Heightened innate immunity may trigger chronic inflammation, fatigue and [PEM]…, 2025, Che, Hornig, Bateman, Klimas, Komaroff, Lipkin+

On the Prusty paper thread @cassava7 quoted a section of the paper where they looked at LPS stimulation.

Prusty paper thread said:
One of the most prominent candidate molecules that can provide strong antiviral defense is IFN. Hence, we tested IFN response in A549 cells upon treatment with ME/CFS or HC serum. We observed a strong decrease in mRNA levels of IFN-β, IFIT-1, and ICAM-1 within the A549 cells in presence of ME/CFS serum in comparison with HC serum (Fig. 5D–F). Then we asked whether the secretory IFN response in isolated PBMCs is higher in ME/CFS patients. For this we used a different cohort of 22 CFS patients and 22 HC. Upon challenge with LPS, we found lower levels of secreted TNF-α (p < 0.01) and IFN-γ (p < 0.05) from CFS patient PBMCs compared with HC (Supplemental Fig. 2B). No significant differences were seen for IL-1 and IL-5. These results ruled out a potential role of IFN response in the mitochondrial fragmentation and antiviral response in ME/CFS patients.
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This paper explains the method and how the Tru-culture system compares to conventional PBMC methods
Standardized whole blood stimulation improves immunomonitoring of induced immune responses in multi-center study.
Whole blood and PBMCs from healthy donors were exposed to LPS, anti-CD3 anti-CD28 antibodies, or media alone. 55 protein analytes were analyzed centrally by Luminex multi-analyte profiling in a CLIA-certified laboratory. TruCulture responses showed greater reproducibility and improved the statistical power for monitoring differential immune response activation. The use of TruCulture addresses a major unmet need through a robust and flexible method for immunomonitoring that can be reproducibly applied in multi-center clinical studies.
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Paper is coming out today it seems:

www.eurekalert.org

Study Reveals Details of Overactive Immune System in Patients with Chronic Fatigue Syndrome (ME/CFS)

Led by researchers at the Center for Infection and Immunity (CII) at Columbia University Mailman School of Public Health with a multicenter team of leading ME/CFS researchers, the new study reveals molecular-level details into the syndrome’s lasting effects on inflammation and immune response...
www.eurekalert.org

News Release 1-Sep-2025

Study Reveals Details of Overactive Immune System in Patients with Chronic Fatigue Syndrome (ME/CFS)​

Peer-Reviewed Publication
Columbia University's Mailman School of Public Health


Patients with chronic fatigue syndrome/myalgic encephalomyelitis (ME/CFS) have heightened innate immune responses to bacteria, viruses and fungi. While these responses are essential to fight infection, they can cause damage when unchecked. Led by researchers at the Center for Infection and Immunity (CII) at Columbia University Mailman School of Public Health with a multicenter team of leading ME/CFS researchers, the new study reveals molecular-level details into the syndrome’s lasting effects on inflammation and immune response that could inform the development of targeted therapeutic interventions to reduce symptoms of ME/CFS and other postinfectious syndromes such as post-treatment Lyme disease and Long COVID. Study findings are published in the journal npj Metabolic Health and Disease.

Symptoms of ME/CFS include unexplained fatigue, post-exertional malaise (PEM), and cognitive dysfunction. According to the Centers for Disease Control and Prevention, the United States alone has up to 3.3 million ME/CFS cases, and an annual economic burden of up to 51 billion dollars. Once thought to be a psychological disorder, there is abundant evidence from studies of blood, muscle and brain that ME/CFS is a physical syndrome. Most patients report an influenza-like illness prior to developing ME/CFS. Researchers have hypothesized that the condition is the result of an abnormal response to infection that results in inflammation and cellular damage that impairs energy metabolism. The overlap in symptoms between ME/CFS and Long COVID confirms that infection can trigger the syndrome.

As part of the new study, researchers analyzed blood samples from 56 ME/CFS patients and 52 healthy controls recruited in New York and California. They used molecular testing to map the metabolome (metabolites of cellular metabolism) and proteome (proteins produced through biological processes). They also examined immune responses to microbial stimulation—a simulated infection—before and after exercise.

In ME/CFS patients, they observed disruptions in interconnected pathological processes that are often observed in chronic inflammatory conditions, suggesting a state of metabolic dysfunction, immune dysregulation, and tissue damage, potentially triggering a systemic inflammatory response. Understanding these relationships is crucial for developing therapeutic strategies targeting multiple aspects of the disease process.

  • Impaired cellular energy production, which may lead to physical and mental exhaustion and the accumulation of toxic metabolites.
  • Lipid abnormalities that contribute to tissue damage and perpetuate inflammation.
  • Disruptions to the extracellular matrix which provides structural support and regulates cell behavior and release of signaling molecules that promote inflammation.
  • Disruption of epithelial barriers, particularly in the gut which can contribute to the development of gut dysbiosis, where the balance of gut microbiota is altered resulting in the translocation of bacterial products into the blood where they trigger inflammation.
  • Activation of the complement system of the innate immune system, the overactivation of which can contribute to tissue damage, inflammation, and sustained fatigue.
  • Disturbances in copper-dependent antioxidant pathways, which can promote oxidative stress, promote inflammation, and contribute to tissue injury.
  • Dysregulation of tryptophan-serotonin-kynurenine pathways, which can lead to impaired cognitive function.
In patients with ME/CFS, researchers observed that Peripheral Blood Mononuclear Cells (PBMCs)—blood cells that play a key role in the immune response—stimulated in a way to simulate infection using LPS (a bacterial product that activates immune responses) or poly I:C (a synthetic analogue of double-stranded RNA, mimicking viral infection) produced increased levels of IL-6, a cytokine central to inflammation. In addition, researchers used the TruCulture system to stimulate an immune response with Staphylococcus enterotoxin B and HKCA (heat-killed Candida albicans). The result was the release of higher levels of pro-inflammatory cytokines compared to healthy controls. These responses were higher in women than in men, with the highest levels in women over the age of 45 with lower levels of the sex hormones estradiol.

Clinical Trials and Targeted Therapies for ME/CFS Subtypes

The study’s authors write that their findings suggest potential candidates for clinical trials and targeted therapies. In addition to metformin—a medication primarily used to manage blood sugar levels in people with type 2 diabetes—the regulatory cytokine IL-37 and the mTOR inhibitor rapamycin, an immunosuppressive, may help ME/CFS individuals with evidence of enhanced innate immunity or hypersensitivity to microbial stimuli. Patients with evidence of an imbalanced gut microbiome may benefit from prebiotics (inulin) and probiotics (F. prausnitzii) that enhance GI barrier integrity and regulate immune responses. Low baseline levels of 12,13-diHOME, a lipid molecule, and high post-exercise levels of GDF15, a hormone produced in response to various stressors that plays a role in regulating appetite and energy expenditure, may identify individuals with pronounced metabolic disruption who are more likely to respond to dietary supplementation with 12,13-diHOME or to treatment with a GDF15-neutralizing antibody. Individuals with abnormalities in metabolism of tryptophan, an essential amino acid, may respond to supplementation with 5-hydroxytryptophan or SSRIs. In patients with low levels of carnitine, a compound involved in metabolism, carnitine supplementation may restore carnitine shuttle function and enable use of lipids for energy source. Estrogen supplements may modulate the inflammatory response in older women with ME/CFS.

“Our findings indicate that people with ME/CFS have dysregulated immune responses to common infections” says Xiaoyu Che, PhD, co-first author. “These results suggest that specific intracellular pathways correlate with symptoms,” adds Amit Ranjan, PhD, co-first author.

“While what gives rise to ME/CFS remains obscure, understanding the ways it disrupts the body’s various biological processes on the molecular level is revealing biomarkers for specific ME/CFS subtypes that may inform clinical research and lead to targeted interventions,” says senior author W. Ian Lipkin, MD.

The authors are grateful for generous support from Hutchins Family Foundation through the Chronic Fatigue Initiative and NIH/NIAID (grant 4U54AI138370).

Xiaoyu Che, assistant professor of biostatistics in the CII, and Amit Ranjan, associate research scientist in the CII, are co-first authors. W. Ian Lipkin, John Snow Professor and director of the CII and the Center for Solutions for ME/CFS, is the study’s senior author. A complete list of authors is available in the journal article.

The authors declare no competing interests.

Journal​

npj Metabolic Health and Disease

DOI​

10.1038/s44324-025-00079-w

Method of Research​

Observational study

Subject of Research​

People

Article Title​

Heightened innate immunity may trigger chronic in ammation, fatigue and post- exertional malaise in ME/CFS

Article Publication Date​

1-Sep-2025

COI Statement​

The authors declare no competing interests.

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www.nih.gov

Overactive immune responses in ME/CFS

Scientists found signs of overactive immune responses in people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
www.nih.gov www.nih.gov

September 23, 2025

Overactive immune responses in ME/CFS​

At a Glance​

  • Researchers found signs of overactive immune responses in people with myalgic encephalomyelitis/chronic fatigue syndrome, or ME/CFS.
  • The findings provide insights into the causes of ME/CFS and suggest new treatment approaches.
Image
Young woman lying on a sofa with her eyes shut.
By analyzing blood samples from dozens of people who have ME/CFS, researchers identified molecular pathways and other factors that shed new light on this poorly understood condition.
Adobe Stock

ME/CFS involves unexplained fatigue that may worsen after exertion and cause problems with thinking and memory that lasts at least six months. People with ME/CFS often report symptoms consistent with infection before developing ME/CFS. Yet no single microbe has been found to be responsible. This suggests that ME/CFS may be caused by a more general immune response to infection.

To test this idea, a research team from several institutions, led by Dr. W. Ian Lipkin at Columbia University Mailman School of Public Health, collected blood samples from 56 people with ME/CFS and 52 matched healthy people. The study appeared in npj Metabolic Health & Disease on September 3, 2025.

The team exposed the blood samples taken before and after exercise to elements from different microbes. They found higher levels of molecules involved in inflammation in blood from people with ME/CFS than in healthy controls. This suggests that the immune system in ME/CFS may be hypersensitive to infection. People with ME/CFS also had altered levels of certain proteins consistent with immune dysregulation.

The team found several molecular pathways that were disrupted in people with ME/CFS in ways that could lead to inflammation. People with ME/CFS had altered levels of proteins involved in maintaining the extracellular matrix, which provides structural support to tissues. They also showed signs of impairment in the urea cycle. This detoxifies ammonia, a waste product of metabolism. After exercise, people with ME/CFS had increased activity in antioxidant pathways. This indicates increased cellular stress from oxidation, a type of molecular damage.

In addition, the team found evidence of impaired energy production in the people with ME/CFS, particularly after exercise. People with ME/CFS had higher levels of fats in their blood and lower levels of molecules involved in fat breakdown. These point to a reduced ability to use fats for energy. The resulting accumulation of fats could lead to inflammation.

Altered levels of metabolites from microbes were also found in people with ME/CFS. This suggests disruption of the gut microbiome, called dysbiosis. There were signs that the gut mucosal barrier was weakened in ME/CFS. The findings suggested that gut dysbiosis led to impaired metabolism of foreign compounds, such as drugs and toxins.

After exercise, people with ME/CFS also showed reduced conversion of the amino acid tryptophan to serotonin. Serotonin plays a role in many functions, including mood, sleep, and cognition. This finding suggests a link to cognitive problems in ME/CFS.

The molecular problems observed in the people with ME/CFS correlated with fatigue symptoms. This supports the view that these abnormalities are related to the illness. Overall, the enhanced inflammatory responses in ME/CFS were stronger in women than in men.

The findings provide additional support for the view that ME/CFS results from inflammation and altered immune responses. They also suggest candidate treatments for clinical trials. These include immune suppressing drugs, pre- and probiotics to restore the gut microbiome, dietary supplementation with compounds deficient in people with ME/CFS, and drugs to boost serotonin levels.

“While what gives rise to ME/CFS remains obscure, understanding the ways it disrupts the body’s various biological processes on the molecular level is revealing biomarkers for specific ME/CFS subtypes that may inform clinical research and lead to targeted interventions,” Lipkin says.

—by Brian Doctrow, Ph.D.

Related Links​

References​

Heightened innate immunity may trigger chronic inflammation, fatigue and post-exertional malaise in ME/CFS. Che X, Ranjan A, Guo C, Zhang K, Goldsmith R, Levine S, Moneghetti KJ, Zhai Y, Ge L, Mishra N, Hornig M, Bateman L, Klimas NG, Montoya JG, Peterson DL, Klein SL, Fiehn O, Komaroff AL, Lipkin WI. NPJ Metab Health Dis. 2025 Sep 3;3(1):34. doi: 10.1038/s44324-025-00079-w. PMID: 40903540.

Funding​

NIH’s National Institute of Allergy and Infectious Diseases (NIAID); Hutchins Family Foundation.

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Dolphin said:
The findings provide additional support for the view that ME/CFS results from inflammation and altered immune responses. They also suggest candidate treatments for clinical trials. These include immune suppressing drugs, pre- and probiotics to restore the gut microbiome, dietary supplementation with compounds deficient in people with ME/CFS, and drugs to boost serotonin levels.
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Why is RECOVER-TLC not exploring any of this? Why do they insist on working siloed off from the rest of the post infectious illness field? I will never understand.
 
Dolphin said:
People with ME/CFS had higher levels of fats in their blood and lower levels of molecules involved in fat breakdown.
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My guess is that there is no clear abnormality in cholesterol or other lipid markers in routine pathology testing in pwme right?

I am very interested in this particular issue and trying to piece it all together. I have a model under construction of how something might be going wrong here at the cellular level based on culture evidence, just trying to wrap my head around how it might plausibly eventuate physiologically in the absence of an overt genetic cause (I have pored and pored over DecodeME and I can't see a thread relevant to what we are specifically seeing go wrong in lipid metabolism in particular cell populations).

I have an experimental paper in peer review at the moment plus still trying to make sense of everything which is my only reason for being restrained with detail. When published and clear I might make a new thread or hijack my paper's thread to hash out follow-up ideas and make sure the model is plausible before putting forth to funders.
 
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DMissa said:
My guess is that there is no clear abnormality in cholesterol or other lipid markers in routine pathology testing in pwme right?

I am very interested in this particular issue and trying to piece it all together. I have a model under construction of how something might be going wrong here at the cellular level based on culture evidence, just trying to wrap my head around how it might plausibly eventuate physiologically in the absence of an overt genetic cause (I have pored and pored over DecodeME and I can't see a thread relevant to what we are specifically seeing go wrong in lipid metabolism in particular cell populations).

I have an experimental paper in peer review at the moment which is my only reason for being restrained with detail. When published I might make or hijack the thread to hash out my follow-up ideas and make sure the model is plausible before putting forth to funders.
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Wasn't there something with high tryglicerides without high cholesterol?
It did come up in my regular blood tests.
 
DMissa said:
My guess is that there is no clear abnormality in cholesterol or other lipid markers in routine pathology testing in pwme right?
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Always within normal for me, including annual routine bloods. (Occasionally get a borderline number, but always settles back to within range by the following year's sample.)

Only consistent significant result I get is persistently high ALP, since at least my mid-20s, typically in the 130-160 range, with no other associated measures or conditions indicating anything worth following up. Also, ALP normal levels are not well defined, so overall not a practically meaningful number.
 
DMissa said:
My guess is that there is no clear abnormality in cholesterol or other lipid markers in routine pathology testing in pwme right?
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I’ve been trying to see if I could use EHR data to confirm this but unfortunately it doesn’t seem feasible to accurately assess an ME/CFS diagnosis through EHR (in the US, at least)
 
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Dolphin said:
In addition, the team found evidence of impaired energy production in the people with ME/CFS, particularly after exercise. People with ME/CFS had higher levels of fats in their blood and lower levels of molecules involved in fat breakdown. These point to a reduced ability to use fats for energy. The resulting accumulation of fats could lead to inflammation.
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I had a complete RBC fatty acid test done years ago that didn't show higher levels of fats. Which fats did they test? My test only showed below normal levels of omega 3s

Normal cholesterol and lower end triglycerides.
 
Dolphin said:

Study Reveals Details of Overactive Immune System in Patients with Chronic Fatigue Syndrome (ME/CFS)​

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Replace overactive with hyperactive, and Jay Levy said exactly same thing 40 years ago. Too bad he walked away from ME/CFS because of the controversies.

If innate PBMC are found overactive, it is not unreasonable to extrapolate that innate neuroimmune cells are also overactive. I think that's where the problem lies, not in the periphery.
 
I just remembered Hornig et al published a paper some 10 years ago stating that the inflammation level does not predict the symptom severity and that immune system goes from hyperactive to hypoactive at around 3-year mark. I wonder how they square the current paper with that one.
 
Blog Summary
Imagine if a fire alarm kept ringing long after the smoke was gone. That’s similar to what happens in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), where the body seems stuck in “high alert” mode. A new multi-center study, co-authored by Bateman Horne Center’s Chief Medical Officer, Dr. Lucinda Bateman, sheds light on why even small amounts of activity can leave people with ME/CFS feeling much worse. This hallmark symptom is called post-exertional malaise (PEM).


The study at a glance​

Researchers at Columbia University and across the U.S. collected blood samples from 56 people with ME/CFS and 52 healthy volunteers, before and 24 hours after a carefully monitored exercise challenge. Then they ran an unusually broad set of tests, looking at immune activity, metabolism (energy use), and proteins that keep tissues healthy.


Key findings:​


  • Immune system on edge: The immune system in people with ME/CFS reacted more strongly to microbial “danger signals” than in healthy controls, even before exercise. After activity, some responses looked blunted, suggesting a system that is both over-reactive and easily exhausted.

  • Energy problems: Cells in ME/CFS appeared to have trouble producing clean energy after exercise. Researchers saw signs of stalled mitochondria (the “power plants” of our cells), along with chemical markers that reflect stress and fatigue.

  • Gut barrier leaks: Signals suggested that the lining of the gut may be more permeable, allowing microbial fragments to “leak” into the bloodstream and trigger inflammation.

  • Brain fog explained: After exertion, tryptophan (an amino acid important for serotonin and brain health) was shifted away from making protective molecules and toward producing inflammatory byproducts. This may help explain the disabling “brain fog” many people with ME/CFS experience after activity.



Why this matters​

This study reinforces what patients have long described: activity can set off a cascade of problems throughout the body: immune, metabolic, and neurological. It also offers concrete biological “fingerprints” of PEM, which could guide both diagnosis and treatment in the future.

Looking ahead​

The researchers outlined several possibilities for future therapies, including:


  • Calming the overactive immune response

  • Supporting mitochondrial (cellular energy) function

  • Strengthening the gut barrier

  • Restoring balance in brain chemistry pathways

These are not treatments available today, but they point the way for clinical trials which is exactly the type of research BHC is committed to advancing.
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audio of summary also available at link
full blog:
batemanhornecenter.org

When the Body’s Alarm Won’t Turn Off

Blog Summary Imagine if a fire alarm kept ringing long after the smoke was gone. That’s similar to what happens in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), where the body seems…
batemanhornecenter.org batemanhornecenter.org
 
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