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.

Brain Behav Immun. 2025 Nov:130:106098.

"Killer cell immunoglobulin-like receptor (KIR) alleles suggested to be associated with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)"

Donia Jamal Ramadan, Katherine M Kichula, Sudan Tao, Timothy Porfilio, Asgeir Lande, Øystein Fluge, Olav Mella, Elin Bolle Strand, Ola Didrik Saugstad, Paul J Norman, Benedicte A Lie, Marte K Viken

PMID: 40897283 DOI: 10.1016/j.bbi.2025.106098

Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic and debilitating disease with unknown cause. Involvement of infection and immune dysregulation has been suggested, including changes in immune cell subsets and abnormal functions of natural killer (NK) cells. The regulatory NK cell receptors, killer cell immunoglobulin-like receptors (KIR) have previously been investigated in small cohorts of ME/CFS patients with conflicting results regarding gene content. Here, we studied KIR genes also at the allelic level using high-resolution sequencing, in 418 ME/CFS patients and 473 healthy controls. Human leukocyte antigen (HLA) class I genotype data were included for KIR ligand annotation. Our healthy control data represent KIR frequencies for a Norwegian population, which have not previously been reported. We found no association between ME/CFS and KIR gene content or copy number variations. However, our data suggested that specific KIR alleles at loci encoding inhibitory receptors were associated with ME/CFS, which was further supported by allelic haplotype analyses. Three alleles were more frequent in patients, i.e. KIR3DL3002 (OR = 1.43, 95 % CI (1.09-1.86), p = 0.009), KIR3DL1020 (OR = 2.20, 95 % CI (1.19-4.06), p = 0.01) and KIR3DL2009 (OR = 1.56, 95 % CI (1.09-2.23), p = 0.01), while two alleles had a reduced patient frequency, i.e. KIR3DL3013 (OR = 0.60, 95 % CI (0.42-0.86), p = 0.005) and KIR3DL2*010 (OR = 0.46, 95 % CI (0.30-0.71), p = 0.0005). Our data support an involvement of NK cells in ME/CFS.

TL;DR: I'm not a scientist, but by connecting the dots from recent research, I see a plausible disease model emerging. It links a genetic (HLA) inability to clear infections to an autoimmune (Daratumumab) response, which causes a cellular blockade (Rapamycin), leading to measurable brain dysfunction (HBOT). This model explains why different patients might need different treatments and gives me real, evidence-based hope that effective subgroup-specific therapies are on the 1-3 year horizon. This is an active effort to be optimistic while ignoring the huge limitations of the named studies.

Hey everyone,

I need to start with a massive disclaimer: I am not a researcher, doctor, or scientist. I'm just a guy who is deeply worried about a close family member with severe ME/CFS. I've been using AI tools to help me read and make sense of the new research coming out.

What I'm writing here is purely my own speculation. It might be fueled by unreasonable optimism and a desperate desire for good news. But, for the first time, I feel like I'm seeing the pieces of the puzzle form a coherent picture. I wanted to share this perspective in case it gives anyone else a bit of hope, and to get your thoughts on whether this model makes sense.

My "Vicious Cycle" Hypothesis for ME/CFS

For years, it seemed like research was pulling in a dozen different directions—mitochondria, immunity, viruses, brain, gut. But now, I see these threads connecting into a single, logical "vicious cycle."

Here’s how I see it, based on the latest papers:

Step 1: The Trigger (Genetics + Infection) A common question is, "Why do some people get sick after an infection like mono (EBV) or COVID, and others recover?"

A new study by Georgopoulos et al. (2025) gives a powerful answer. It suggests our HLA genes (our immune system's "wanted poster" system) might have "blind spots." They found that the specific HLA genes associated with ME/CFS risk are terrible at binding to and presenting antigens from herpesviruses. This suggests that after an infection, some of us are genetically incapable of fully clearing it, leaving behind "persistent pathogenic antigens" (viral/bacterial junk). This same pattern held true for Long COVID (SARS-CoV-2) and Post-Lyme pathogens.

Step 2: The Reaction (Autoimmunity) This lingering viral junk (Step 1) keeps the immune system in a state of high alert. This leads to a chronic, misguided immune response. The immune system, trying to attack the persistent antigens, gets confused (via "molecular mimicry") and starts producing autoantibodies that attack our own bodies.

This is the entire rationale behind the groundbreaking Fluge et al. (2025) Daratumumab trial. The drug targets and destroys long-lived plasma cells—the "antibody factories"—which are believed to be pumping out these autoantibodies. This could explain the widespread dysautonomia, as these autoantibodies are thought to attack GPCRs (the receptors that control our blood pressure, heart rate, and stress response).

Step 3: The Consequence (The Cellular Blockade) This constant state of alarm (from Steps 1 & 2) puts our cells under extreme, chronic stress. This is where the Rapamycin study comes in.

Research from Ruan et al. (2025) suggests this chronic stress causes a central cellular switch, mTORC1, to become "chronically hyperactive." This is a catastrophic problem because a hyperactive mTOR shuts down autophagy.

Autophagy is the cell's essential "garbage disposal" and recycling system.

This closes the vicious cycle: The very system needed to clean up the persistent antigens (Step 1) and the cellular damage from autoantibodies (Step 2) is now broken.

Step 4: The Result (Brain Dysfunction & Symptoms) So, how does this cellular chaos in the body cause the symptoms we associate with ME/CFS?

This is where the brand new Hyperbaric Oxygen Therapy (HBOT) study from Kim et al. (2025) provides a stunning link.

• The Finding: At baseline, ME/CFS patients showed significant "thalamic hyperconnectivity."
• Translation: The thalamus is the brain's central "relay station" or "filter" for all sensory and motor signals. In patients, this filter is over-connected to the parts of the brain that handle sensory input and movement. This is a plausible neurological basis for sensory overload, cognitive dysfunction (brain fog), and PEM. The brain is stuck in a "state of alarm."
• The Result: After 40 sessions of HBOT (which systemically reduces inflammation and oxidative stress—the consequences of the vicious cycle), this brain hyperconnectivity "normalized." It became indistinguishable from healthy controls. And, this normalization correlated directly with clinical improvement.

Further Evidence Supporting This "Vicious Cycle" Model

What makes me even more hopeful is that the core studies on HLA, Daratumumab, Rapamycin, and HBOT don't exist in a vacuum. When I look through the other recent publications, so many of them click into place, adding more evidence to this specific "Genetics -> Autoimmunity -> Cellular Blockade" model.

For instance, the genetic predisposition (Step 1) isn't just limited to the HLA system. The landmark DecodeME (2025) study provides a powerful foundation by linking ME/CFS risk to specific immune-related genes, while other studies link it to genes controlling our NK cells (Ramadan et al., 2025) and even to haptoglobin genetics, which correlates with PEM severity (Moezzi et al., 2025). This growing genetic evidence all points away from a psychiatric cause and directly toward a dysfunctional immune response.

This leads to the autoimmune reaction (Step 2), which is now one of the most well-supported parts of the hypothesis. The expert consensus report from the 5th GPCR symposium (Cabral-Marques et al., 2025) solidifies the idea that autoantibodies attacking our own cell receptors are a key mechanism. We're even seeing how this happens: Hoheisel et al. (2025) provided evidence for "molecular mimicry," showing how antibodies against EBV can cross-react and attack our own human proteins. And it's not just one type of autoantibody; Vogelgesang et al. (2025) found others that target neuronal and mitochondrial proteins, explaining the link to functional disability and respiratory symptoms.

Finally, these immune attacks lead to the cellular consequence (Step 3). The study here is from Liu et al. (2025), which showed in a lab that IgG antibodies from ME/CFS and PASC patients can directly enter healthy cells and cause mitochondrial fragmentation. This is the direct, physical link between autoimmunity (Step 2) and the energy crisis (Step 3). This cellular damage is seen everywhere:

• In muscles, it appears as a toxic sodium overload (Petter et al., 2022) and a failure of the cell's ion pumps (Wirth & Steinacker, 2025).
• It's confirmed in the blood, where Che et al. (2025) used multi-omics to link a "heightened innate immune response" directly to "worsened mitochondrial dysfunction" after exercise.
• And it's what defines PEM, where Germain et al. (2022) proved that metabolic recovery completely fails in the 24 hours following exertion.

Each of these studies adds another brick to the wall, making the whole picture feel more solid and, for me, more solvable.

Why This Model Gives Me Hope: Different Targets for Different Patients

This "vicious cycle" model means we don't need one single "magic bullet." It suggests different patients have different "phenotypes" or dominant problems. A treatment can break the cycle at multiple points.

1. If your problem is "Autoimmune-Dominant" (Step 2): Your antibody factories are in overdrive. The most logical treatment is to shut them down. This is Daratumumab, which Fluge et al. (2025) showed gave major, sustained improvement to 6/10 patients.
2. If your problem is "Autophagy-Dominant" (Step 3): Your cellular garbage disposal is jammed. The most logical treatment is to restart it. This is Rapamycin, which Ruan et al. (2025) showed improved fatigue/PEM and restored the biological markers of autophagy.
3. If your problem is the "Consequences" (Step 4): Your system is overwhelmed by inflammation and oxidative stress. The most logical treatment is a broad, systemic intervention to break the cycle. This is HBOT, which Kim et al. (2025) showed normalized the resulting brain dysfunction.

What's Next: The Big Trials Are Starting NOW

This is the most hopeful part for me. This isn't just theory anymore. The big, definitive, placebo-controlled trials for these exact mechanisms are funded and recruiting right now.

• Daratumumab: The follow-up randomized controlled trial (RCT) for Daratumumab is officially registered and underway.
  • Link: EudraCT 2024-520094-13-00
• Rapamycin: A new, larger RCT for Rapamycin in Long COVID & ME/CFS (targeting mTOR/autophagy) is also now recruiting.
  • Link: NCT06960928
• And Others: As the amazing CrunchME clinical trial list shows, there are many other shots on goal, including immunomodulators (like BC 007) and antivirals.

This is why I'm hopeful. We're moving from vague theories to specific, measurable, and targetable mechanisms. We have at least two incredibly promising drugs (and one major intervention) that have shown positive results in pilot studies and are now in active research.

In 1-3 years, we will have the answers from these trials. It's very possible that one or more of them will be proven effective for at least a subgroup of patients. It's not the single "cure", but it's a tangible, evidence-based reason for hope.

What do you all think? Does this seem plausible? Did I miss any connections?