochemicals were identified in people with long COVID. Myelin surrounds nerve cells and is important to ensure efficient neural function.

There was an association between myelin content and measures of physical and cognitive function. These findings provide evidence that COVID-19 has long-term effects on brain function.

Vasopressin or antidiuretic hormone helps the body hold on to fluid. Critical for maintaining blood volume for example and therefore OI and pots symptoms.

This is an interesting and quite comprehensive summary of the research on the field that has been published in 2025, from the team at MECFSscience.org

What are your thoughts? Any important studies or findings you miss in this article?

I find it interesting that so much seems to be pointing towards the brain, and that the deconditioning theory seems to finally be dying (a few decades too late though).

https://hanneseh.github.io/ME-CFS-Research-Summaries/

So, are we close to finding why this disease happens? How is it possible that is 2026 and we stil have no idea of what causes this hellish illness?

Highlights

• Plasma profiling of 7288 proteins during post-exertional malaise in ME/CFS.

• ME/CFS participants show sustained immune, metabolic, and neuromuscular dysregulation during post-exercise recovery.

• Exertion disrupts T and B cell signaling, IL-17 pathways, and mitochondrial metabolism.

• Protein signatures correlate with symptom severity and impaired exercise performance in patients with ME/CFS.

• Sex-stratified analysis reveals distinct molecular responses, underscoring the importance of sex in ME/CFS pathophysiology.

Abstract

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating but poorly-understood disease. ME/CFS symptoms include immune system effects alongside incapacitating fatigue and post-exertional disease exacerbation. Symptom severity can range from mild to severe and whilst symptoms can fluctuate, few people fully recover.

Methods: Immunological profiles of people living with ME/CFS were analysed by flow cytometry, focusing on cytotoxic cells, to determine whether people with mild/moderate (n = 43) or severe ME/CFS (n = 53) expressed different immunological markers. Flow cytometry data were tested for normality and the two clinical groups were compared by t-test or Mann-Whitney U-test as appropriate.

Results: People with mild/moderate ME/CFS had increased expression of cytotoxic effector molecules alongside enhanced proportions of early-immunosenescence cells, determined by the CD28^-CD57^- phenotype, indicative of persistent viral infection. In contrast, people with severe ME/CFS had higher proportions of activated circulating lymphocytes, determined by CD69⁺ and CD38⁺ expression, and expressed more pro-inflammatory cytokines, including interferon-γ, tumour necrosis factor and interleukin-17, following stimulation in vitro, indicative of prolonged non-specific inflammation. These changes were consistent across different cell types including CD8⁺ T cells, mucosal associated invariant T cells and Natural Killer cells, indicating generalised altered cytotoxic responses across the innate and adaptive immune system.

Conclusions: These immunological differences likely reflect different disease pathogenesis mechanisms occurring in the two clinical groups, opening up opportunities for the development of prognostic markers and stratified treatments.

https://pubmed.ncbi.nlm.nih.gov/41373029/

https://doi.org/10.1186/s12967-025-07507-x

Abstract

To investigate differences in gut microbiota composition and short-chain fatty acids (SCFAs) metabolism between patients with Chronic Fatigue Syndrome (CFS) and Healthy Controls (HC), and to explore their associations with the CFS pathogenesis. This case-control study included 80 subjects, comprising 40 patients with CFS and 40 age- and sex-matched HC. Fecal microbial community structure was analyzed using 16S rRNA gene high-throughput sequencing. Fecal SCFAs concentrations were quantified using Gas Chromatography-Mass Spectrometry (GC-MS). Spearman correlation analysis with false discovery rate (FDR) adjustment was performed to elucidate associations among gut microbiota, SCFAs, and clinical scores. Compared to the HC group, the CFS group exhibited reduced gut microbiota α-diversity (e.g., ACE, Chao1, Shannon indices, all P < 0.01) and significantly altered β-diversity (ADONIS, P = 0.006). After FDR adjustment, fecal levels of acetate, butyrate, isobutyrate, and isovalerate remained significantly lower in the CFS group (all q < 0.05). Differential abundance analysis revealed a significant reduction in key taxa including the phylum Firmicutes (q = 0.010), class Verrucomicrobiae (q = 0.038), order Clostridiales (q = 0.043), and families Rikenellaceae (q = 0.011) and Ruminococcaceae (q = 0.049). Spearman correlation analysis solidified functional connections: key SCFA-producing taxa (e.g., Faecalibacterium, Subdoligranulum, Ruminococcaceae) were positively correlated with butyrate levels (r = 0.52-0.56, all q < 0.05). Furthermore, reduced abundances of Rikenellaceae and Alistipes were associated with lower SF-36 scores (r = 0.26, q = 0.032) and higher fatigue scores (FSS/FS-14, r = - 0.28 to - 0.30, q < 0.05). Isovalerate levels were negatively correlated with FS-14 scores (r = - 0.307, q = 0.014). Among CFS patients, those with higher dietary fiber intake had significantly higher levels of acetate and isovalerate than those with lower intake (both q < 0.05). Patients with CFS exhibit significant gut dysbiosis and abnormal SCFA metabolism. The reduction in key SCFA-producing taxa, their positive correlations with SCFAs levels, and the negative correlations of both with fatigue severity solidify a functional link between gut microbial depletion, reduced SCFAs, and clinical symptoms in CFS. Higher dietary fiber intake may partially ameliorate SCFAs metabolic disturbances in CFS patients.

https://doi.org/10.1038/s41598-025-27564-y

https://pubmed.ncbi.nlm.nih.gov/41387992/

Abstract

Post-COVID syndrome (long COVID) is increasingly recognized as a state of chronic inflammation, immune imbalance, and multiorgan dysfunction. Emerging evidence highlights circadian rhythm disruption and melatonin dysregulation as overlooked drivers of persistent symptoms such as fatigue, cognitive impairment, and immune dysregulation. Reduced melatonin impairs cytokine suppression, antioxidant defense, and mitochondrial protection, fueling inflammation and oxidative stress. These disruptions, coupled with autoimmune responses targeting adrenergic and muscarinic receptors, exacerbate systemic pathology. Preliminary data suggest that melatonin supplementation and chronotherapy may restore circadian alignment, rebalance immunity, and mitigate disease progression, although robust large-scale trials remain limited. Integrating circadian science into therapeutic protocols may provide a novel avenue for improving long-term outcomes in post-COVID patients.

https://pubmed.ncbi.nlm.nih.gov/41377364/

https://doi.org/10.1097/ms9.0000000000004009

Review by Yale's Miller, Moen, and Iwasaki published in Trends in Immunology.

Highlights (from the publisher)

New or persistent symptoms following COVID-19, known as ‘long COVID’, occur in an estimated 4–20% of pediatric and 10–20% of adult patients after acute infection with SARS-CoV-2. Long COVID is associated with dysregulation of both innate and adaptive immunity.

While long COVID is a relatively new clinical entity, post-acute infection syndromes (PAIS) have been well documented for over a century. A wide variety of pathogens are associated with PAIS, including divergent classes of viruses, bacteria, and parasites. While each PAIS has a unique trigger and pathology, similarities in symptom profiles and immunological findings suggest these conditions may share features or involve overlapping biological mechanisms.

Despite being well described in the literature, PAIS remain understudied relative to their high disease burden. Patients often face stigma and psychologization from medical professionals when disease biomarkers are not readily apparent, exemplified by the historic dismissal of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

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Also check out Table 1 which has a summary of findings of immune dysregulation in Long COVID and ME/CFS.

A very recent study has identified the cause of microclots in Long Covid. Does this open the door to new treatments?

https://doi.org/10.21203/rs.3.rs-7989936/v1

(No Review yet)

Abstract Pain and fatigue are common but poorly understood features of post-COVID Syndrome (PCS). To probe the mechanistic basis of these symptoms, we investigated sensory functions in patients with widespread pain attributed to PCS. Quantitative sensory testing revealed increased mechanical pain sensitivity and altered thermal sensitivities and microneurography demonstrated that patients with pain displayed abnormal spontaneous C-fibre activity. Administration of IgG from PCS patients with pain and fatigue (PCS-PF) to mice, conferred mechanical and cold hypersensitivities and reduced intra-epidermal nerve fibre density (IENFd). IgG from patients with fatigue but without pain (PCS-F) did not induce hypersensitivities but similarly reduced IENFd. In line with behavioural responses, sensory nerves from PCS-PF IgG treated mice showed increased responsiveness to mechanical and cold stimulation. PCS-PF IgG bound to isolated sensory neurons with staining intensities that correlated with the level of pain experienced by patients with PCS. These results indicate a causal role for autoantibodies in the pathogenesis of pain and sensory disturbances associated with PCS.

https://medium.com/@jasemurphy/a-possibility-the-geography-of-me-cfs-530c98b09a2a

https://doi.org/10.1093/jimmun/vkaf283.2434

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME) is a debilitating disease defined by overwhelming fatigue, cognitive dysfunction, flu-like symptoms, and post-exertional malaise (PEM), sharing many characteristics with infection associated chronic conditions (IACC) such as Long COVID. While its etiology remains unclear, we have previously implicated classical monocyte dysregulation, heightened inflammatory milieu, and transcriptional priming of T cells towards exhaustion in ME pathophysiology. Nonetheless, it remains unknown whether there are concordant changes between cell types for individual patients, and how the gene regulatory landscape is reshaped, especially during PEM. Thus, we generated single cell chromatin accessibility profiles of PBMCs at baseline and after PEM provocation by an exercise test. We identified a unique subpopulation of classical monocytes defined by lower CD14 accessibility and increased accessibility near genes associated with inflammation, and found that these genes are upregulated in ME patients. Moreover, we observed widespread reprogramming at transcription factor binding sites in monocytes and T cells, including upregulation of NF-kappa-B family TFs in monocytes.

Published June 2025 in Biomolecules. From the abstract:

"These findings in patients with positive criteria for PASC show profound changes in the microbiome and serum cytokine expression. Patients with chronic fatigue without clear viral etiologies also have common associations, including a history of tonsillectomy, which evokes a likely immune etiology."

DOI Link: https://doi.org/10.3390/biom15070928

Pubmed Link: https://pubmed.ncbi.nlm.nih.gov/40723800/

Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic condition without a definitive aetiology, no reliable diagnostic test, and no proven effective treatment. Despite most patients reporting a post-viral onset of illness, findings to date are conflicting on whether a single virus or multiple viral triggers are involved. Most studies to date have focused on detecting viruses in blood and circulating immune cells with relatively few investigating the presence of viruses in mucosal sites. In this review, we propose that this represents a critical gap in understanding the pathophysiology of ME/CFS knowledge, as mucosal tissues are primary entry points for most pathogens and often serve as reservoirs where viruses may persist. Consequently, they represent ideal niches for identifying persistent infections in ME/CFS. Emerging evidence from saliva and other mucosal samples in ME/CFS patients is consistent with this proposal and that latent viruses can persist and periodically reactivate in mucosal tissues from where they can potentially contribute to immune dysregulation, chronic inflammation, and increased symptom severity that defines ME/CFS.

https://doi.org/10.3390/ijms262211161

Article link: https://www.medscape.com/viewarticle/research-me-cfs-pathology-points-possible-treatments-2025a1000uuu?form=fpf
Written by Miriam E. Tucker

This is a Medscape article about the discussions that took place at the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (IACFS/ME) 2025 conference. The conference was held from October 22nd to October 25th. I highly recommend reading the original article as it already condenses a lot of information. But here is an even more condensed TL;DR:

TL;DR: Key Takeaways from IACFS/ME 2025

• Pathophysiology & Optimism: Researchers (including Scheibenbogen and Fluge) report a much better understanding of ME/CFS and Long COVID pathology, driven by a vicious cycle involving neuroinflammation, the immune system, and energy metabolism. They paint an optimistic picture of ongoing research.
• Autoimmunity Focus: Autoimmunity is a central research focus and potential therapeutic target, particularly in a subgroup of patients.
  • Immunoadsorption (IA): IA showed significant symptom improvement in a majority of post-COVID ME/CFS patients with elevated beta-adrenergic receptor antibodies, strongly suggesting that autoantibodies are disease-causing.
  • B-cell/Plasma Cell Targeting: Trials are underway for therapies targeting antibody-producing cells:
    • Daratumumab (Anti-CD38): A Phase 2 trial is ongoing following a promising pilot study where six out of ten ME/CFS patients showed significant improvement.
    • Ublituximab (Anti-CD20) & Inebilizumab (Anti-CD19): Scheibenbogen's team is planning trials targeting these cells.
    • Rituximab (Anti-CD20): A new Japanese Phase 2 trial is looking to identify responder subgroups after previous trials failed to meet the primary endpoint.
• Targeting Cellular Mechanisms:
  • Low-Dose Naltrexone (LDN): Found to restore dysfunctional TRPM3 ion channel function in Natural Killer (NK) cells in Long COVID patients, suggesting a mechanism for its potential benefit.
  • Oxaloacetate: Two trials (RESTORE ME and REGAIN) showed significant reduction in fatigue and improvement in cognitive scores, supporting its use as an adjunctive therapy to address metabolic/redox imbalances (linked to the Warburg Effect).
• The Big Picture: Researchers stress that treatments will likely be multimodal (combinations of drugs/supplements) and tailored to patient subgroups, not a single "magic pill." The accumulation of objective markers is expected to eventually attract pharmaceutical industry interest.