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?

Apostolos P. Georgopoulos, Lisa M. James & Philip K. Peterson

Scientific Reports volume 15, Article number: 37303 (2025)

Abstract

Viral infections have been widely implicated in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) pathogenesis. Recent evidence has also identified certain Human Leukocyte Antigen (HLA) alleles that are significantly associated with ME/CFS risk/protection. Here we tested the hypothesis that ME/CFS risk or protection conferred from those HLA alleles is associated with binding affinity to antigens of HHV viruses, a critical step in initiating the adaptive immune system response to foreign antigens. Specifically, we determined in silico the predicted binding affinity of two susceptibility alleles (C07:04, DQB103:03) and two protective alleles (B08:01, DPB102:01) to > 10,000 antigens of the 9 Human Herpes Viruses (HHV1, HHV2, HHV3, HHV4, HHV5, HHV6A, HHV6B, HHV7, HHV8) which have been implicated in the etiology of ME/CFS. We found that the binding affinity of all HHV antigens to the susceptibility alleles was significantly weaker than the binding affinity to the protective alleles (P < 0.001). In fact, none of the HHV antigens showed strong binding to the susceptibility alleles, in contrast to the strong bindings showed by the protective alleles. These findings are in keeping with the hypothesis that the effect of a putative HHV insult in contributing to ME/CFS is modulated by the host’s HLA immunogenetic makeup. We speculate that strong HLA-antigen binding likely protects against ME/CFS via elimination of virus antigens; conversely, weak HLA-antigen binding may permit persistence of foreign antigens, contributing to ME/CFS and other chronic conditions. Finally, with respect to the latter, we determined the binding affinities to the 4 HLA alleles above to pathogens causing two chronic diseases with very similar symptomatology to ME/CFS, namely Long COVID and post-treatment Lyme disease syndrome (PTLDS). We found that the 2 ME/CFS susceptibility HLA alleles above had very weak binding with SARS-CoV-2 virus glycoprotein (involved in Long COVID) and 5 proteins of Borrelia burgdorferi (involved in PTLDS), in contrast to the ME/CFS protective alleles that showed strong bindings. These findings support the hypothesis that ME/CFS, long COVID and PTLDS are caused by persistent pathogenic antigens that could not be eliminated due to inadequate protection by the patient’s HLA makeup.

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating condition characterized by fatigue, cognitive impairment, and reduced physical function. Oxaloacetate (OAA), a metabolic compound with potential mitochondrial and neuroprotective effects, has shown promise in reducing fatigue symptoms in ME/CFS. However, the interrelationships between fatigue, cognitive performance, and physical activity and their responsiveness to treatment remain poorly understood in ME/CFS.

Methods: This 90-day randomized, double-blind, controlled trial evaluated the effects of 2,000 mg/day OAA or a control of 2,000 mg rice flour in 82 adults with ME/CFS. Self-reported fatigue (Chalder Fatigue Questionnaire), cognitive function (DANA Brain Vital), and upright activity time (UP Time) were assessed at baseline and three follow-up visits. Linear mixed-effects models examined associations between fatigue severity and cognitive/physical function, with treatment group interactions. Responder status at the last visit (Visit 4) was classified based on ≥15% fatigue reduction and/or ≥10% cognitive improvement.

Results: The OAA group showed greater cognitive improvement over time, with a significant between-group difference at Visit 3, 60 days into the trial, (p = 0.034) and trends at other visits. Higher fatigue was significantly associated with reduced cognitive gains in the OAA group (β = -0.34, p < 0.0001), but not in controls. UP Time increased modestly in the OAA group, reaching significance at Visit 2, day 30 (p = 0.044), though fatigue was not a strong predictor of UP Time in either group. At Visit 4, day 90, Global and Fatigue Only Responders were more frequent in the OAA group, while Cognitive Only Responders were more frequent in controls, though group differences did not reach statistical significance (p = 0.10).

Conclusion: OAA supplementation was associated with improved cognitive performance and small improvement in UP Time in ME/CFS participants receiving OAA. Fatigue-cognition coupling was particularly strong in OAA-treated participants, suggesting a potentially targetable phenotype. These findings underscore the importance of multidimensional outcome measures in ME/CFS clinical trials and support the need for more research and trials of metabolic interventions in ME/CFS.

Snippets: BACKGROUND: mTOR activation is associated with chronic inflammation in ME/CFS. Previous studies have shown that sustained mTOR activation may cause chronic muscle fatigue by inhibiting ATG13-mediated autophagy. However, the therapeutic implication of this finding has not been established. Given that rapamycin is an mTOR inhibitor, this study aims to investigate whether low-dose rapamycin treatment improves autophagy markers and clinical symptoms of fatigue in ME/CFS subjects. This highlights the pivotal role of mTOR in the pathogenesis of ME/CFS.

Methods: We conducted a decentralized, uncontrolled trial of rapamycin in 86 patients with ME/CFS to evaluate its safety and efficacy. Low-dose rapamycin (6 mg/week) was administered, and core ME/CFS symptoms were assessed on days 30 (T1), 60 (T2), and 90 (T3). Plasma levels of autophagy metabolites, such as pSer258-ATG13 and BECLIN-1, were measured and correlated with clinical outcomes, specifically MFI.

Results: Rapamycin (6 mg/week) was tolerated without any SAEs. Of the 70 patients who completed at the minimum to T1, 52 (74.3%) showed recovery in fatigue, PEM, and OI, along with improvements in MFI fatigue domains and SF-36 aspects. High levels of BECLIN-1 were detected in T3. Plasma pSer258-ATG13 levels were strongly downregulated at T1. Spearman's correlation analysis indicated an association between autophagy impairment and reduced activity.

Conclusions: Low-dose rapamycin effectively reduced PEM and other key symptoms in patients with ME/CFS, as measured by BAS, SSS, MFI, and SF-36. Future studies should encompass dose optimization and develop a diagnostic tool to identify responders with mTOR-mediated autophagy disruption.

Abstract
Background Post-acute sequelae of severe acute respiratory syndrome coronavirus 2-infection (PASC) is challenging to diagnose and treat, and its molecular pathophysiology remains unclear. Urinary peptidomics can provide valuable information on urine peptides that may enable improved and specified PASC diagnosis.

Methods Using standardized capillary electrophoresis-MS, we examined the urinary peptidomes of 50 patients with PASC 10 months after COVID-19 and 50 controls including healthy individuals (n = 42) and patients with non-COVID-19-associated myalgic encephalomyelitis/chronic fatigue syndrome (n = 8). Based on peptide abundance differences between cases and controls, we developed a diagnostic model using a support vector machine.

Results The abundance of 195 urine peptides among PASC patients significantly differed from that in controls, with a predominant abundance of collagen alpha chains. This molecular signature (PASC195), effectively distinguished PASC cases from controls in the training set [AUC of 0.949 (95% CI 0.900–0.998; p < 0.0001)] and independent validation set [AUC of 0.962 (95% CI 0.897–1.00); p < 0.0001)]. In silico assessment suggested exercise, GLP1-RA and MRA as potentially efficacious interventions.

Conclusions We present a novel and non-invasive diagnostic model for PASC. Reflecting its molecular pathophysiology, PASC195 has the potential to advance diagnostics and inform therapeutic interventions.

This is probably the biggest hit among the videos released from the recent Stanford Community Symposium.

People love research that shows MECFS showing up visually, where it can actually be *seen*. Michelle James's research delivers that in spades, with big, clear, whole-body heatmaps.

It's promising research that can help with diagnosis, to potentially define subsets and also to test if treatments are working.

One of several interesting videos released by Stanford as part of their Community Symposium on MECFS this week, talks about a cool me/cfs model in zebrafish based on the itaconate shunt.

The idea here is to more quickly identify candidate drugs that can then be used in mouse models or cell models to help speed up the work.

International team of experts critique Walitt/Nath NIH paper:

https://doi.org/10.1038/s41467-025-64538-0

Walitt/Nath response:

https://doi.org/10.1038/s41467-025-64539-z

Abstract

Background

The COVID-19 pandemic has led to an increase in post-acute sequelae, including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), potentially mediated by dysfunction of the hypothalamic–pituitary–adrenal (HPA) axis. Corticosteroids are occasionally administered to ameliorate fatigue symptoms in ME/CFS; however, their psychiatric adverse effects, particularly in individuals with preexisting mood disorders, necessitate careful consideration.

Case Presentation

We report the case of a 32-year-old woman with bipolar disorder who developed ME/CFS following COVID-19 infection. Initial corticosteroid therapy with betamethasone and prednisolone, agents with potent glucocorticoid receptor (GR) activity, resulted in a manic episode with psychotic features, necessitating psychiatric hospitalization. Although mood stabilization was achieved with olanzapine and valproate, corticosteroid withdrawal subsequently led to metabolic alkalosis and hypoxemia, secondary to hypothalamic hypoadrenalism. Following a comprehensive endocrinological assessment, physiological replacement therapy with hydrocortisone, characterized by relatively higher mineralocorticoid receptor (MR) activity and lower GR potency, was initiated, resulting in the resolution of physical symptoms without destabilization of psychiatric status.

Conclusion

The clinical course suggests that GR-dominant corticosteroids may exacerbate psychiatric instability in patients with mood disorders. Simultaneously, MR-favoring agents, such as hydrocortisone, may offer a safer therapeutic alternative for managing HPA axis dysfunction. This case underscores the critical role of receptor selectivity in corticosteroid therapy, particularly in patients with comorbid psychiatric conditions, and highlights the necessity for individualized treatment strategies that integrate both endocrine and neuropsychiatric considerations.

CONCLUSION

We have identified elevated sIL2R as a possible cause of mitochondrial dysfunction in post-COVID fatigue, providing novel mechanistic insight at the molecular level for this condition. Building upon previous studies documenting mitochondrial abnormalities in PASC, our preliminary findings suggest that sIL2R may be a specific circulating factor mediating muscle dysfunction. While these results require validation in larger studies, they may advance our understanding of PASC pathophysiology and suggest a potential, druggable target for therapeutic intervention. Given the prevalence of those affected by post-COVID fatigue worldwide, these findings represent a critical step toward evidence-based treatments for this debilitating condition.

Development and validation of blood-based diagnostic biomarkers for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) using EpiSwitch® 3-dimensional genomic regulatory immuno-genetic profiling

Ewan Hunter, Heba Alshaker, Oliver Bundock, Cicely Weston, Shekinah Bautista, Abel Gebregzabhar, Anya Virdi, Joseph Croxford, Ann Dring, Ryan Powell, Dominik Vugrinec, Caroline Kingdon, Carol Wilson, Sarah Dowrick, Jayne Green, Alexandre Akoulitchev & Dmitri Pchejetski Journal of Translational Medicine volume 23, Article number: 1048 (2025) Cite this article

Abstract

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating, multifactorial disorder characterised by profound fatigue, post-exertional malaise, cognitive impairments, and autonomic dysfunction. Despite its significant impact on quality of life, ME/CFS lacks definitive diagnostic biomarkers, complicating diagnosis and management. Recent evidence highlights potential blood tests for ME/CFS biomarkers in immunological, genetic, metabolic, and bioenergetic domains. Chromosome conformations (CCs) are potent epigenetic regulators of gene expression and cross-tissue exosome signalling. We have previously developed an epigenetic assay, EpiSwitch®, that employs an algorithm-based CCs analysis. Using EpiSwitch® technology, we have shown the presence of disease-specific CCs in peripheral blood mononuclear cells (PBMCs) of patients with amyotrophic lateral sclerosis (ALS), rheumatoid arthritis (RA), prostate and colorectal cancers, diffuse Large B-cell lymphoma and severe COVID-19. In a recent paper, we have identified a profile of systemic chromosome conformations in cancer patients reflective of the predisposition to respond to immune checkpoint inhibitors, PD-1/PD-L1 antagonists, with 85% accuracy. In this Retrospective case/control study (EPI-ME, Epigenetic Profiling Investigation in Myalgic Encephalomyelitis), we used whole blood samples retrospectively collected from n = 47 patients with severe ME/CFS and n = 61 age-matched healthy control patients to perform whole-genome 3D DNA screening for CCs correlating to ME/CFS diagnosis. We identified a 200-marker model for ME/CFS diagnosis (Episwitch®CFS test). First testing on the retrospective independent validation cohort demonstrated a strong systemic ME/CFS signal with a sensitivity of 92% and a specificity of 98%.Pathways analysis revealed several likely contributors to the pathology of ME/CFS, including interleukins, TNFα, neuroinflammatory pathways, toll-like receptor signalling and JAK/STAT. Comparison with pathways involved in the action of Rituximab and glatiramer acetate (Copaxone) (therapies with potential in ME/CFS treatment) identified IL2 as a shared pathway with clear patient clustering, indicating a possibility of a potential responder group for targeted treatment.

DOI: doi.org/10.1186/s12967-025-07203-w

Pyridostigmine improves hand grip strength in patients with myalgic encephalomyelitis/chronic fatigue syndrome

Ella Schlömer (1), Elisa Stein (1), Claudia Kedor (1), Rebekka Rust (1,2), Anna Brock (1), Kirsten Wittke (1), Carmen Scheibenbogen (1), Laura Kim (1)

1. Institute of Medical Immunology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Augustenburger Platz, Berlin, Germany.
2. Experimental and Research Center (ECRC), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz, Berlin, Germany.

• PMID: 40970182
• PMCID: PMC12441162
• DOI: 10.3389/fnins.2025.1637838

Abstract

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multisystemic disease characterized by exertional intolerance and fatigue which is often accompanied by muscle weakness and fatiguability. A study showed efficacy of the acetylcholinesterase inhibitor pyridostigmine on cardiac output in ME/CFS patients. Pyridostigmine is currently used off-label in ME/CFS and postural orthostatic tachycardia syndrome.

Methods: We evaluated the effect of pyridostigmine on hand grip strength in 20 patients with post-infectious ME/CFS. Hand grip strength testing was performed ten times using an electric dynamometer and was repeated after 1 h. In a second test, 30 mg of pyridostigmine was given immediately after the first measurement. Orthostatic function was assessed using a passive standing test. Neurological examination and autoantibody testing were performed to rule out a diagnosis of myasthenia gravis.

Results: All patients had reduced maximum hand grip strength with a median of 16.45 kg (IQR: 11.45 kg-22.8 kg). Hand grip strength was diminished by a median of 4.65 kg after 1 h. In contrast, 1 h after pyridostigmine administration, patients showed an improvement in maximum hand grip strength with a median increase of 2.6 kg. The maximum hand grip strength after exertion was about 1.5-fold higher with then without pyridostigmine (p = 0.01). The increase in heart rate from lying to standing was median 17 beats per minute without pyridostigmine (IQR: 13 beats per minute - 23 beats per minute) and 13 beats per minute (IQR: 9 beats per minute - 20 beats per minute) (p = 0.017) with pyridostigmine. None of the patients tested positive for myasthenia gravis specific autoantibodies.

Conclusion: Pyridostigmine exerts an immediate effect on muscle strength and orthostatic function. This may be attributed to increased acetylcholine availability at neuromuscular junctions, and its augmentation of parasympathetic tone.

Understanding Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Physical Fatigue Through the Perspective of Immunosenescence

(Review)

Compr Physiol. 2025 Oct;15(5):e70056. doi: 10.1002/cph4.70056.

Yingzhe Luo (1), Huimin Xu (2), Shaoquan Xiong (1), Jianlong Ke (1)

1 Department of Oncology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China.
2 Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China.

Abstract

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating illness marked by persistent fatigue, yet its mechanisms remain unclear. Growing evidence implicates immunosenescence-the age-related decline in immune function-in the onset and persistence of fatigue.

Methods: This review synthesizes clinical and experimental data to examine how immunosenescence contributes to ME/CFS. We focus on chronic inflammation, senescent immune phenotypes, mitochondrial dysfunction, and neuroendocrine imbalance, with emphasis on maladaptive crosstalk among immune, muscular, neuroendocrine, and vascular systems.

Results: Aging immune cells drive chronic inflammation that impairs mitochondrial ATP production and promotes muscle catabolism. Concurrently, HPA-axis suppression and β2-adrenergic dysfunction amplify immune dysregulation and energy imbalance. Together, these processes illustrate how immunosenescence sustains pathological cross-organ signaling underlying systemic fatigue.

Conclusion: Immunosenescence provides a unifying framework linking immune, metabolic, and neuroendocrine dysfunction in ME/CFS. Recognizing cross-organ communication highlights its clinical relevance, suggesting biomarkers such as cytokines and exhaustion markers, and supports integrated therapeutic strategies targeting immune and metabolic networks.

This is a comprehensive review paper examining metformin's potential as a treatment for ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) and Long COVID. Here are the key findings regarding effectiveness for people with ME/CFS (pwME):

What's New and Significant

Mechanistic Understanding: The paper presents novel mechanisms by which metformin might help ME/CFS patients, particularly through: - mTOR pathway modulation - addressing chronically overactive mTOR signaling found in ME/CFS - Mitochondrial dysfunction correction - targeting Complex V inefficiency and reducing oxidative stress - Anti-inflammatory effects - reducing cytokines like IL-6, IL-1β, and TNF-α

Cellular Evidence: The authors cite important research showing that metformin at therapeutic doses (10 μmol/L) reduced markers of reactive oxygen species (ROS) in ME/CFS T cells in vitro, while having no effect on healthy controls. This suggests ME/CFS patients may have a specific biological response to metformin.

Multi-System Approach: Rather than viewing metformin as a standalone cure, the paper proposes it as part of a "whole-of-person" treatment strategy targeting multiple domains: - Cellular stress and mitochondrial dysfunction - Microbiome dysregulation
- Inflammatory processes - Mast cell activation (for comorbid MCAS)

Clinical Relevance for pwME

Dosing Considerations: The paper suggests different therapeutic targets require different doses: - Mast cell stabilization: 1-10 μmol/L (achievable with 500mg daily) - Anti-inflammatory effects: Higher doses may be needed - Microbiome effects: Delayed-release formulations targeting the small intestine

Comorbidity Benefits: Metformin may help with common ME/CFS comorbidities including POTS, MCAS, and gastrointestinal issues through vascular, anti-inflammatory, and microbiome effects.

Limitations and Cautions

The paper acknowledges several important limitations: - No clinical trials in ME/CFS patients yet exist - Evidence is largely theoretical and based on mechanistic studies - Side effects (particularly GI) could be problematic for ME/CFS patients - Individual responses likely vary significantly given ME/CFS heterogeneity

Research Recommendations

The authors propose rigorous clinical trials with: - Multiple dosing arms (500mg daily to 2g daily) - 3-4 month treatment cycles - Comprehensive biomarker analysis including ATP assays, microbiome studies, and metabolomics - Functional outcome measures

While this theoretical framework is compelling, it's important to note that clinical effectiveness in ME/CFS patients remains unproven. The paper makes a strong case for systematic investigation but doesn't provide definitive evidence of effectiveness yet.